Presentation on theme: "The Diabetic Retinopathy Clinical Research Network"— Presentation transcript:
1The Diabetic Retinopathy Clinical Research Network Randomized Trial Evaluating Short-Term Effects of Intravitreal Ranibizumab or Triamcinolone Acetonide on Diabetic Macular Edema Following Panretinal PhotocoagulationJoseph M. Googe, MDSupported 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
2Background PRP in Eyes with Central DME Scatter or panretinal photocoagulation (PRP) is standard treatment for PDRReported 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 (25th, 75th percentile = +5 or +6, +20 or +34 µm) with little decreased acuity 17 weeks after initiating PRP in eyes without central DME
3BackgroundIs 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)
4Background PRP in Eyes with Central DME 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 acuityProtocolNMedian Change in OCT Central Subfield Thickness (25th, 75th quartiles)Median Change in Visual Acuity (25th, 75th quartiles)Protocol B311-33 (-90, 13)2 (-4, 7)Protocol K119-27 (-61, 13)1 (-3, 6)Protocol I268-34 (-101, 10)2 (-3, 8)
5Background PRP in Eyes with Central DME 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
6Background Anti-VEGF and Triamcinolone for DME Inflammation and increased levels of vascular endothelial growth factor (VEGF) contribute to the development or exacerbation of DMEDRCR.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
7Laser-Ranibizumab-Triamcinolone+PRP Randomized Clinical Trial for DME Study ObjectiveEvaluate 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.
8Randomized, multi-center clinical trial Study DesignRandomized, multi-center clinical trialAt least 1 eye meeting all of the following criteria:Severe NPDR or PDR requiring prompt PRPPresence of central DME on clinical exam and CST on OCT ≥250 micronsBest corrected E-ETDRS visual acuity letter score ≥24 (~20/320 or better)Sham+Focal/Grid/PRP LaserRanibizumab+Focal/Grid/PRP LaserTriamcinolone+Focal/Grid/PRP LaserPrimary outcome: Change in visual acuity from baseline to 14 weeks (intent to treat analysis)
9Follow-up Schedule 1st injection at baseline Safety visit 3-10 days Focal/grid laser 3-10 daysInitial PRP (following focal/grid ) 3-14 daysBaseline to2 Weeks2nd injection (ranibizumab for ranibizumab group and sham for sham and triamcinolone groups)Follow-up visit4 WeeksLast day to complete PRP was 49 days from baseline14 WeeksPrimary outcome visit34 Weeks &56 WeeksSafety follow-up visits
13Panretinal Photocoagulation Treatment Sham+Focal/Grid/PRP LaserRanibizumab+Triamcinolone+Initial PRP on the same day as focal/grid laser planned/performedYes/Yes50%53%Yes/No7%4%8%No/Yes5%6%No/No37%33%34%PRP and/or focal/laser not done1%3%
14Panretinal Photocoagulation Treatment Sham+Focal/Grid/PRP LaserRanibizumab+Triamcinolone+Number of PRP sittings performed*140%34%38%247%50%46%3 or 4†12%15%PRP not done1%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
15Panretinal Photocoagulation Treatment Sham+Focal/Grid/PRP LaserN = 122Ranibizumab+N = 111Triamcinolone+N = 107PRP automated pattern used30%19%20%Median total number of burns154114101430Proportion of eyes with PRP completed in the protocol window89%87%81%
16Additional Treatment for DME Sham+Focal/Grid/PRP LaserN = 123Ranibizumab+N = 113Triamcinolone+N = 109Prior to 14 weeksEyes with additional treatments14 weeks to 56 weeks714845Additional treatment*Bevacizumab (+/- Laser)22179Ranibizumab (+/- Laser)13Triamcinolone (+/- Laser)10127Laser3121Vitrectomy2Bevacizumab+Triamcinolone (+/- Laser)Triamcinolone+VitrectomyEyes 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
18Change in Visual Acuity at 14 Weeks Primary OutcomeChange in Visual Acuity at 14 WeeksChange in visual acuity (letters)Sham+Focal/Grid/PRP LaserN = 123Ranibizumab+N = 113Triamcinolone+N = 109Mean-4+1+2Difference in mean change from Sham +Focal/Grid/PRP Laser [P Value]*+5.6[P < 0.001]+6.7*Adjusted for baseline visual acuity, number of planned PRP sittings, and correlation between 2 study eyes.
19Mean Change in Visual Acuity* from Baseline On the graph of Ranibizumab the mean change in VA was 1 letter at 14 weeks but graph shows it closer to 2. This needs to be fixed please.Randomized Phase(DME treatment according to protocol)Safety Phase(DME treatment at investigator discretion)Safety Phase(DME treatment at investigator discretion)* Values that were ±30 letters were assigned a value of 30
20Change in Visual Acuity at 56 Weeks Change in visual acuity (letters)Sham+Focal/Grid/PRP LaserN = 111Ranibizumab+N = 95Triamcinolone+N = 93Mean-6-4-5Difference 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.
