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The Diabetic Retinopathy Clinical Research Network Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide.

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Presentation on theme: "The Diabetic Retinopathy Clinical Research Network Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide."— Presentation transcript:

1 The Diabetic Retinopathy Clinical Research Network Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide on Diabetic Macular Edema Following Panretinal Photocoagulation Joseph M. Googe, MD 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 1

2 Background PRP in Eyes with Central DME 2  Scatter or panretinal photocoagulation (PRP) is standard treatment for PDR  Reported side effects of PRP include: Worsening macular edema and loss of visual acuity (prior to OCT) DRCR.net protocol F reported PRP in 1 or 4 sittings, respectively, results in median +14 or +15 µm increase in OCT CSF (25 th, 75 th percentile = +5 or +6, +20 or +34 µm) with little decreased acuity 17 weeks after initiating PRP in eyes without central DME

3 Background 3 Is change in OCT CSF and change in visual acuity similar in eyes receiving PRP with central DME which, around the same time, also receive focal/grid laser for the DME? 3 DRCR.net protocols evaluating focal/grid laser for DME as a monotherapy showed a median decrease in CSF of 30 microns and a median increase in VA of 1 or 2 letters following focal/grid laser of central DME without PRP (at 16 weeks)

4 Background PRP in Eyes with Central DME 4  Focal/grid laser of central DME in absence of prompt PRP usually associated with short term improvement (at 16 weeks) of macular edema with little change in visual acuity Protocol N Median Change in OCT Central Subfield Thickness (25 th, 75 th quartiles) Median Change in Visual Acuity (25 th, 75 th quartiles) Protocol B 311 -33 (-90, 13)2 (-4, 7) Protocol K 119 -27 (-61, 13)1 (-3, 6) Protocol I 268 -34 (-101, 10)2 (-3, 8)

5 Background PRP in Eyes with Central DME 5  If some eyes with central DME receiving PRP at the time of focal/grid laser have at least short term substantial worsening of macular edema and visual acuity loss,... ... then reducing the proportion of eyes with worsening of macular edema and visual acuity loss following PRP might improve quality of life for individuals undergoing this therapy in the short term

6 Background Anti-VEGF and Triamcinolone for DME 6  Inflammation and increased levels of vascular endothelial growth factor (VEGF) contribute to the development or exacerbation of DME  DRCR.net, RESTORE, RIDE and RISE reported benefits for ≥1 year after initiating intravitreal ranibizumab for DME in the absence of DR requiring prompt PRP (Protocol I)  DRCR.net studies and other studies have suggested a benefit of intravitreal corticosteroids for DME (though not superior to ranibizumab or focal/grid laser)  Anti-VEGF drugs or corticosteroids might have a role in reducing PRP-induced exacerbation of macular edema in eyes with DME and severe NPDR or PDR for which PRP is given around the time that focal/grid is given for the DME

7 7 Laser-Ranibizumab-Triamcinolone+PRP Randomized Clinical Trial for DME Laser-Ranibizumab-Triamcinolone+PRP Randomized Clinical Trial for DME Study Objective Evaluate short term effects of intravitreal ranibizumab or intravitreal triamcinolone on exacerbation of macular edema and associated visual acuity loss in eyes requiring PRP for severe NPDR or PDR and receiving focal/grid laser for center-involved DME.

8 Study Design 8 Primary outcome: Change in visual acuity from baseline to 14 weeks (intent to treat analysis) At least 1 eye meeting all of the following criteria:  Severe NPDR or PDR requiring prompt PRP  Presence of central DME on clinical exam and CST on OCT ≥250 microns  Best corrected E-ETDRS visual acuity letter score ≥24 (~20/320 or better) Randomized, multi-center clinical trial Sham+ Focal/Grid/PRP Laser Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser

