Date post: | 13-Apr-2017 |
Category: |
Healthcare |
Upload: | drsomduttprasad |
View: | 348 times |
Download: | 4 times |
Diabetic Retinopathy: Ranizizumab
Somdutt Prasad MS FRCSEd FRCOphth FACSSenior Consultant Ophthalmologist
AMRI Medical Centre & Fortis Medical CentreKolkata, India
[email protected] www.somduttprasad.com +91 7044 06 7754
A tale of two protocols
Protocol T
Protocol S
A tale
• a story about imaginary events : an exciting or dramatic story
• a story about someone's actual experiences
• an exciting story that may not be completely true
Diabetes
• 1550 BC - Ebers Papyrus of ancient Egypt
• 171 million worldwide• India – 2000 - 31.7 million• 366 million in 2030
– Maximum increase in India– 79.4 million India– 42.3 million China
Avastin Ziv –Aflibercept or Zaltrap
Aflibercept or EyeLeaRanibizumabLucentis / Accentrix
BMJ Open 2014;4:e004015 doi:10.1136/bmjopen-2013-004015
For the first time in at least five decades, diabetic retinopathy/maculopathy is no longer the leading cause of certifiable blindness among working age adults in England and Wales, having been overtaken by inherited retinal disorders
Main causes of severe sight impairment (blindness) in England and Wales in working age adults (age 16–64): certifications 2009–2010.
Liew G et al. BMJ Open 2014;4:e004015
©2014 by British Medical Journal Publishing Group
This change may be related to factors including the introduction of nationwide diabetic retinopathy screening programmes in England and Wales and improved glycaemic control
Ranibizumab 0.5 mg clinical use in DME supported by extensive
scientific evidence
PROTOCOL-IRETAIN
REVEALRESPOND
RESTORE
RESOLVE
RISE
RIDE
8 randomized controlled trials
1800patients
Sham and laser as control
Monthly, PRN and
T&E regimens
Duration* of up to 5
years
*Duration ranged from 1 to 5 years for the different studies
DME patient population is younger than nAMD patients, and has many associated co-morbid
conditions
1. Petrella RJ, et al. J Ophthalmol 2012;1591672. Bandello F. Presented at COPHy 2014, Lisbon,
Portugal
Average age at diagnosis
DME patients are of working age and require long-term
management80
years2
AMD
50-60 years1,2
DME
Disease driven by Age Diabetes2
DME patients often present with
co-morbidities
FDA approval - drugs for DME
• Ranibizumab - August 2012• Aflibercept – March 2015• Bevacizumab - unlicensed
Key points
• Ranibizumab injections – monthly for 3 visits – then as needed depending on VA (with
OCT) stability• Follow-up monthly for 6-12 months• Once visual stability maintained for
3 consecutive visits, follow-up intervals can be prolonged to between 2 and 4 months
Key points…Laser
• If response to anti-VEGF treatment is unsatisfactory – ‘rescue’
• DME not involving center
Key points…Vitrectomy
• IF VMT shown on spectral domain OCT AND Vision affected
• Role of adjunctive antiVEGF, steroid, laser
Steroids
• Triamcinolone– Pseudophakic eyes– Resistant cases
• Dexamethasone– Ozurdex
• Fluocinolone Acetonide– Iluvien, Retisert
American Journal of Ophthalmology 2014 157, 505-513.e8DOI: (10.1016/j.ajo.2013.11.012)
DRCR.net Protocol T: First head to head study in DME with three anti-VEGF agents
Study objective: compare the efficacy and safety of intravitreal aflibercept, intravitreal bevacizumab, and intravitreal ranibizumab for the treatment of
DME in eyes of 660 patients with VA between 20/32 and 20/320
ClinicalTrials.gov. Available from: http://clinicaltrials.gov/ct2/show/NCT01627249 [Accessed 27 October 2014]; Wells JA, et al. NEJM 2015, epub ahead of print
DME, diabetic macular edema; DRCR.net, Diabetic Retinopathy Clinical Research Network; NEI, National Eye Institute; VA, visual acuity; VEGF, vascular endothelial growth factor
Randomization
22
Bevacizumab (1.25 mg)N = 218
Aflibercept (2.0 mg)N = 224
Ranibizumab(0.3 mg)N = 218
Randomly Assigned Eyes(one per participant):
N = 660
N = 206 (94%)N = 208 (93%) N = 206 (94%)One Year
97%94% 96%One Year Excluding
Deaths
Baseline
Study design: RZB 0.3 mg / Aflibercept 2.0mg / BZB 1.25mg in a PRN regimen
660 patients with DME randomized 1:1:1
OCT, optical coherence tomography; PRN, pro re nata (as needed)Wells JA, et al. NEJM 2015;372:1193-203; Wells JA, et al. Ophthalmology 2016
Visits every 4 ± 1 weeks* Treatment at baseline and thereafter using defined retreatment criteria
Year 1
Year 2Visits every 4–16 weeks, depending on treatment course
*A minimum of 21 days between visits
At or after Week 24, focal/grid laser was initiated if OCT ≥250 μm or edema threatened the fovea and the eye was not improved on OCT or visual acuity from the last two consecutive injections
2.0 mg intravitreal aflibercept(n = 224)
1.25 mg intravitreal bevacizumab (n = 218)
0.3 mg intravitreal ranibizumab (n = 218)
1st year - Topline results
• Clinically meaningful VA improvement with all three medications– +13.3 letters with Aflibercept, – +11.2 with Ranibizumab, – +9.7 with Bevacizumab
1st year - Topline results…2
• When the initial visual-acuity loss was mild, there were no apparent differences, on average, among study groups.
