Transcript Funding Mechanism - Jaeb Center for Health Research

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
Disclosure
 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.
2
Background
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
* CDC: National diabetes fact sheet, 2007
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Background
Panretinal photocoagulation (PRP) has
been the treatment for PDR over last 4
decades
 Substantially reduces risk of severe vision loss, but . . .
˗ Inherently destructive
˗ Peripheral visual field loss
˗ Night vision loss
˗ Exacerbation of pre-existing DME
˗ Not perfect: 5% severe vision loss (worse than 5/200
at 2 consecutive visits) despite PRP
 Anti-VEGF, when given for DME, decreases risk
of diabetic retinopathy worsening and increases
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chance of improved retinopathy level
Study Design
Randomized, multi-center clinical trial (55 Sites)
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):
• PDR
• No history of PRP
• Best corrected visual acuity letter score ≥24
(~Snellen equivalent 20/320 or better)
• Eyes with or without central-involved DME were eligible
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)
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Primary Question
 Is visual acuity using ranibizumab for PDR
not worse than treatment with PRP at 2 years?
 Non-inferiority margin of 5 letters
Secondary Question
 Are there potential benefits of ranibizumab on:




Vision throughout follow-up (area under the curve)
Peripheral vision
Macular edema
Incidence of vitrectomy
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Follow-up Schedule
 PRP group: Visits every 16 weeks*
Baseline to
1 Year
 Ranibizumab group: Visits every 4
weeks to assess for PDR treatment
 Both groups simultaneously
evaluated for DME treatment
 PRP group: Visits every 16 weeks*
1 Year to
2 Years
 Ranibizumab group: Visits every 4wk
to 16wk to assess for PDR treatment
 Interval 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.
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PDR Treatment Schedule:
Ranibizumab Group – Year 1
 6 initial injections q4 weeks
 One exception: if no neovascularization (NV) at
4-month or 5-month visit, then injection withheld
Starting at 6-month visit:
 Inject if NV improved compared with any previous 3
consecutive visits where injection given
 Withhold injections if NV stable over previous 3
consecutive injections
After injection withheld, resume injections if NV
worsens
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PDR Treatment Schedule:
PRP Group
 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.
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DME Treatment Schedule:
Ranibizumab or PRP Groups
 Eyes in both groups could receive 0.5-mg
ranibizumab for DME treatment
 At randomization, treatment was required for central
DME with visual acuity 20/32 or worse – defined as
“Baseline DME” throughout remainder of presentation
 Otherwise initiation and retreatment with ranibizumab
for DME at follow-up was at investigator discretion
 DRCR.net protocol comparing ranibizumab with
prompt or deferred focal/grid laser with focal/grid
laser (Protocol I) retreatment regimen provided as
guideline
 Focal/grid laser at investigator discretion
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Randomization
Participants:
N = 304
Eyes: N = 394
Baseline
Ranibizumab Group
N = 191
PRP Group
N = 203
2-Years
N = 160 (84%)
N = 168 (83%)
2-Years
Excluding
Death
N = 88%
N = 86%
N = 22 (18, 24)
N = 16 (9, 22)
Median
(Quartiles)
No. Visits
over 2 years
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Baseline Characteristics
Ranibizumab
Group
(N = 191)
PRP
Group
(N = 203)
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Women
43%
45%
Race
White
Type 2 diabetes
Duration of Diabetes (yrs)
Median HbA1c (%)
52%
73%
18
8.6
50%
76%
17
8.9
Age (yrs) – Median
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Ocular Baseline Characteristics
Ranibizumab
Group
(N = 191)
PRP
Group
(N = 203)
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%
Mean visual acuity letter
score (~Snellen Equivalent)
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Ocular Baseline Characteristics
Mean OCT CST* (µm)
< 250 µm
250 to 349 µm
≥ 350 µm
Presence of centralinvolved DME with VA
loss**
Ranibizumab
Group
(N = 189)
262
PRP
Group
(N = 201)
249
66%
19%
15%
67%
26%
7%
Required ranibizumab at baseline
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
Ocular Baseline Characteristics
Ranibizumab
PRP
Group
Group
(N = 189)
(N = 199)
Diabetic Retinopathy Severity by Reading Center
NPDR†
10%
13%
Mild to moderate PDR
52%
49%
High risk PDR to
advanced PDR
38%
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.
