The Diabetic Retinopathy
Clinical Research Network
Intravitreous Anti-VEGF Treatment
for Prevention of Vision
Threatening Diabetic Retinopathy
in Eyes at High Risk
Investigator Training Slides 2.0
[Protocol version 1.0]
1
Background
 Eyes with severe NPDR are at high risk for DR
worsening and subsequent VA loss
• 52% develop PDR over 1 year
• 60% develop PDR with HRC over next 5 years
2
Background
No clear treatment mandate for severe NPDR although
some eyes may benefit from early PRP
Risk of Severe Visual Loss or Vx
Deferred Scatter
Type 2
Early Scatter
10%
Type 1
5%
Type 2
P=0.43
P=0.0001
0%
0
1
2
Years
3
4
5
P (Interaction) = 0.0002
Ferris F. Early photocoagulation in patients with either type I or type II diabetes. Trans Am Ophthalmol Soc. 1996;94:505-37.
More Recent Data:
DRCR.net Trial Laser Groups
(DME at baseline)
Proportion with PDR at 2 Years by
Baseline Level of Retinopathy
40%
35%
30%
N = 45
N = 41
N = 21
37%
38%
N = 17
36%
31%
25%
20%
15%
N = 46
16%
N = 32
10%
10%
5%
0%
Protocol A
Protocol B
Level 53
Level 47B-D
Protocol I
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DRCR.net Protocol I: Comparison
to Anti-VEGF Treated Eyes
Proportion with PDR at 2 Years
40%
N = 21
35%
38%
N = 17
36%
30%
25%
20%
15%
N = 22
10%
12%
N = 88
5%
6%
0%
Level 53
Laser Group
Level 47
Ranibizumab Groups
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RISE/RIDE: Risk of PDR Outcomes in
Sham vs Ranibizumab Groups
Time to First Progression to PDR Outcome
3 fold higher
risk in sham
group
Months
Cumulative probabilities calculated using the Kaplan-Meier method. Progression was defined by (1) progression from NPDR (DR severity level < 60) at baseline to
PDR (DR severity level  60) at a later time point, (2) need for PRP laser, (3) vitreous hemorrhage (AE or slit lamp grade 0 at baseline to > 0 at a later time point, (4)
cases identified by ophthalmoscopy, (5) vitrectomy, (6) iris neovascularization AE, or (7) retinal neovascularization AE. 1 month = 30 days. AE, adverse event; PRP,
panretinal photocoagulation.
Proportion of Patients Requiring PRP
From Baseline to Week 100
VISTA
Proportion of patients
VIVID
133
136
PRP: Panretinal Photocoagulation
IAI: Intravitreal Aflibercept Injection
135
154
155
152
DME Development
Eyes with severe NPDR and no CI-DME at
baseline are also at risk for developing
DME requiring anti-VEGF treatment
• 15% in ETDRS developed CI-DME on
photos by 2 years
DRCR.net Protocol R included eyes with
non-CI DME and any level of retinopathy
and 14% developed CI-DME on OCT or
required treatment by 1 year
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Primary Objective
To determine safety and efficacy of
prompt anti-VEGF versus observation in eyes
presenting with severe NPDR and no CI-DME for
prevention of vision threatening outcomes
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 at 2 years
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Follow-Up and Treatment
Overview
 Total duration: 4 years
• Primary outcome: 2 years for anatomic outcome – if
anatomic benefit through 2 years, continue follow-up
through 4 years to determine if VA benefit too
 Visits at 1, 2, and 4 months; every 4 months
thereafter
 Injections (intravitreous or sham) required at
each of the above visits through 2 years
 Thereafter, evaluate at each visit for retreatment:
• If eye is “Mild NPDR” or better, defer injection
• If “Moderate NPDR” or worse, injection is required
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Composite Primary Outcome:
Part 1 – PDR
 Development of NV within the 7 modified ETDRS
fields on fundus photography or FA, confirmed
by Reading Center
 NVI, NVA, or NVG on clinical exam
 Traction retinal detachment, vitreous
hemorrhage, or pre-retinal hemorrhage
presumed to be from PDR, documented on
fundus photography or FA
 PRP, anti-VEGF, or vitrectomy for PDR, images
should be obtained prior to treatment
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Composite Primary Outcome:
Part 2 – DME
 Center-involved DME on clinical exam with ≥10%
increase in central subfield thickness from
baseline and visual acuity loss, defined as:
• 1) at least 10 letter VA loss at a single visit, or
• 2) 5 to 9 letter VA loss at 2-consecutive visits,
presumed to be from DME
 Treatment for DME performed without meeting
above criteria (protocol deviation)
Note: An eye will be considered to have met the primary
outcome if any one of the above PDR or DME criteria are
met
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Outcome Estimates
Anti-VEGF group
• Based on Protocol I and RIDE/RISE data, we
estimate ~ 15% of eyes in this study that
receive the study anti-VEGF regimen will
develop PDR/DME outcome.