• At worse levels of initial visual acuity, Aflibercept was more effective at improving vision
Recommendations
• If Bevacizumab (& Ranibizumab / Aflibercept are not affordable) is available appropriately compounded it should be used for eyes with good VA
• For eyes with poor VA at presentation Aflibercept is preferred
Discussion
• Bevacizumab used in trials (CATT, IVAN, Protocol T) – is Avastin +
• Same preparation not available to most ophthalmologists
Similar VA gains in overall population between aflibercept and ranibizumab at 2
years
Mea
n ch
ange
from
bas
elin
e in
vi
sual
acu
ity le
tter s
core
25
20
25
10
5
00 4 8 12 16 20 24 28 32 36 40 44 48 52 68 84 104
Aflibercept Bevacizumab Ranibizumab
Week
+12.8+12.3+10.0
At Year 1, the improvement was greater, but not clinically meaningful, with aflibercept than with the other two drugs.1 At Year 2, the difference in VA gain between aflibercept and ranibizumab was no longer significant (p = 0.47), indicating that a dose of ranibizumab
that is 60% of the 0.5 mg ex-U.S. approved dose produced equivalent VA gains over 2 years to the full aflibercept 2.0 mg dose.2
1. Wells JA, et al. NEJM 2015;372:1193-203; 2. Wells JA, et al. . Ophthalmology 2016
+13.5+11.5+10.0
No significant difference in the proportion of patients with ≥10- or ≥ 15-letter gains between aflibercept and ranibizumab at 2
years
≥10-letter gain ≥15-letter gain ≥10-letter loss ≥15-letter loss0
10
20
30
40
50
60
70
Aflibercept(n = 201)
Bevacizumab(n = 185)
Ranibizumab(n = 191)
Pro
porti
on o
f pat
ient
s (%
)
p = 0.22 p = 0.50
p = 0.51
p = 0.49 p = 0.15
p = 0.39
p = 0.70 p = 0.70
p = 0.70
p = 0.84 p = 0.84
p = 0.84
There were no significant differences in the proportion of patients that had a ≥10 or
≥15-letter improvementor worsening
Proportion of patients with ≥10- or ≥15-letter gain or loss
Wells JA, et al. Ophthalmology 2016;XX:1-9
OCT outcomes: bevacizumab less efficacious reducing macular edema compared with ranibizumab and aflibercept at 2 years
CSFT, central subfield thicknessWells JA, et al. Ophthalmology 2016;XX:1-9
Bevacizumab -126 µm
Ranibizumab -149 µmAflibercept -171 µm
p < 0.001*
p = 0.08
0 4 8 12 16 20 24 28 32 36 40 44 48 52 68 84 104
Mea
n ch
ange
from
ba
selin
e in
CS
FT (μ
m)
0
–50
–100
–150
–200
–250
Aflibercept Bevacizumab Ranibizumab
Week
*Also for aflibercept vs. bevacizumab
The difference in CSFT change from baseline between aflibercept and ranibizumab was no longer significant at Year 2
No difference in injection frequency over 2 yearsacross the three treatment arms
Aflibercept Bevacizumab
Ranibizumab
p valueaflibercept–ranibizumab
Total no. of injections in Year 11*
(maximum = 13) N = 208 N = 206 N = 206
Mean (standard deviation) 9.2 (2.0) 9.7 (2.3) 9.4 (2.1)