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Treatment For
Proliferative
Diabetic Retinopathy
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PRP Group
Baseline PRP
Overall
(N = 203)
Completed initial full PRP
Performed in 1 Sitting
98%
54%
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PRP Group
Additional 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
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Ranibizumab Group
# of Ranibizumab Injections
Eyes With
Baseline DME
(N = 36)
Prior to 1-year Visit (Max possible = 13)
Median
9
Mean
8.9
Prior to 2-year visit (Max possible= 26)
Median
14
Mean
13.3
Note: 97% of protocol-required injections for PDR were given
Eyes Without
Baseline DME
(N = 133)
7
6.9
10
10.1
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Ranibizumab Group
Received PRP for PDR
Overall
N = 191
Received PRP* before 2 years
12 (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
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Treatment For
Diabetic Macular Edema
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PRP Group
Ranibizumab Treatment for DME
Timing of first ranibizumab
injection for DME
Overall
(N = 203)
Never
47%
Baseline
35%
Follow-up
18%
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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
Mean
5
0
5.7
1.4
9
0
9.1
2.2
Prior to 2-year Visit (Max = 26)
Median
Mean
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Additional Treatment for DME
Focal/grid laser
Received 1 or more alternative
treatment
Ranibizumab
Group
PRP
Group
8%
10%
<1%
2%
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Efficacy
25
Visual Acuity
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Mean Change in Visual Acuity
Mean Visual Acuity Change
(Letter Score)
15
10
5
0
-5
0
16
32
52
Visit Week
Outlying values were truncated to 3 SD from the mean
68
84
104
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Mean Change in Visual Acuity
Mean Visual Acuity Change
(Letter Score)
15
10
5
0
+ 0.2
-5
0
N = 203
16
32
52
Visit Week
PRP Group
Outlying values were truncated to 3 SD from the mean
68
84
104
N = 168
28
Mean Change in Visual Acuity
Mean Visual Acuity Change
(Letter Score)
15
10
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)
5
+ 2.8
0
+ 0.2
-5
0
N = 191
N = 203
16
32
52
Visit Week
Ranibizumab Group
Outlying values were truncated to 3 SD from the mean
68
84
PRP Group
104
N = 160
N = 168
29
Mean Change in Visual Acuity
Area under the Curve Analysis
Mean Visual Acuity Change
(Letter Score)
15
Adjusted Mean Difference over 2 years (AUC): +4.2
P-value<0.001
95% Confidence Interval: (+3.0, +5.4)
10
5
+ 4.5
0
-0.3
-5
0
N = 191
N = 203
16
32
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Visit Week
Ranibizumab Group
68
84
104
N = 160
N = 168
PRP Group
Area under the curve (AUC) analysis: Pre-planned secondary outcome
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Mean Change in Visual Acuity
(Letter Score)
Mean Change in Visual Acuity
Subset that Completed 2 Yrs
15
10
5
+ 2.8
0
+ 0.2
-5
0
16
N = 160 of 191
32
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Visit Week
Ranibizumab Group
68
84
104
N = 168 of 203
PRP Group
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Mean Change in Visual Acuity:
Eyes “Baseline DME”
Mean Visual Acuity Change
(Letter Score)
15
10
+7.9
5
+1.9
0
2-Year Adjusted Mean Difference: +3.0 letters
95% Confidence Interval: (-4.2, +10.3)
-5
0
N = 42
N = 46
16
32
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Visit Week
68
84
104
N = 33
N = 37
Ranibizumab Group
PRP Group
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Mean Change in Visual Acuity
Eyes Without “Baseline DME”
Mean Visual Acuity Change
(Letter Score)
15
2-Year Adjusted Mean Difference: +1.4 letters
95% Confidence Interval: (-1.5, +4.4)
10
5
+1.8
0
-0.5
-5
0
N = 147
N = 155
16
32
