AMD updated - page 182

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the same procedures with exception of the scleral pen-
etration performed in the group of intravitreous injection
simulation. The ophthalmologist performing the injec-
tions was not authorized to undertake the patients’ follow
up in order to guarantee the researcher’s concealment.
For ethical reasons, treatment with PDT (Visudyne
®
) was
allowed in some clinical centers in patients with mainly
classic lesions, in all branches of the study and according
to the researcher’s criteria.
The primary study outcome measure was the proportion
of patients who lost <15 letters of VA at the end of week
54. Additional efficacy end-points included: proportion of
patients maintaining or gaining > 0, 5, 10, or 15 letters, or
losing > 30 letters (severe vision loss); mean changes in VA
from baseline to week 54, and the proportion of patients
with VA of 20/200 or worse in the study eye at week 54.
In total, 1186 subjects received at least one study treat-
ment (mean, 8.5 of 9 possible injections)
(61)
. All pegap-
tanib doses were superior to sham with regard to loss of <
15 letters of VA: 70, 71 and 65% for 0.3 mg (p < 0.001),
1 mg (p < 0.001) and 3 mg (p < 0.03) groups, respec-
tively, versus 55% for sham. Overall, the 0.3 mg dose
was found to be most effective and further discussion is
limited to the 0.3 mg (approved) dose.
Pegaptanib was significant superior to sham in the per-
centage of subjects maintaining or gaining 0, 5, 10 or
15 lines of vision (p <0.05)
(71)
. Pegaptanib treated sub-
jects were less likely to have severe vision loss (10 versus
22%, p < 0.001) or progress to VA < 20/200 (38 versus
56%; < 0.001). Mean VA loss at week 54 was 7.95 let-
ters for pegaptanib compared with 15.05 letters for sham
(p < 0.05; 47% relative difference). Treatment effect was
independent of angiographic subtype, baseline VA and
lesion size, sex, age, race or iris color
(71)
.
VISION
trial had an extension for 48 additional weeks.
Those patients receiving pegaptanib were randomized
to either continue their pegaptanib dose or discontinue
treatment. Subjects initially receiving sham were reran-
domized to continue or discontinue sham or to receive
one of the three pegaptanib doses. Overall, 1053 sub-
jects were rerandomized; 941 (89%) were assessed at
week 102 (mean, 15.7 of 17 possible total injections).
Compared with sham (sham over 2 years or randomized
to discontinue sham in year 2), more of those receiving
pegaptanib 0.3 mg during 2 years lost < 15 letters (45
versus 59%; p < 0.05). Subjects continuing pegaptanib
had the greatest benefits
(72)
.
An exploratory analysis was conducted to assess the
vision benefit of treating early subfoveal choroidal neo-
vascularization secondary to AMD with pegaptanib in
the
VISION
trials. Subjects were grouped according
to two different definitions of early disease. Group 1
included those with lesions < 2 disc areas and a baseline
VA of ≥ 54 letters, no prior PDT or laser photocoagula-
tion and scarring or atrophy (n = 34 for pegaptanib 0.3
mg and n = 28 for sham). Group 2 included those with
occult with no classic CNV, with an absence of lipid
and worse VA in the study eye versus the fellow eye (n
= 30 for pegaptanib 0.3 mg and n = 35 for sham)
(70)
.
At week 54, the responder rates (lost < 15 letters) were
significantly higher for pegaptanib versus sham (group
1: 76 versus 50%; p = 0.03; group 2: 80 versus 57%;
p = 0.05). Pegaptanib-treated subjects in group 1 were
approximately 10-times less likely to have severe vision
loss than those receiving sham (3 versus 29%; p < 0.01);
differences for group 2 were not as large (10 versus 17%;
p = 0.17). On average, subjects in both pegaptanib-
treated groups lost less VA (group 1: -5.6 versus -16.6
letters; p < 0.01; group 2: -4.0 versus -16.7 letters; p <
0.006). Notably, among those receiving pegaptanib 0.3
mg 12% of subjects in group 1 and 20% in group 2
gained ≥ 3 lines of vision, compared with 6% in the
VISION study. These findings suggest that pegaptanib
treatment early in the course of wet AMD may improve
visual outcomes
(65, 70)
.
4.3 Safety
During the
VISION
study and the second and third year
extension no increased risk of systemic adverse events was
identified, but patients with high risk of cardiovascular and
cerebrovascular events were excluded from the clinical trials.
Most adverse events reported in the study eyes were
attributed to the injection procedure. The low risk of
serious injection-related adverse events, such as endo-
phthalmitis, traumatic cataract and retinal detachment
were found to be modifiable with injection protocols
changes during the study (Table 1).
Because VEGF is involved in a wide range of physiologi-
cal processes, inhibition of this factor raises many safety
concerns particularly in the context of extended treat-
ment regimens
(75-77)
.
The pegaptanib sodium selectively inhibits the most
biologically active isoform of VEGF (VEGF 165), and
according to some authors this quality allows a theoreti-
cal advantage in terms of safety comparing to the non-
selective anti-VEGF like ranibizumab and bevacizumab.
The systemic risks of non-selective VEGF inhibition
have been illustrated with the use of intravenous injec-
tion of bevacizumab for the treatment of metastatic
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