9 Follow-up Schedule 9 34 Weeks & 56 Weeks 34 Weeks & 56 Weeks 1 st injection at baseline Safety visit 3-10 days Focal/grid laser 3-10 days Initial PRP (following focal/grid ) 3-14 days 1 st injection at baseline Safety visit 3-10 days Focal/grid laser 3-10 days Initial PRP (following focal/grid ) 3-14 days Safety follow-up visits 14 Weeks 4 Weeks Baseline to 2 Weeks Baseline to 2 Weeks 2 nd injection (ranibizumab for ranibizumab group and sham for sham and triamcinolone groups) Follow-up visit 2 nd injection (ranibizumab for ranibizumab group and sham for sham and triamcinolone groups) Follow-up visit Primary outcome visit

10 Study Enrollment 10 Ranibizumab+ Focal/Grid Laser & PRP N = 116 Ranibizumab+ Focal/Grid Laser & PRP N = 116 Sham+ Focal/Grid Laser & PRP N = 133 Sham+ Focal/Grid Laser & PRP N = 133 Triamcinolone+ Focal/GridLaser & PRP N = 115 Triamcinolone+ Focal/GridLaser & PRP N = 115 Eyes Randomized: N = 364 (333 Study Participants) Eyes Randomized: N = 364 (333 Study Participants) 14 Week Visit Completion* (Primary Outcome): 95% 14 Week Visit Completion* (Primary Outcome): 95% 56 Week Visit Completion*: 87% 56 Week Visit Completion*: 87% *Includes deaths

11 11 Baseline Characteristics (N=345) Overall Median age (yrs) 57 Women 39% Race White 61% African-American 13% Hispanic or Latino 23% Asian 2% Other 1% Unknown/not reported 1% Median HbA1c (%) 8.1 Diabetes type Type I 13% Type II 84% Uncertain 3%

12 12 Baseline Characteristics Sham+ Focal/Grid & PRP N = 123 Ranibizumab+ Focal/Grid & PRP N = 113 Triamcinolone+ Focal/Grid & PRP N = 109 Median E-ETDRS © visual acuity letter score (Snellen equivalent) 67 (20/50)68 (20/50)67 (20/50) Median OCT CSF thickness (µm) 355352359 No prior treatment for DME 65%66%

13 13 Panretinal Photocoagulation Treatment Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Initial PRP on the same day as focal/grid laser planned/performed Yes/Yes 50%53%50% Yes/No 7%4%8% No/Yes 5%8%6% No/No 37%33%34% PRP and/or focal/laser not done 1%3%

14 14 Panretinal Photocoagulation Treatment Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Number of PRP sittings performed* 1 40%34%38% 2 47%50%46% 3 or 4 † 12%15% PRP not done 1%2% Number of sittings planned prior to randomization was similar to the number of sittings performed. † Only 1 study participant had 4 PRP sittings performed

15 15 Panretinal Photocoagulation Treatment Sham+ Focal/Grid/PRP Laser N = 122 Ranibizumab+ Focal/Grid/PRP Laser N = 111 Triamcinolone+ Focal/Grid/PRP Laser N = 107 PRP automated pattern used 30%19%20% Median total number of burns 154114101430 Proportion of eyes with PRP completed in the protocol window 89%87%81%

16 16 Additional Treatment for DME Sham+ Focal/Grid/PRP Laser N = 123 Ranibizumab+ Focal/Grid/PRP Laser N = 113 Triamcinolone+ Focal/Grid/PRP Laser N = 109 Prior to 14 weeks Eyes with additional treatments 000 14 weeks to 56 weeks Eyes with additional treatments 714845 Additional treatment* Bevacizumab (+/- Laser) 22179 Ranibizumab (+/- Laser) 133 Triamcinolone (+/- Laser) 10127 Laser 311021 Vitrectomy 210 Bevacizumab+Triamcinolone (+/- Laser) 202 Triamcinolone+Vitrectomy 010 Eyes with non-protocol anti- VEGF trt (# of trts applied) 28 (39)23 (32)17 (32) *Number of eyes, each combination of treatment only counted once

