Prompt PRP vs Ranibizumab Deferred PRP for PDR Study 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 ID: 759612
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Slide1
The Diabetic Retinopathy Clinical Research Network
Prompt PRP vs. Ranibizumab + Deferred PRP for PDR Study 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
Slide2Disclosure
2
Funding/Support:
Cooperative Agreement with NEI and NIDDK of NIH, U.S. Department of Health and Human Services.
Additional
Contributions
: Genentech Inc.
provided the
ranibizumab and clinical site funding.
A
complete list of all DRCR.net investigator financial disclosures can be found at
www.drcr.net
.
Slide3Background
Proliferative diabetic retinopathy (PDR):Left untreated, is a leading cause of blindness~12,000 to 24,000 new cases of diabetic retinopathy-induced blindness each year*Without treatment, ~50% of eyes with high-risk PDR experience severe vision loss within 5 years
3
* CDC: National diabetes fact sheet, 2007
Slide4Background
Panretinal photocoagulation (PRP) has been the treatment for PDR over last 4 decadesSubstantially reduces risk of severe vision loss, but . . .Inherently destructivePeripheral visual field lossNight vision lossExacerbation of pre-existing DMENot perfect: 5% severe vision loss (worse than 5/200 at 2 consecutive visits) despite PRPAnti-VEGF, when given for DME, decreases risk of diabetic retinopathy worsening and increases chance of improved retinopathy level
4
Slide5Study Design
5
Participants meeting all of the following criteria:Age ≥18 years with Type 1 or type 2 diabetes Study eye(s) meeting all of the following criteria (a participant can have 2 study eyes):PDRNo history of PRPBest corrected visual acuity letter score ≥24 (~Snellen equivalent 20/320 or better) Eyes with or without central-involved DME were eligible
Randomized, multi-center clinical trial (55 Sites)
Primary
Objective:
Compare the
efficacy and safety of
PRP with that of
intravitreous
ranibizumab (0.5-mg
in
0.05 mL) for proliferative diabetic retinopathy (PDR)
Slide6Primary Question
Is visual acuity using ranibizumab for PDR not worse than treatment with PRP at 2 years?Non-inferiority margin of 5 lettersSecondary QuestionAre there potential benefits of ranibizumab on:Vision throughout follow-up (area under the curve)Peripheral vision Macular edemaIncidence of vitrectomy
6
Slide7Follow-up Schedule
Baseline to
1 Year
1 Year to
2 Years
PRP group:
Visits every 16 weeks*Ranibizumab group: Visits every 4 weeks to assess for PDR treatment Both groups simultaneously evaluated for DME treatment
7
PRP group: Visits every 16 weeks*Ranibizumab group: Visits every 4wk to 16wk to assess for PDR treatmentInterval is extended if injections for PDR and DME deferred (“Defer and Extend”)
*Eyes with DME could be seen more frequently for DME treatment as needed.
Slide8PDR Treatment Schedule: Ranibizumab Group – Year 1
6 initial injections q4 weeksOne exception: if no neovascularization (NV) at 4-month or 5-month visit, then injection withheldStarting at 6-month visit:Inject if NV improved compared with any previous 3 consecutive visits where injection givenWithhold injections if NV stable over previous 3 consecutive injectionsAfter injection withheld, resume injections if NV worsens
8
Slide9PDR Treatment Schedule: PRP Group
9
Prompt PRP- Initial
1 to 3 sittings within 8 weeks of randomization
Standard laser initial full session = 1200 to 1600 burns
Automated pattern initial full session = 1800 to 2400 burns
Ranibizumab required for eyes with central involved DME and vision loss at baseline.
If the size or amount of NV increased following initial PRP, then additional PRP could be given.