22Subgroup AnalysesNo obvious clinically important difference in results at 14-week primary outcome visit for any of the following subgroups:Prior treatment for DMEBaseline visual acuityBaseline OCT-measured central subfield thickeningBaseline level of diabetic retinopathy on photosBaseline HbA1c levelDescription of edema by ophthalmologist as predominantly focal or predominantly diffusePRP in a single sitting vs. multiple sittingsWhat about duration of DME as defined by clinician? Did that effect VA outcomes?2222
24Change in Retinal Thickening at 14 Weeks* Change in OCT Central Subfield Thickening*Sham+Focal/Grid/PRP LaserN = 115Ranibizumab+N = 100Triamcinolone+N = 103Mean change from baseline (µm)-5-39-92Difference 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 baseline38%17%10%Thickness <250 µm with at least a 25 µm decrease from baseline27%* 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.
25Correlation between Visual Acuity and Central Subfield Thickness at 14 Weeks Sham+Focal/Grid/PRP LaserRanibizumab+Triamcinolone+Central subfield thickness ≥10% increase with at least a 25 µm increase from baselineN=44N=17N=10Above OCT CST change AND concordant decrease in visual acuity of ≥10 letters at 14 weeks15 (34%)2 (12%)1 (10%)Of the 44 eyes in the sham group exhibiting central subfield thickness increase ≥ 10% with a least a 25 micron increase, 15 (34%) had concordant decrease in visual acuity of ≥ 10 letters at 14 weeks, and represented approximately half of the eyes in this group with this amount of visual acuity loss. Similarly, of the 17 and 10 eyes, respectively, in the ranibizumab and triamcinolone groups with central subfield thickness increase ≥10% with at least a 25 micron increase at 14 weeks, 2 (12%) and 1 (10%) had concordant decreases in visual acuity of ≥10 letters at 14 weeks.
26Change in Retinal Thickening at 56 Weeks* Change in OCT Central Subfield Thickening*Sham+Focal/Grid/PRP LaserN = 101Ranibizumab+N = 92Triamcinolone+N = 89Mean change from baseline (µm)-71-52-40Difference 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 baseline28%20%Thickness <250 µm with at least a 25 µm decrease from baseline27%29%*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.
27Mean Change in Retinal Thickness from Baseline Randomized Phase(DME treatment according to protocol)Safety Phase(DME treatment at investigator discretion)Safety Phase(DME discretion)
28≥ 2 Step Improvement in LogOCT Central Subfield Thickness from Baseline Randomized Phase(DME treatment according to protocol)Safety Phase(DME treatment at investigator discretion)Safety Phase(DME discretion)
30Major Ocular Adverse Events Prior to the 14-Week Visit Sham+Focal/Grid/PRP LaserN = 133Ranibizumab+N = 116Triamcinolone+N = 115Number of injections227115Endophthalmitis*1 (0.9%)Ocular vascular eventTraction retinal detachment3 (2%)1 (1%)VitrectomyVitreous Hemorrhage16 (12%)6 (5%)7 (6%)Endophthalmitis occurred 2 days after the second injection* One case related to study drug injection in the ranibizumab+focal/grid/PRP laser group.3030
31Major Ocular Adverse Events from 14 Weeks to 56 Weeks Adverse events from 14 to 56 weeksSham+Focal/Grid/PRP LaserN = 131Ranibizumab+N = 111Triamcinolone+N = 112EndophthalmitisOcular vascular eventTraction retinal detachment4 (3%)5 (5%)1 (1%)Vitrectomy17 (13%)8 (7%)7 (6%)Vitreous Hemorrhage28 (21%)25 (23%)20 (18%)3131
32Elevated Intraocular Pressure/Glaucoma Prior to the 14-Week Visit Sham+Focal/Grid/PRP LaserN = 133Ranibizumab+N = 116Triamcinolone+N = 115Number of injections227115Elevated Intraocular Pressure/GlaucomaIncrease ≥10 mmHg from baseline3 (2%)20 (17%)IOP ≥30 mmHg2 (2%)5 (4%)Initiation of IOP-lowering meds at any visit*Number of eyes meeting ≥1 of the aboveGlaucoma surgery32*Excludes eyes with IOP lowering medications at baseline32
33Elevated Intraocular Pressure/Glaucoma from 14 Weeks to 56 Weeks Sham+Focal/Grid/PRP LaserN = 131Ranibizumab+N = 111Triamcinolone+N = 112Increase ≥10 mmHg from baseline6 (5%)10 (9%)IOP ≥30 mmHg4 (3%)4 (4%)Initiation of IOP-lowering meds at any visit*7 (5%)5 (5%)17 (15%)Number of eyes meeting ≥1 of the above11 (8%)7 (6%)20 (18%)Glaucoma surgery†1 (1%)*Excludes eyes with IOP lowering medications at baseline† Includes 2 Ahmed valve (neovascular glaucoma)3333
34Cataract Surgery During Follow-up Up to 14 weeks none of the phakic eyes in all groups required CE14 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).