17 Visual Acuity 17

18 18 Primary Outcome Change in Visual Acuity at 14 Weeks Primary Outcome Change in Visual Acuity at 14 Weeks Change in visual acuity (letters) Sham+ Focal/Grid/PRP Laser N = 123 Ranibizumab+ Focal/Grid/PRP Laser N = 113 Triamcinolone+ Focal/Grid/PRP Laser N = 109 Mean-4+1+2 Difference in mean change from Sham +Focal/Grid/PRP Laser [P Value]* +5.6 [P < 0.001] +6.7 [P < 0.001] *Adjusted for baseline visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

19 Mean Change in Visual Acuity* from Baseline 19 Safety Phase (DME treatment at investigator discretion) Safety Phase (DME treatment at investigator discretion) Randomized Phase (DME treatment according to protocol) * Values that were ±30 letters were assigned a value of 30

20 20 Change in Visual Acuity at 56 Weeks Change in visual acuity (letters) Sham+ Focal/Grid/PRP Laser N = 111 Ranibizumab+ Focal/Grid/PRP Laser N = 95 Triamcinolone+ Focal/Grid/PRP Laser N = 93 Mean-6-4-5 Difference in mean change from Sham +Focal/Grid/PRP Laser [P Value]* +1.9 [P = 0.44] +1.2 [P = 0.63] *Adjusted for baseline visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

21 Visual Acuity Subgroup Analysis 21

22 22 Subgroup Analyses  No obvious clinically important difference in results at 14-week primary outcome visit for any of the following subgroups: Prior treatment for DME Baseline visual acuity Baseline OCT-measured central subfield thickening Baseline level of diabetic retinopathy on photos Baseline HbA1c level Description of edema by ophthalmologist as predominantly focal or predominantly diffuse PRP in a single sitting vs. multiple sittings

23 Retinal Thickening 23

24 Change in Retinal Thickening at 14 Weeks* 24 Change in OCT Central Subfield Thickening * Sham+ Focal/Grid/PRP Laser N = 115 Ranibizumab+ Focal/Grid/PRP Laser N = 100 Triamcinolone+ Focal/Grid/PRP Laser N = 103 Mean change from baseline (µm) -5-39-92 Difference in mean change from Sham+ Focal/Grid/PRP Laser [P Value] † -35 [P = 0.007] -100 [P < 0.001] Thickness ≥10% increase with at least a 25 µm increase from baseline 38%17%10% Thickness <250 µm with at least a 25 µm decrease from baseline 10%17%27% * Missing (or ungradeable) data as follows for the sham+focal/grid/PRP laser group, ranibizumab+focal/grid/PRP laser group, and triamcinolone+focal/grid/PRP laser groups, respectively: 3, 3, 2 † Adjusted for baseline OCT retinal thickness and visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

25 Correlation between Visual Acuity and Central Subfield Thickness at 14 Weeks 25 Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Central subfield thickness ≥10% increase with at least a 25 µm increase from baseline N=44N=17N=10 Above OCT CST change AND concordant decrease in visual acuity of ≥10 letters at 14 weeks 15 (34%)2 (12%)1 (10%)

26 Change in Retinal Thickening at 56 Weeks* 26 Change in OCT Central Subfield Thickening * Sham+ Focal/Grid/PRP Laser N = 101 Ranibizumab+ Focal/Grid/PRP Laser N = 92 Triamcinolone+ Focal/Grid/PRP Laser N = 89 Mean change from baseline (µm) -71-52-40 Difference in mean change from Sham+ Focal/Grid/PRP Laser [P Value] † +22 [P = 0.25] +15 [P = 0.45] Thickness ≥10% increase with at least a 25 µm increase from baseline 28%20%28% Thickness <250 µm with at least a 25 µm decrease from baseline 27%29%20% *Missing (or ungradeable) data as follows for the sham+focal/grid/PRP laser group, ranibizumab+focal/grid/PRP laser group, and triamcinolone+focal/grid/PRP laser group, and respectively: 10, 3, 4 † Adjusted for baseline OCT retinal thickness and visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.