Median (25th, 75th percentile) 9 (8, 11) 10 (8, 12) 10 (8, 11) 0.19
Total no. of injections in Year 22 N = 201 N = 185 N = 192**
Mean (standard deviation) 5.0 (3.4) 5.5 (3.9) 5.4 (3.8)
Median (25th, 75th percentile) 5 (2, 7) 6 (2, 9) 6 (2, 9) 0.32
Total no. of injections over 2 years2 N = 201 N = 185 N = 192
Mean (standard deviation) 14.2 (4.6) 15.3 (5.3) 14.8 (5.0)
Median (25th, 75th percentile) 15 (11, 17) 16 (12, 20) 15 (11, 19) 0.081. Wells JA, et al. NEJM 2015;372:1193-2032. Wells JA, et al. . Ophthalmology 2016;XX:1-9
Percentage of laser treatments over 2 years
Aflibercept Bevacizumab Ranibizumabp value
aflibercept–ranibizumab
N = 208 N = 206 N = 206†
At least one focal/grid photocoagulation laser treatment between 24 weeks and 1 year1*, %
37% 56% 46% 0.058
N = 201 N = 185 N = 192At least one focal/grid photocoagulation laser treatment in Year 22, %
20% 31% 27% 0.12
At least one focal/grid photocoagulation laser treatment over 2 years2, %
41% 64% 52% 0.04
1. Wells JA, et al. NEJM 2015;372:1193-203;2. Wells JA, et al. . Ophthalmology 2016;XX:1-9
≥15 Letter Improvement at 2 YearsBaseline Visual Acuity 20/32 to 20/40
36Aflib
ercep
t
Bevac
izumab
Ranibizu
mab
20% 17% 19%
Observed Data
Perc
ent
Treatment Group Comparisons*
Adjusted Difference CIP-
Value
Aflibercept vs
Bevacizumab+1% -10% to +11% 0.89
Aflibercept vs
Ranibizumab+2% -8% to +11% 0.89
Ranibizumab vs
Bevacizumab-1% -11% to +10% 0.89
* P-values adjusted for baseline visual acuity and multiple comparisons
≥10 Letter Worsening at 2 YearsBaseline Visual Acuity 20/32 to 20/40
37Aflib
ercep
t
Bevac
izumab
Ranibizu
mab
4% 4% 1%
Observed Data
Perc
ent
Treatment Group Comparisons*
Adjusted Difference CIP-
Value
Aflibercept vs
Bevacizumab0 -6% to +5% 0.96
Aflibercept vs
Ranibizumab+3% -3% to +8% 0.55
Ranibizumab vs
Bevacizumab-3% -8% to +3% 0.55
* P-values adjusted for baseline visual acuity and multiple comparisons
≥15 Letter Improvement at 2 YearsBaseline Visual Acuity 20/50 or worse
38Afliberc
ept
Bevac
izumab
Ranibizu
mab
58%52% 55%
Observed Data
Perc
ent
Treatment Group Comparisons*
Adjusted Difference CIP-
ValueAflibercept
vs Bevacizumab
+8% -9% to +25% 0.74
Aflibercept vs
Ranibizumab+2% -11% to +15% 0.75
Ranibizumab vs
Bevacizumab+6% -8% to +20% 0.75
* P-values adjusted for baseline visual acuity and multiple comparisons
≥10 Letter Worsening at 2 YearsBaseline Visual Acuity 20/50 or worse
39Afliberc
ept
Bevac
izumab
Ranibizu
mab
5% 9%2%
Observed Data
Perc
ent
Treatment Group Comparisons*
Adjusted Difference CIP-
ValueAflibercept
vs Bevacizumab
-3% -10% to +3% 0.49
Aflibercept vs
Ranibizumab+2% -3% to +7% 0.49
Ranibizumab vs
Bevacizumab-5% -13% to +3% 0.33
* P-values adjusted for baseline visual acuity and multiple comparisons
RBZ 0.3 mg versus RBZ 0.5 mg?