35Cataract Surgery During Follow-up Sham+Focal/Grid/PRP LaserRanibizumab+Triamcinolone+Prior to 14 week visitPhakic at baselineN = 120N = 93N = 105Eyes that had cataract surgery14 to 56 week visitPhakic at 14 weeksN = 119N = 91N = 1022 (2%)3 (3%)6 (6%)35
36Number of Deaths Sham N = 133 Ranibizumab N = 116 Triamcinolone 2
37Cardiovascular or Cerebrovascular Events According to Antiplatelet Trialists’ Collaboration through 56 WeeksATC EventShamN* = 102RanibizumabN* = 116TriamcinoloneN* = 115Non-fatal myocardial infarction1 (1%)3 (3%)Non-fatal cerebrovascular accident-ischemic or hemorrhagic (or unknown)4 (3%)Vascular death (from any potential vascular or unknown cause)2 (2%)Any APTC event4 (4%)8† (7%)Antiplatelet Trialists’ Collaboration. BMJ Jan 8;308(6921):*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 injection37
38Cardiovascular Events According to Antiplatelet Trialists’ Collaboration* through 56 Weeks Vascular or unknown deathShamRanibizumabMissing deaths in TA group and 1 in sham group. Would add into this slide and we can delete slide 36 and 37Triamcinolone4143456Randomized Phase(DME treatment according to protocol)Safety Phase(DME treatment at investigator discretion)*Antiplatelet Trialists’ Collaboration. BMJ Jan 8;308(6921):Non-fatal cerebrovascular accidents include ischemic, hemorrhagic or unknown. Vascular death includes any potential vascular or unknown cause.
40Summary Randomized Phase 14 week primary outcome visit: Safety Phase 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 PRPSafety Phase14 week to 56 week visits:Differences in visual acuity and retinal thickness outcomes seen at 14 weeks not sustained
41Median Change in Visual Acuity from Baseline to 16 Weeks Summary Macular Edema after Prompt PRP in Eyes with Central DME Also Receiving Focal/Grid Laser – Sham Injection GroupFocal/grid laser of central DME in absence of prompt PRP usually associated decreased macular edema by 16 weeksProtocols by DRCR.net Involving Focal/Grid Laser as Monotherapy for DME without PRP given for Severe NPDR or PDRMedian Change in OCT Central Subfield Thickness from Baseline to 16 Weeks (25th, 75th quartiles)Median Change in Visual Acuity from Baseline to 16 Weeks(25th, 75th 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)
42Macular 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 Laser14 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 DMEThickness ≥10% increase with at least a 25 µm increase from baselineMedian Change in Visual Acuity(25th, 75th quartiles)Protocol F - eyes w/ PRP but w/o central DME: 17 week follow-up28%-1 (-4, +2)Protocol J - eyes w/ sham injection plus focal/grid plus PRP: 14 week follow-up38%-2 (-8, +3)
43Macular 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 Laser34 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 DME34 Week VisitThickness ≥10% increase with at least a 25 µm increase from baselineMedian Change in Visual Acuity(25th, 75th quartiles)Protocol F - eyes w/ PRP but w/o central DME: 34 week follow-up34%-1 (-5, +2)Protocol J - eyes w/ sham injection plus focal/grid plus PRP: 34 week follow-up30%0 (-7, +6)
44Summary Safety Ranibizumab: Triamcinolone: Endophthalmitis: one eye receiving ranibizumabLong term safety of ranibizumab injections remains largely unknownTriamcinolone:Increased risk of elevated IOP between 14 and 56 weeks; even with only one treatment at baselineNot associated with higher incidence of cataract surgery (unlike prior studies)Why? Only 1 injection? Younger cohort? Lower enthusiasm to operate on cataracts in this advance DR cohort? Other factors?
45Summary SafetyThis 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.
46ConclusionsEyes 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 laserEyes with central DME receiving foca/grid laser but no prompt PRP
47ConclusionsThe 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
48Conclusions – 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
49Conclusions – 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)
50Conclusions – Other Considerations Single study injection of intravitreal triamcinolone appears associated with increased risk of elevated IOP, even between 14 and 56 weeksFurther 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
51Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net) 48 clinical study sitesStudy participants who volunteered to participate in this trialDRCR.net Data and Safety Monitoring CommitteeGenentech (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 staff51