27 Mean Change in Retinal Thickness from Baseline 27 Randomized Phase (DME treatment according to protocol) Safety Phase (DME discretion) Safety Phase (DME treatment at investigator discretion)

28 Safety Phase (DME discretion) ≥ 2 Step Improvement in LogOCT Central Subfield Thickness from Baseline 28 Randomized Phase (DME treatment according to protocol) Safety Phase (DME treatment at investigator discretion)

29 Safety 29

30 30 Major Ocular Adverse Events Prior to the 14-Week Visit Adverse events prior to the 14-week visit Sham+ Focal/Grid/PR P Laser N = 133 Ranibizumab+ Focal/Grid/PRP Laser N = 116 Triamcinolone+ Focal/Grid/PRP Laser N = 115 Number of injections227115 Endophthalmitis*01 (0.9%)0 Ocular vascular event000 Traction retinal detachment 3 (2%)1 (1%) Vitrectomy1 (1%)0 Vitreous Hemorrhage16 (12%)6 (5%)7 (6%) * One case related to study drug injection in the ranibizumab+focal/grid/PRP laser group.

31 31 Major Ocular Adverse Events from 14 Weeks to 56 Weeks Adverse events from 14 to 56 weeks Sham+ Focal/Grid/PRP Laser N = 131 Ranibizumab+ Focal/Grid/PRP Laser N = 111 Triamcinolone+ Focal/Grid/PRP Laser N = 112 Endophthalmitis000 Ocular vascular event000 Traction retinal detachment4 (3%)5 (5%)1 (1%) Vitrectomy17 (13%)8 (7%)7 (6%) Vitreous Hemorrhage28 (21%)25 (23%)20 (18%)

32 32 Elevated Intraocular Pressure/Glaucoma Prior to the 14-Week Visit Sham+ Focal/Grid/PRP Laser N = 133 Ranibizumab+ Focal/Grid/PRP Laser N = 116 Triamcinolone+ Focal/Grid/PRP Laser N = 115 Number of injections227115 Elevated Intraocular Pressure/Glaucoma Increase ≥10 mmHg from baseline 3 (2%)020 (17%) IOP ≥30 mmHg 2 (2%)05 (4%) Initiation of IOP-lowering meds at any visit* 2 (2%)0 Number of eyes meeting ≥1 of the above 3 (2%)020 (17%) Glaucoma surgery000 *Excludes eyes with IOP lowering medications at baseline

33 33 Elevated Intraocular Pressure/Glaucoma from 14 Weeks to 56 Weeks Elevated Intraocular Pressure/Glaucoma Sham+ Focal/Grid/PRP Laser N = 131 Ranibizumab+ Focal/Grid/PRP Laser N = 111 Triamcinolone+ Focal/Grid/PRP Laser N = 112 Increase ≥10 mmHg from baseline 6 (5%) 10 (9%) IOP ≥30 mmHg 4 (3%)4 (4%) Initiation of IOP-lowering meds at any visit* 7 (5%)5 (5%)17 (15%) Number of eyes meeting ≥1 of the above 11 (8%)7 (6%)20 (18%) Glaucoma surgery † 01 (1%) *Excludes eyes with IOP lowering medications at baseline † Includes 2 Ahmed valve (neovascular glaucoma)

34 Cataract Surgery During Follow-up  Up to 14 weeks none of the phakic eyes in all groups required CE  14 to 56 weeks CE was performed in a small percentage of patients (2 to 3 % in sham and ranibizumab groups and 6% in the TA group). 34