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Visit Week
68
84
104
N = 126
N = 130
Ranibizumab Group
PRP Group
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Mean Change in Visual Acuity
Stratified by Baseline DME
Without “Baseline DME”
Mean Visual Acuity Change
(Letter Score)
With “Baseline DME”
14
12
10
8
6
4
2
0
-2
-4
+7.9
+1.8
+2
- 0.5
0
16
N = 42
N = 46
32 52 68
Visit Week
84 104
N = 33
N = 37
Ranibizumab Group
*Outlying values were truncated to 3 SD from the mean
0
16
N = 147
N = 155
32 52 68
Visit Week
PRP Group
84
104
N = 126
N = 130
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≥10 Letter Score Improvement*
Percentage of Eyes (%)
60
50
43%
40
36%
30
20
10
2-Year Adjusted Difference: 6%
95% Confidence Interval: (-8%, +21%)
0
0
N = 104
N = 110
16
32
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Visit Week
Ranibizumab Group
*Baseline VA 20/32 or worse
68
84
PRP Group
104
N = 81
N = 86
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≥10 Letter Score Worsening
Percentage of Eyes (%)
60
2-Year Adjusted Difference: -4%
95% Confidence Interval: (-11%, +2%)
50
P= #
40
30
20
14%
9%
10
0
0
N = 191
N = 203
16
32
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Visit Week
Ranibizumab Group
68
84
104
N = 160
N = 168
PRP Group
36
≥15 Letter Score Worsening
Percentage of Eyes (%)
60
2-Year Adjusted Difference: -2%
95% Confidence Interval: (-8%, +3%)
50
40
30
20
10%
10
8%
0
0
N = 191
N = 203
16
32
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68
84
Visit Week
Ranibizumab Group
PRP Group
104
N = 160
N = 168
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Peripheral Visual Field Outcomes
2-Year Visit
Humphrey Visual Field
30-2 + 60-4
Ranibizumab
Group
(N = 58)
Cumulative Point Score Change from Baseline
PRP
Group
(N = 57)
Mean
-23
Difference (P-Value)
372 dB (P<0.001)
-422
Mean Deviation Change from Baseline
Mean
Difference (P-Value)
-0.08
-2.50
2.2 (P< 0.001)
38
Optical Coherence Tomography
Central Subfield Thickness
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Central Subfield Thickness
Change: 2-Year Visit
Mean Change (µm)
Adjusted Difference (P-value)
Ranibizumab
Group
PRP
Group
-47
-3
-45 µm (P < 0.001)
Eyes with “Baseline DME”
Mean Change (µm)
Adjusted Difference (P-value)
-153
-48
-54 µm (P = 0.006)
Eyes without “Baseline DME”
Mean Change (µm)
Adjusted Difference (P-value)
-18
+10
-31 µm (P < 0.001)
Proportion of Eyes Developing Center
Involved DME with Vision Impairment
(Eyes without Baseline DME and Vision Impairment)
2-Year Adjusted Difference: 19%
95% Confidence Interval: (10% to 28%)
P-value < 0.001
N = 155
N = 147
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Diabetic Retinopathy
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Complications of PDR
Ranibizumab
Group
(N = 191)
PRP Group
(N = 203)
P-value
Any retinal detachment
6%
10%
0.08
Neovascular glaucoma
2%
3%
0.50
Iris neovascularization
1%
1%
0.96
Vitreous hemorrhage
27%
34%
0.09
Vitrectomy
4%
15%
< 0.001
PDR = proliferative diabetic retinopathy
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Diabetic Retinopathy: 2-Year Visit
Ranibizumab
Group
(N = 142)
Prompt PRP
Group
(N = 148)
Fundus Photos Graded by Reading Center*
Pvalue
0.41
No PDR
35%
30%
-
Regressed NV
23%
24%
-
Active NV
42%
46%
-
* Only includes eyes with active NV at baseline
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Diabetic Retinopathy Improvement:
Ranibizumab Group
(Note: Cannot determine for PRP Group)
Ranibizumab
Group
2-Year Visit
Eyes improving 2 or more steps in DR
severity on fundus photos
N = 142
47%
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Safety
46
Ocular Adverse Events*
Ranibizumab
Group
N = 191
PRP Group
N = 203
P-value
0.5%
0%
--
Inflammation
1%
4%
0.02
Retinal Tear
0%
0%
--
Cataract Surgery
2%
6%
0.06
Elevation in IOP
9%
13%
0.16
Endophthalmitis
*Event defined as occurring at least once through 2 years.