Slide10DME Treatment Schedule: Ranibizumab or PRP Groups
Eyes in both groups could receive 0.5-mg ranibizumab for DME treatmentAt randomization, treatment was required for central DME with visual acuity 20/32 or worse – defined as “Baseline DME” throughout remainder of presentationOtherwise initiation and retreatment with ranibizumab for DME at follow-up was at investigator discretionDRCR.net protocol comparing ranibizumab with prompt or deferred focal/grid laser with focal/grid laser (Protocol I) retreatment regimen provided as guidelineFocal/grid laser at investigator discretion
10
Slide11Randomization
11
Participants:
N = 304
Eyes: N = 394
Ranibizumab Group N = 191
PRP Group N = 203
N = 168 (83%)
N = 86%
N = 160 (84%)
N = 88%
2-Years
2-Years
Excluding Death
Baseline
N = 16 (9, 22)
N = 22 (18, 24)
Median (Quartiles) No. Visits over 2 years
Slide12Baseline Characteristics
12
Ranibizumab
Group
(N = 191)
PRP
Group
(N = 203)
Age (
yrs
) – Median
52
51
Women
43%
45%
Race
White
52%
50%
Type 2 diabetes
73%
76%
Duration of Diabetes (
yrs
)
18
17
Median HbA1c (%)
8.6
8.9
Slide13Ocular Baseline Characteristics
13
Ranibizumab
Group
(N = 191)
PRP
Group
(N = 203)
Mean visual acuity
letter score
(~Snellen Equivalent)
75.0
(20/32)
75.2
(20/32)
20/25 or better
46%
46%
20/32 to 20/40
34%
33%
20/50 to 20/100
16%
17%
20/125 to 20/320
5%
4%
Slide14Ocular Baseline Characteristics
RanibizumabGroup(N = 189)PRPGroup(N = 201)Mean OCT CST* (µm)262249< 250 µm66%67%250 to 349 µm19%26%≥ 350 µm15%7%Presence of central-involved DME with VA loss**22%23%
*OCT values are Stratus equivalents **Eyes with visual acuity letter score ≤ 78 (20/32 or worse) AND OCT CST ≥ machine and gender specific thresholds
Required ranibizumab at baseline
Slide15Ocular Baseline Characteristics
15
RanibizumabGroup(N = 189)PRPGroup(N = 199)Diabetic Retinopathy Severity by Reading CenterNPDR†10%13%Mild to moderate PDR52%49%High risk PDR to advanced PDR38%37%
†
There were
46 eyes (12%) for
which NV was not identified by the reading center on the submitted color images or quality precluded identification. In
29 of
these
cases (63%),
subsequent review of additional images (e.g. FA) confirmed
NV, leaving 17 (4%) of 394 subjects with no photographic documentation of PDR.
Slide16Treatment For Proliferative Diabetic Retinopathy
16
Slide1717
PRP Group Baseline PRP
Overall
(N = 203)
Completed initial full PRP
98%
Performed in 1 Sitting
54%
Slide1818
PRP GroupAdditional PRP
Overall
(N = 203)
Eyes given additional PRP
(after
completing initial full PRP)
45%
Distribution of timing to additional PRP
From completion of initial full PRP
:
median time to additional PRP
~7 months
Slide1919
Ranibizumab Group # of Ranibizumab Injections
Eyes With Baseline DME(N = 36)Eyes Without Baseline DME(N = 133)Prior to 1-year Visit (Max possible = 13)Median9 7Mean8.96.9Prior to 2-year visit (Max possible= 26)Median1410 Mean13.310.1
Note: 97% of protocol-required injections for PDR were given
Slide2020
Ranibizumab Group Received PRP for PDR
OverallN = 191Received PRP* before 2 years12 (6%)
*1 met failure criteria, 1 with Protocol Chair approval,
1
without Chair approval, 8 during vitrectomy (e.g., via endolaser), and 1 by non-study physician
Slide21Treatment For Diabetic Macular Edema
21
Slide22PRP GroupRanibizumab Treatment for DME
22
Timing of first ranibizumab injection for DME
Overall
(N
= 203)
Never
47%
Baseline
35%
Follow-up
18%
Slide2323
PRP Group:# of Ranibizumab Injections for DME
Eyes with baseline DME
(N = 42)
Eyes without
baseline DME
(N = 135)
Prior to 1-year Visit (Max = 13)
Median
5
0
Mean
5.7
1.4
Prior to 2-year Visit (Max = 26)
Median
9
0
Mean
9.1
2.2
Slide2424
Additional Treatment for DME
Ranibizuma
b Group
PRP
Group
Focal/grid laser
8%
10%