35 Cataract Surgery During Follow-up 35 Sham+ Focal/Grid/PRP Laser Ranibizumab+ Focal/Grid/PRP Laser Triamcinolone+ Focal/Grid/PRP Laser Prior to 14 week visit Phakic at baselineN = 120N = 93N = 105 Eyes that had cataract surgery 000 14 to 56 week visit Phakic at 14 weeksN = 119N = 91N = 102 Eyes that had cataract surgery 2 (2%)3 (3%)6 (6%)

36 Number of Deaths 36 Sham N = 133 Ranibizumab N = 116 Triamcinolone N = 115 Deaths332

37 Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’ Collaboration through 56 Weeks 37 ATC Event Sham N * = 102 Ranibizumab N * = 116 Triamcinolone N * = 115 Non-fatal myocardial infarction 1 (1%)3 (3%)0 Non-fatal cerebrovascular accident-ischemic or hemorrhagic (or unknown) 1 (1%)3 (3%)4 (3%) Vascular death (from any potential vascular or unknown cause) 2 (2%)3 (3%)0 Any APTC event 4 (4%)8 † (7%)4 (3%) * N=Number of Study Participants. Study participants with 2 study eyes are assigned to the non-sham group. Multiple events within a study participant are only counted once per event. † 1event occurred between baseline and 4 week injections, 1 event occurred about 3 weeks after the 4 week injection, and the other events from the remaining 6 study participants occurred over 4 weeks after the 4 week injection

38 Cardiovascular Events According to Antiplatelet Trialists’ Collaboration* through 56 Weeks 38 Safety Phase (DME treatment at investigator discretion) *Antiplatelet Trialists’ Collaboration. BMJ. 1994 Jan 8;308(6921):81-106. Non-fatal cerebrovascular accidents include ischemic, hemorrhagic or unknown. Vascular death includes any potential vascular or unknown cause. Vascular or unknown death Randomized Phase (DME treatment according to protocol) Triamcinolone Ranibizumab Sham 4143456

39 Discussion 39

40 Summary Randomized Phase  14 week primary outcome visit: Both ranibizumab and triamcinolone significantly improved visual acuity (+5.6 and +6.7 letters) and retinal thickness (-35 and -100 microns) compared to sham injection in eyes with central DME receiving focal/grid laser and requiring prompt PRP Safety Phase  14 week to 56 week visits: Differences in visual acuity and retinal thickness outcomes seen at 14 weeks not sustained 40

41 Summary Macular Edema after Prompt PRP in Eyes with Central DME Also Receiving Focal/Grid Laser – Sham Injection Group  Focal/grid laser of central DME in absence of prompt PRP usually associated decreased macular edema by 16 weeks 41 Protocols by DRCR.net Involving Focal/Grid Laser as Monotherapy for DME without PRP given for Severe NPDR or PDR Median Change in OCT Central Subfield Thickness from Baseline to 16 Weeks (25 th, 75 th quartiles) Median Change in Visual Acuity from Baseline to 16 Weeks (25 th, 75 th quartiles) Protocol B (“Laser vs. Steroids for DME”) -33 (-90, 13)2 (-4, 7) Protocol K (“Response to Laser for DME”) -27 (-61, 13)1 (-3, 6) Protocol I (“LRT for DME”) -34 (-101, 10)2 (-3, 8) Protocol J (Sham group only at 14 weeks) – Laser-Ranibizumab-Triamcinolone for DME Plus PRP for Diabetic Retinopathy”) 0 (-80, +70)-2 (-8, +3)

42 Macular Edema after Prompt PRP in Eyes with Central DME Receiving Focal/ Grid Laser – Sham Injection Group Compared to Eyes without Central DME and No Focal/Grid Laser  14 week primary outcome visit: The magnitude and frequency of short term OCT central subfield thickening and visual acuity loss following prompt PRP appears similar in eyes with central DME receiving focal/grid laser than eyes without central DME 42 Thickness ≥10% increase with at least a 25 µm increase from baseline Median Change in Visual Acuity (25 th, 75 th quartiles) Protocol F - eyes w/ PRP but w/o central DME: 17 week follow-up 28%-1 (-4, +2) Protocol J - eyes w/ sham injection plus focal/grid plus PRP: 14 week follow-up 38%-2 (-8, +3)