Observation (Sham) group
• Based on available data from Protocols A, B, I,
we estimate ~ 30% of eyes in this study that
receive no treatment will develop PDR/DME
outcome.
SAMPLE SIZE  386 eyes (193 per group)
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Long-Term Objectives
If there is a clinically important difference
identified among the treatment groups for
the primary outcome at 2 years, the study
will also evaluate whether increased
chance of prevention of PDR/DME with
anti-VEGF at 2 years results in long-term
beneficial visual outcomes at 4 years.
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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 longterm 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 visionthreatening complications will be available for
patients.
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Major Inclusion/Exclusion
Criteria in Study Eye
 Severe NPDR (ETDRS level 53) according to
investigator
4-2-1 rule
o Severe hemorrhages in at least 4 quadrants, or
o Definite venous beading in at least 2 quadrants, or
o Moderate IRMA in at least 1 quadrant
 VA letter score 20/25 or better
 No CI-DME using standard OCT thresholds
 No history of DME/DR treatment in prior 12
months and <4 prior injections at any time
 No prior PRP
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Determining Eligibility
Using Standard Photos
 “All 4 midperipheral quadrants show severe
hemorrhages or microaneurysms (at least as
great as Standard photograph 2a, approximately
20 dot and blot hemorrhages”
Link to “Standard
photograph 2a” will
be available on
website
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Standard Photos
 OR “At least 2 fields of definite venous beading
in the midperipheral quadrants, at least as
severe as Standard photograph 6A”
Link to “Standard
photograph 6a” will
be available on
website
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Standard Photos
 OR “At least 1 field of moderate intraretinal
microvascular abnormalities (IRMA) in the
midperipheral quadrants, at least as severe as
Standard photograph 8A”
Link to “Standard
photograph 8a” will
be available on
website
19
Website Tools
NPDR definition provided
Links to standard photos
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DR Level Confirmation
 At Screening Visit, investigator must confirm eye
has severe NPDR on photos and no PDR within
the 7-modified ETDRS fields on FA or clinical
exam
 The FA and photos must be uploaded
immediately for Reading Center grading
 The Reading Center will confirm eligibility prior
to randomization
• Expected turnaround within 1 week
 If eligible, the Randomization Visit must occur
within 35 days of Screening Visit
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Use of Wide-Field Imaging for FA
 UWF color photos will not be permitted
 For FA, sites should use OPTOS if available at
baseline
• Presence of NV outside of the 7-modified
ETDRS fields will NOT be an exclusion.
 If a new OPTOS machine is obtained during
follow-up, FA images should then be taken for
ALL participants going forward
• Peripheral NV outside the 7 modified ETDRS fields will
not meet the primary outcome and generally should
not be treated unless high risk
 Note: Heidelberg UWF device not permitted at this time
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Randomization Reminder
 Before submitting the Randomization Visit, the
investigator MUST
• Confirm eligibility
• Confirm patient’s willingness to accept either
assignment and to complete all treatment/follow-up
• Be available to perform the injection (intravitreous or
sham) THAT DAY
 Educate patient with a thorough ICF process so
that they understand:
• Time commitment
• Treatment requirements
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Assessment Visits
Baseline
(0)
Month
1
Month
2
Month 12
Month
16
Month
20
Month 24
Month
28
Month
32
Month 36
Month
40
Month
44
Month
4
Month
8
First 2 Years: Injections
given at every visit
≥2 Years: Injections given if
worse than mild NPDR
Final Visit
(48M)
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When are photos/FA required?