Received 1 or more alternative treatment
<1%
2%
Slide25Efficacy
25
Slide26Visual Acuity
26
Slide27Mean Change in Visual Acuity
27
Outlying values were truncated to 3 SD from the mean
Slide28Mean Change in Visual Acuity
28
Outlying values were truncated to 3 SD from the mean
Slide29Mean Change in Visual Acuity
29
Outlying values were truncated to 3 SD from the mean
2-Year Adjusted Mean Difference: +2.2 letters
95% Confidence Interval: (-0.5, +5.0)
(Meets pre-specified non-inferiority criterion: lower bounds of the 95% CI of -0.5 letters was greater than the non-inferiority limit of -5.0 letters)
Slide30Mean Change in Visual AcuityArea under the Curve Analysis
30
Area under the curve (AUC) analysis: Pre-planned secondary outcome
Slide31Mean Change in Visual AcuitySubset that Completed 2 Yrs
31
N = 160 of 191
N = 168 of 203
Slide32Mean Change in Visual Acuity:Eyes “Baseline DME”
32
N = 33
+7.9
N = 37
N = 42
Slide33Mean Change in Visual AcuityEyes Without “Baseline DME”
33
Slide3434
- 0.5
+1.8
N = 42
N = 33
N = 147
N = 46
N = 37
N = 155
N = 130
N = 126
*Outlying values were truncated to 3 SD from the mean
Mean Change in Visual Acuity
Stratified by Baseline DME
Slide35≥10 Letter Score Improvement*
35
*Baseline VA 20/32 or worse
N = 104
N = 110
N = 81
N = 86
Slide3636
≥10 Letter Score Worsening
P= #
Slide37≥15 Letter Score Worsening
37
N = 191
N = 203
N = 160
N = 168
2-Year Adjusted Difference: -2%
95% Confidence Interval: (-8%, +
3
%)
Slide38Peripheral Visual Field Outcomes2-Year Visit
38
Humphrey Visual Field
30-2 + 60-4
Ranibizumab
Group
(N = 58)
PRP
Group
(N = 57)
Cumulative Point Score Change from Baseline
Mean
-23
-422
Difference (P
-Value)
372 dB
(
P
<0.001)
Mean Deviation Change from Baseline
Mean
-0.08
-2.50
Difference (P
-Value)
2.2 (P
< 0.001)
Slide39Optical Coherence TomographyCentral Subfield Thickness
39
Slide40Central Subfield Thickness Change: 2-Year Visit
Ranibizumab
Group
PRP
Group
Mean Change (µm)
-47
-3
Adjusted Difference (P-value)
-45
µm (P
< 0.001)
Eyes with “Baseline DME”
Mean Change (µm)
-153
-48
Adjusted Difference (P-value)
-54
µm (
P
= 0.006)
Eyes without “Baseline DME”
Mean Change (µm)
-18
+10
Adjusted Difference (P-value)
-31
µm
(P < 0.001)
Slide41Proportion of Eyes Developing Center Involved DME with Vision
Impairment
(Eyes without Baseline DME and Vision Impairment)
41
2-Year Adjusted Difference: 19% 95% Confidence Interval: (10% to 28%)P-value < 0.001
N = 155
N = 147
Slide42Diabetic Retinopathy
42
Slide43Complications of PDR
43
Ranibizumab Group(N = 191)PRP Group(N = 203)P-valueAny retinal detachment6%10%0.08Neovascular glaucoma2%3%0.50Iris neovascularization1%1%0.96Vitreous hemorrhage27%34%0.09Vitrectomy4%15%< 0.001
PDR = proliferative diabetic retinopathy
Slide44Diabetic Retinopathy: 2-Year Visit
44
Ranibizumab Group(N = 142)Prompt PRP Group(N = 148)P-valueFundus Photos Graded by Reading Center*0.41No PDR35%30%-Regressed NV23%24%-Active NV42%46%-
* Only includes eyes with active NV at baseline
Slide4545
Diabetic Retinopathy Improvement: Ranibizumab Group(Note: Cannot determine for PRP Group)
Ranibizumab Group
2-Year Visit
N = 142
Eyes improving 2 or more steps in DR severity on fundus photos
47%
Slide46Safety
46
Slide47Ocular Adverse Events*
47
Ranibizumab GroupN = 191PRP GroupN = 203P-valueEndophthalmitis0.5%0%--Inflammation1%4%0.02Retinal Tear0%0%--Cataract Surgery2%6%0.06Elevation in IOP9%13%0.16
*Event defined as occurring at least once through 2 years.
Slide48Systemic Adverse EventsAPTC Events*
48
One Study Eye 2- Study EyesN = 89Ranibizumab GroupN = 102PRP GroupN = 114Non-fatal MI2%3%2%Non-fatal stroke1%2%4%Vascular/Unknown Death 4%4%<1%Any APTC eventP = 0.808%9%6%
*Anti-platelet Trialists` Collaboration defined events. Occurring at least once
through 2 years.