43 43 34 Week Visit Thickness ≥10% increase with at least a 25 µm increase from baseline Median Change in Visual Acuity (25 th, 75 th quartiles) Protocol F - eyes w/ PRP but w/o central DME: 34 week follow-up 34%-1 (-5, +2) Protocol J - eyes w/ sham injection plus focal/grid plus PRP: 34 week follow-up 30%0 (-7, +6)  34 week visit: The magnitude and frequency of OCT central subfield thickening and visual acuity loss following prompt PRP appears similar in eyes with central DME receiving focal/grid laser than eyes without central DME Macular Edema after Prompt PRP in Eyes with Central DME Receiving Focal/ Grid Laser – Sham Injection Group Compared to Eyes without Central DME and No Focal/Grid Laser

44 Summary Safety  Ranibizumab: Endophthalmitis: one eye receiving ranibizumab Long term safety of ranibizumab injections remains largely unknown  Triamcinolone: Increased risk of elevated IOP between 14 and 56 weeks; even with only one treatment at baseline Not associated with higher incidence of cataract surgery (unlike prior studies) oWhy? Only 1 injection? Younger cohort? Lower enthusiasm to operate on cataracts in this advance DR cohort? Other factors? 44

45 Summary Safety  This study did not identify an increased risk of traction retinal detachments beyond that which could be attributed to chance alone in these eyes which were receiving PRP for PDR or severe NPDR.  Cerebrovascular or cardiovascular events did not occur with a difference in frequency among the 3 groups that could not be attributed to chance alone. 45

46 Conclusions  Eyes with central DME receiving prompt PRP at time of focal/grid laser for DME appear more likely to have increased macular edema and visual acuity loss in short term than: Eyes without central DME receiving prompt PRP but no focal/grid laser Eyes with central DME receiving foca/grid laser but no prompt PRP 46

47 Conclusions  The risk of short-term exacerbation of macular edema and associated visual acuity loss following prompt PRP in eyes also receiving focal/grid laser for DME can be reduced by intravitreal triamcinolone or ranibizumab. Benefits were not maintained at 1 year, but study injections were discontinued after 1 (triamcinolone) or 2 (ranibizumab) injections 47

48 Conclusions – Other Considerations  Eyes with central DME requiring prompt PRP which receive ranibizumab or triamcinolone at the time of PRP and focal/grid laser may be less likely to need additional PRP, develop vitreous hemorrhage, develop traction retinal detachment, or undergo vitrectomy 48

49 Conclusions – Other Considerations  Effects of ranibizumab or triamcinolone on diabetic retinopathy appear consistent with similar findings in eyes with the following: Central DME not requiring prompt PRP treated with triamcinolone alone (Protocol B) or triamcinolone + prompt focal/grid laser (Protocol I) Central DME not requiring prompt PRP treated with intravitreal ranibizumab with deferred (>24 weeks) or prompt focal/grid laser (Protocol I) 49

50 Conclusions – Other Considerations  Single study injection of intravitreal triamcinolone appears associated with increased risk of elevated IOP, even between 14 and 56 weeks  Further study seems necessary to assess long- term risks and benefits of intravitreal injections of ranibizumab or corticosteroids in persons with central DME also receiving prompt PRP 50

51 Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) 51  48 clinical study sites  Study participants who volunteered to participate in this trial  DRCR.net Data and Safety Monitoring Committee  Genentech (provided the ranibizumab) and Allergan, Inc. (provided the triamcinolone) for the study and collaborated in a manner consistent with the Network’s DRCR.net Industry Collaboration Guidelines, the DRCR.net had complete control over the design of the protocol, ownership of the data, and all editorial content of presentations and publications related to the protocol.  DRCR.net investigators and staff


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