 At 4-month visit and annually
• Reading Center will perform a masked assessment of
whether primary endpoint has been met
 If initiating PDR or DME treatment and primary
endpoint not previously confirmed by RC at one
of the time points above
• Note: Images will not be sent as soon as early NV
detected
• There is concern with unmasked investigators
detecting NV earlier in the sham group than in the
anti-VEGF group, this approach is intended to
minimize such potential bias
 To document TRD, VH, or PRH for primary
endpoint
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Intravitreous Injection Procedure
 Two individuals must confirm the study eye and drug
number against the printout or website
 Mark the eye for injection
 Apply topical anesthetic
• Subconjunctival anesthetic may only be given if topical
anesthetic is not sufficient to minimize discomfort
 Place the lid speculum
 Apply povidone iodine directly over and surrounding the
injection site
• DRCR.net injections must NOT be given without the use of
povidone iodine in any circumstance
 Pre- and post-injection topical antibiotics should NOT be
used (prior discussion with Protocol Chair or her
designate will be required prior to use)
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Endophthalmitis Rates by
Antibiotic Use
24,052*
Intravitreal Injections
(2,596 eyes)
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Cases of
Endophthalmitis
3 (0.02%)
Without
Topical Antibiotics
6 (0.06%)
With
Topical Antibiotics
*Excluding injections given without povidone iodine (13 injections in 2 eyes)
P = 0.19
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Evolution of Antibiotic Use
in DRCR.net Over Time
If you are in the 34% and are planning to participate
in this protocol and still are uncomfortable omitting
antibiotics, please discuss with Network leadership
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Povidone-Iodine Use
24,065
Intravitreal Injections
(2,598 eyes)
13 injections (2 eyes)
without Povidone-Iodine
(protocol violation)
100% of eyes developed
endophthalmitis
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Sham Injection Procedure
 Same procedure as intravitreous injection,
including:
•
•
•
•
Confirming/marking the study eye
Apply topical anesthetic (subconj should not be used)
Place the lid speculum
Apply povidone iodine directly over and surrounding
the injection site (allowing sufficient time for the
povidone iodine to dry)
o Sham injections must NOT be given without the use
of povidone iodine in any circumstance
 A syringe without a needle will be used, with the
hub pressed against the conjunctival surface to
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simulate the force of an actual injection
Successful
Sham Masking
 In DRCR.net Protocol I, participants with 1 study
eye (N = 423)
Participant Response
to type of injections
Always Real
Sometimes real
/sometimes sham
Always Sham
Sham
Group
72%
Ranibizumab
Groups
88-90%
IVT
Group
55%
18%
7-12%
44%
10%
0-4%
1%
 The majority receiving sham thought they were
receiving real injections
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Bilateral Injections
 2 study injections
• Perform all required injection procedures on the
right eye first before initiating any pre-injection prep
of the left eye.
• Study drug for the left eye should not be in the room
before completing all right eye injection procedures.
 One non-study injection
• Perform all required injection procedures on the
study eye before initiating any pre-injection prep of
the non-study eye.
• Study drug for the non-study eye should not be in
the room before completing all study eye injection
procedures.