Slide49Pre-Specified Systemic Adverse Events*
49
One Study Eye 2- Study EyesN = 89Ranibizumab GroupN = 102PRP GroupN = 114P-valueDeath (any cause)4%6%4%0.70Hospitalization42%47%35%0.20Serious adverse event43%48%37%0.26Hypertension 16%25%18%0.23
*Occurring at least once through 2 years
Slide50MedDRA Systems (P value < 0.05)
50
N = 26 Systems
One Study Eye
% Per Participant
2- Study Eyes
N = 89
Ranibizumab Group
N = 102
PRP Group
N = 114
P
-value
Cardiac
13%
18%
5%
0.01
Endocrine
20%
25%
11%
0.02
Infections/
infestations
28%
27%
14%
0.02
Respiratory
35%
46%
30%
0.04
Skin
20%
24%
11%
0.03
Surgical
8%
24%
16%
0.01
Slide51Discussion
DRCR.net Protocol S (PRP vs. Ranibizumab for PDR):Treatment with 0.5-mg ranibizumab met primary non-inferiority outcome for VA being no worse than PRPSummary of Ranibizumab group results vs. PRP:Mean change in VA from baseline to 2-years with ranibizumab no worse than with PRPSuperior mean visual acuity over course of 2-years (area under the curve analysis)Superior mean visual field outcomesDecreased occurrence of vitrectomies Decreased development of central involved DMEPRP rarely given for failure or futility of ranibizumab
51
Slide52Discussion
No systemic safety concerns with ranibizumab identified among pre-specified major safety outcomesIncreased frequency of adverse events defined by cardiac, endocrine, respiratory, infections/infestations, skin and surgical conditions MedDRA systems in ranibizumab groups could be real, due to chance, or due to ascertainment bias (more visits in ranibizumab group)Interpretation of systemic safety difficult since large proportion of PRP group received ranibizumab per protocol for DME
52
Slide53Discussion
Rates of endophthalmitis or other injection-related serious adverse events were very low
53
Slide54Discussion
Key aspects of study design related to interpretation of resultsParticipant retention through two years (87% of those who had not died) lower than desiredHowever, no obvious baseline differences between groups for completers and non-completers that would suggest bias Participants and clinicians were not masked However, high adherence to PDR treatment protocol Primary outcome assessors were masked Unknown if similar outcomes with 0.3-mg ranibizumab or other anti-VEGF agents (bevacizumab or aflibercept)
54
Slide55Advantages of PRP
Typically able to be completed in one or two visits Often long-lasting effect requiring no additional treatment However, study suggests approximately 45% given additional PRP after initial full PRP was completedFrom completion of initial full PRP, median time to additional PRP ~7 monthsMay cost less than ranibizumab injectionsNo risk of endophthalmitisNo risk of systemic exposure to anti-VEGF
55
Slide56Advantages of Ranibizumab
Mean change in VA from baseline to 2-years no worse than with PRPSuperior mean visual acuity over course of 2-years (area under the curve analysis)Superior mean visual field outcomesDecreased chance of vitrectomies Decreased chance of developing DMEPRP rarely given for futility or failure Unknown if similar outcomes with 0.3-mg ranibizumab or other anti-VEGF agents (bevacizumab or aflibercept)
56
Slide57Potential Impact of DME when Initiating Treatment of PDR
Presence of DME may influence the relative benefit of ranibizumab over PRPWhen DME is present and treatment with an anti-VEGF agent is planned, PRP may be unnecessary in most cases provided that the patient is expected to be compliant with follow-upWhen DME is not present, ranibizumab is more effective than PRP in preserving central and peripheral visual function, on average, but cost, follow-up compliance, and patient preference need to be considered
57
Slide58Conclusions
PRP effective for PDR over last 4 decades; remains effective in 21st centuryRanibizumab for PDR is at least as good as (non-inferior to) PRP for visual acuity at 2 yearsRanibizumab is an effective treatment alternative to PRP for PDRNo substantial safety concerns for at least 2 yearsMay be the preferred initial treatment approach for some patients, for example, those who have both PDR and DME. Longer follow-up should determine whether effects sustained through 5 years
58
Slide59Thank You on Behalf of Diabetic Retinopathy Clinical Research Network (DRCR.net)
59
A complete list of all DRCR.net investigator financial disclosures and
many of these
slides can be found at
www.drcr.net
.
Full protocol available on clinicalTrials.gov (NCT01489189)