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Systemic Adverse Events
APTC Events*
One Study Eye
2- Study Eyes
N = 89
Ranibizumab
Group
N = 102
PRP
Group
N = 114
Non-fatal MI
2%
3%
2%
Non-fatal stroke
1%
2%
4%
4%
4%
<1%
8%
9%
6%
Vascular/
Unknown Death
Any APTC event
P = 0.80
*Anti-platelet Trialists` Collaboration defined events. Occurring at least once
through 2 years.
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Pre-Specified Systemic
Adverse Events*
One Study Eye
2- Study
Eyes
N = 89
Ranibizumab
Group
N = 102
Death (any cause)
4%
6%
4%
0.70
Hospitalization
42%
47%
35%
0.20
Serious adverse
event
43%
48%
37%
0.26
Hypertension
16%
25%
18%
0.23
*Occurring at least once through 2 years
PRP
PGroup
value
N = 114
49
MedDRA Systems (P value < 0.05)
One Study Eye
N = 26 Systems
2- Study
Eyes
N = 89
Ranibizumab
Group
N = 102
PRP
Group
N = 114
Pvalue
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%
0.0150
% Per Participant
Discussion
 DRCR.net Protocol S (PRP vs. Ranibizumab
for PDR):
 Treatment with 0.5-mg ranibizumab met primary noninferiority outcome for VA being no worse than PRP
 Summary of Ranibizumab group results vs. PRP:
 Mean change in VA from baseline to 2-years with
ranibizumab no worse than with PRP
 Superior mean visual acuity over course of 2-years
(area under the curve analysis)
 Superior mean visual field outcomes
 Decreased occurrence of vitrectomies
 Decreased development of central involved DME
 PRP rarely given for failure or futility of ranibizumab
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Discussion
 No systemic safety concerns with ranibizumab
identified among pre-specified major safety
outcomes
 Increased 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
52
ranibizumab per protocol for DME
Discussion
 Rates of endophthalmitis or other injectionrelated serious adverse events were very low
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Discussion
 Key aspects of study design related to
interpretation of results
 Participant retention through two years (87% of those
who had not died) lower than desired
• However, 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
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aflibercept)
Advantages 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 completed
 From completion of initial full PRP, median time to
additional PRP ~7 months
 May cost less than ranibizumab injections
 No risk of endophthalmitis
 No risk of systemic exposure to anti-VEGF
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Advantages of Ranibizumab
Mean change in VA from baseline to 2-years
no worse than with PRP
Superior mean visual acuity over course of 2years (area under the curve analysis)
Superior mean visual field outcomes
Decreased chance of vitrectomies
Decreased chance of developing DME
PRP rarely given for futility or failure
Unknown if similar outcomes with 0.3-mg
ranibizumab or other anti-VEGF agents
(bevacizumab or aflibercept)
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Potential Impact of DME when
Initiating Treatment of PDR
 Presence of DME may influence the relative
benefit of ranibizumab over PRP
 When 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 followup
 When 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
57
need to be considered
Conclusions
 PRP effective for PDR over last 4 decades;
remains effective in 21st century
 Ranibizumab for PDR is at least as good as (noninferior to) PRP for visual acuity at 2 years
 Ranibizumab is an effective treatment alternative to
PRP for PDR
 No substantial safety concerns for at least 2 years
 May 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
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Thank You on Behalf of Diabetic Retinopathy
Clinical Research Network (DRCR.net)
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)
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