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PDR/DME Treatment
During Follow-Up
 It is expected that many eyes will require PDR or
DME treatment at some point during follow-up
• ~15% to 30% in the first 2 years are estimated
to meet PDR/DME endpoint
 Standardizing the criteria to treat and the
treatment itself will allow us to better evaluate
long-term visual acuity outcomes for the two
treatment strategies (prevention vs. observe and
treat)
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PDR Treatment Criteria
 Treatment for PDR must not be given unless:
1. The eye has high-risk characteristics:
o NVD greater than standard photograph 10A
(1/4 to 1/3 disc area)
or
o Any NVD with pre-retinal or vitreous hemorrhage
or
o NVE greater than ½ disc area with pre-retinal or vitreous
hemorrhage
2. The eye has VH requiring treatment that is presumed to
be from PDR
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PDR Treatment Criteria
 If high-risk criteria not met, RC confirmation of
the primary endpoint (NV within 7-modified
fields) should be obtained prior to initiating
treatment whenever possible.
 Treatment for NVE outside of the 7 modified
fields without the presence of pre-retinal or
vitreous hemorrhage is discouraged.
• If the investigator believes treatment for peripheral NV
is necessary, protocol chair review is required.
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Treatment for PDR
 PDR treatment will include intravitreous antiVEGF using DRCR.net Protocol S algorithm
• 3 q4-week injections
• Then each eye will be categorized into one of the
following 5 scenarios:
Category
Resolved
Improved from
last injection
Stable
Not fully treated
(worsening)
Failure/Futility
Injection
PRP
At investigator discretion
No
Required
No
Required 1st 2 times stable; then
at investigator discretion
No
Required
No
At investigator discretion
Yes
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DME Criteria and Treatment
 Treatment for CI-DME must not be given until the
primary endpoint for DME has been met:
 CI-DME on clinical exam with ≥10% increase in
central subfield thickness from baseline and:
• 1) at least 10 letter VA loss at a single visit, or
• 2) 5 to 9 letter VA loss at 2 consecutive visits.
 Once the above endpoint has been met, must
use DRCR.net Anti-VEGF Regimen for DME:
• Continue q4w injections as long as there is
improvement or worsening
• No injection if stable after 2 consecutive injections
and either “success” or >24w from initial injection
• Resume injection if worsen after withholding injection37
PDR/DME Treatment Visits
 Once PDR or DME treatment is initiated, visits are
every 4 weeks for first 6 months and then follow-up
can be extended if injections no longer needed
 Assessment Visits must still be completed on
schedule
Baseline
(0)
Month
1
Month
2
Month
12
Month
16
Month
20
Month
24
Month
25
Month
4
Month
8
1st PDR
Injection
Month
21
Month
22
Month
23
Month
26
Month
27
Month
28
Month
32
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DRCR.net Website
 Like all DRCR.net trials, the website will help
guide you through follow-up, including:
• Assessing eligibility (standard photos
provided)
• Assessing primary outcome (reminders when
imaging is needed)
• Criteria to initiate treatment PDR or DME
• Retreatment criteria once initiated
• Visit schedule
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Complete the Visit Form
 A treatment message will display for each
indication (prevention, PDR, DME)
 The investigator must make a treatment
determination based on all messages
 A second individual should confirm that the
treatment planned is not contrary to the messages
An injection of aflibercept in the left eye must be given at this visit.
An injection of Aflibercept should not be given for PDR at this visit since criteria to initiate anti-VEGF injections for PDR have not been met.
An injection of Aflibercept should not be given in the left eye for DME at this visit since criteria to initiate anti-VEGF injections for DME have
not been met.
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Complete the Visit Form
 You will then indicate whether an injection is planned AND
the indication
 If PDR or DME is entered as an indication for the first time,
the eye will have met that outcome and the retreatment
protocol for PDR or DME will be initiated
It is extremely important
that these questions are
answered accurately
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Treatment Message Questions
 Retreatment calculation depends on correct data
entry
 Prior missed visits/missing data could also impact
the calculations
 If at any time, you do not believe the message is
correct or you wish to deviate, CONTACT US!
An injection of Aflibercept should not be given for PDR at this visit since criteria to initiate anti-VEGF injections for PDR have not been met.
An injection of Aflibercept should not be given in the left eye for DME at this visit since criteria to initiate anti-VEGF injections for DME have
not been met.
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The Diabetic Retinopathy
Clinical Research Network
Only YOU can prevent vision loss!
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