Trend towards higher VA gain with ranibizumab 0.5 mg than 0.3 mg in patients with worst baseline
vision
(~20/80–20/160) (<20/200)
n = 112 n = 106 n = 119 n = 116 n = 21 n = 28
Zarbin M, Macular Society 2015
(≥ ~20/62.5)
Mea
n ch
ange
in B
CVA
fro
m b
asel
ine
to 1
2 m
onth
s (le
tters
)
Difference in VA gains between aflibercept and ranibizumab at
1 year predominantly driven by worst baseline VA patient group
Change in VA from baseline to Year 1 according to baseline VA
Visual acuity letter score(approximate Snellen equivalent)
Mea
n ch
ange
in v
isua
l acu
ity
lette
r sco
re a
t 1 y
ear
30
10
5
0
15
20
25
74–78(20/32)
69–73(20/40)
64–68(20/50)
54–63(20/63–20/80)
24–53(20/100–20/320)
Aflibercept Bevacizumab Ranibizumab
Aflibercept 54 52 36 29 37
Bevacizumab 41 63 35 38 29
Ranibizumab 46 59 32 37 32
N =
Wells JA, et al. NEJM 2015;372:1193–203
RISE and RIDE pooled data: time to first macular laser treatment by Month 36
0 5 10 15 20 25 30 4035
Pro
porti
on o
f pat
ient
s w
ith
mac
ular
lase
r tre
atm
ent
0.8
0.6
0.4
0.2
0.0
Time to first macular laser treatment (months)
Sham/0.5 mg Ranibizumab 0.3 mg Ranibizumab 0.5 mgTreatment Group:
Adamis AP, FDA advisory committee presentation. Available at http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/dermatologicandophthalmicdrugsadvisorycommittee/ucm314199.pdf
Sham/0.5mg 257 123 78 62 49 46 43 41 0Ranibizumab 0.3
mg250 189 159 149 136 125 123 118 0
Ranibizumab 0.5 mg
252 199 181 173 160 151 145 132 0
Subjects at risk
67.7%
31.0%
22.4%
72.0%
37.6%
27.4%
73.2%
38.8%
29.4%
Safety• Systemic APTC rates were higher in the
ranibizumab group, with a greater number of nonfatal strokes and vascular deaths in the ranibizumab group– Once adjusted for baseline
characteristics, the p-values shifted from p=0.047 to p=0.09 for aflibercept versus ranibizumab
– These findings are not consistent with previously reported clinical trials.
• Patient characteristics were, overall, well-balanced at baseline– No substantial differences were observed between
patients who did and did not complete the 2-year follow-up
• Compared with previous DME studies, Protocol T included patients with a higher baseline BCVA and lower CSFT– Median BCVA range: 68–69 letters (69 letters in patients
who completed Year 2 visit)– Median OCT central subfield thickness range: 376–390
µm (377–387 µm in patients who completed Year 2 visit)• Numerically more patients in the ranibizumab arm than the
aflibercept arm had a history of coronary artery disease at enrolment into the study– 34 (16%) versus 22 (10%), respectively
Participant baseline characteristics
Wells JA, et al. NEJM 2015;372:1193-203; Wells JA, et al. Ophthalmology 2016;XX:1-9
Summary Y2 Protocol T• Differences in VA gains observed at 1
year in the overall population and the subgroup of patients treated with ranibizumab or aflibercept with worse baseline BCVA were no longer statistically significant at 2 years
• The mean/median number of injections was similar of aflibercept (14.2/15) and ranibizumab (14.8/15).
Variabilty
DRCR.net Protocol S
Prompt PRP vs.
Ranibizumab 0.5 mg + Deferred PRP for PDR Study
Protocol S 2 year resultsRanibizumab• a viable treatment option for people
with proliferative diabetic retinopathy
• especially for individuals needing anti-VEGF for diabetic macular edema
Study:Protocol S
• 55 sites– 203 eyes PRP group– 109 eyes RZB
• 2 years –VA– 0.2 letters in PRP group– 2.8 letters in RZB group
• Vitrectomies– 15% PRP group– 4% RZB group
51
0 16 32 52 68 84 104
Without “Baseline DME”
Visit Week
0 16 32 52 68 84 104-4-202468
101214
With “Baseline DME”
Ranibizumab Group PRP Group
Visit Week
Mea
n Vi
sual
Acu
ity C
hang
e(L
ette
r Sco
re)
+2
+7.9
- 0.5
+1.8
N = 42 N = 33 N = 147N = 46 N = 37 N = 155 N = 130
N = 126
*Outlying values were truncated to 3 SD from the mean
Mean Change in Visual AcuityStratified by Baseline DME
Advantages of PRP• 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
• Cost less than ranibizumab injections• No risk of endophthalmitis• No risk of systemic exposure to anti-VEGF
Advantages of RanibizumabMean 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 other
anti-VEGF agents (bevacizumab or aflibercept)
Thank You Somdutt PrasadKolkata +917044067754
www.somduttprasad.com