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An Evaluation of Study Participant
Masking of Intraocular Injections in a
Randomized Clinical Trial
Sponsored by the National Eye Institute,
National Institutes of Health, U.S. Department of Health and Human Services
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Background
Bias in Clinical Trials
 Minimizing bias in a randomized clinical trial is a
critical consideration during trial design
 Randomization alone does not ensure unbiased
experiment
 Types of Bias:
• Non-differential bias: Noise affecting outcomes of
treatment groups equally
• Differential bias: Systematic differences in
outcomes between treatment groups
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Background
Minimizing Differential Bias
 Participant masking is one method of minimizing
differential bias
 The decision on whether to mask study participants
to treatment should be based on:
 Subjectivity of trial outcomes
 Type of treatment
 Disease type
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Purpose
Describe a trial design which attempted to
mask participants to treatment allocation
Discuss rationale for masking in the trial
Evaluate success of masking study
participant to treatment assignment
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Study Design
Objective: Evaluate efficacy of 4 treatment groups on
diabetic macular edema (measured by visual acuity)
Randomized Clinical Trial (multi-center)
Sham Injection
+Prompt Laser
Ranibizumab
Injection
+Prompt Laser
Ranibizumab
Injection
+Deferred Laser
Triamcinolone
Injection
+Prompt Laser
Visits every 4 weeks through 52 weeks
52 Week Visit Primary Outcome
Study Design
 Participants with 1 study eye; randomized to 1 of 4
treatment groups
 Participants with 2 study eyes; one eye randomized to 1 of
the 3 study drug groups and sham+prompt laser in the
other
Injection Intervals
(Weeks)
Injection Type
Sham +
Laser
Ranibizumab +
Prompt Laser
Ranibizumab +
Deferred Laser
4W
4W
4W
Always
Sham
Always Real
Always Real
8 (6, 10)
9 (6, 11)
Median (Quartiles)
11 (8,13)
# of injections/13 possible
Triamcinolone +
Laser*
Triam: 16W
Sham: 4Wintermittently
Sometimes sham
and sometimes
real
Triam: 3 (2, 4)
Sham: 5 (3,
6 7)
Masking
 Participants were masked through the 1-year primary
outcome except those in the ranibizumab + deferred
laser group in either eye
 DRCR.net investigators believed that a successful sham
laser treatment was not feasible.
 Investigators were not masked.
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Injection Procedure
 Pre/post injection procedures for sham and
intraocular injections were identical
 Providone iodine prep of the conjunctiva
 Pre-, peri-, or post-injection antibiotics were at
investigator discretion. Comparing real
injections with sham injections, antibiotics were
given:
 Pre- and post-injection 34% vs. 27% of the time
 Only pre-injection 9% vs. 12% of the time
 Only post-injection 21% vs. 14% of the time
 For sham, the hub of a syringe without a needle
was pressed against the conjunctival surface
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Why Mask
 Visual acuity testing requires a study participant
response and knowledge of treatment group could
affect test performance if he/she believes that the
better or worse treatment was received
 Improving diabetes control can have an effect on
diabetic macular edema and subsequently visual
acuity. Knowledge of the treatment group could affect
participant’s behavior in a way that could influence
the course of the disease and the primary outcome
measure
 Investigators believed masking would work
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Assessing Masking Success
 At the completion of the 1-year visit, a
questionnaire was administered to each participant
by the study coordinator;
 Do you think the injections you have been
getting in the [left/right] eye during the study
have been:
1)real injections into the eye,
2)sham injection, meaning that a needle has
not been injected into the eye, or
3)sometimes real and sometimes sham?
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Results: Masking Questionnaire
Participants with 1 Study Eye
Sham +
Laser
N=105
Ran +
Prompt
Laser
N=105
Ran +
Deferred
Laser
N=112
Triam +
Laser
N=118
4%
5%
5%
2%
N=101
N=100
N=106
N=116
Always Real
72%
88%
90%
55%
Sometimes real/
sometimes sham
18%
12%
7%
44%
Always Sham
10%
0
4%
1%
Refused to answer
question
Response
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Results: Masking Questionnaire
Participants with 2 Study Eyes
Ranibizumab +
Prompt Laser
N=42
Ranibizumab +
Deferred Laser
N=42
Triamcinolone
+ Laser
N=37
4%
21%
5%
N=44
N=33
N=35
Correct response
84%
88%
31%
Incorrect response
16%
12%
69%
Correct response
30%
27%
14%
Incorrect response
70%
73%
86%
Refused to answer
question
Injected eye
Sham eye
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Results - Subgroups
Correctness of response within treatment group did
not appear to differ by:
• Prior injection for DME
• Prior laser for DME
• Baseline visual acuity
• Age
• Gender
• Race and ethnicity
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Relationship of Masking and Visual
Acuity – Sham + Laser Group
Change in Visual Acuity
Believed
Believed Real
Sham
Injections were
Injections
Always or
Always Given Sometimes Given
Distribution of visual acuity change
Improved ≥ 5 letters (≥ 1 line): N=60
10%
90%
Changed ± 4 letters: N=29
7%
93%
Worsened ≥ 5 letters (≥ 1 line): N=12
17%
83%
3.6 ± 8.1
6.0 ± 9.4
Mean ± Standard Deviation
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Discussion
 The results suggest that very few participants (4%)
believed they received only sham injections in a
randomized trial comparing sham ocular injections
with real ocular injections.
 Even when visual acuity outcomes did not improve
or worsened, the study participant’s perception as
to whether a sham or real injection was received did
not appear to be influenced.
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Summary
 Compared with the participants who received sham
injections only, participants in the treatment group
that received both real and sham injections in the
same eye more often thought that a sham injection
was at least sometimes given (28% vs. 45%, P-value
= 0.009). This may imply that a participant is more
likely to identify a sham injection when also
receiving a real injection in the same eye.
 It appears that participants with two study eyes
believe sham injections were always given in the
sham eye (24% in this study) compared with
participants with only one study eye (10% in this
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study).
Conclusion
 Sham intraocular injections can mask participants to
treatment group assignments successfully when a
procedure that attempts to mimic a real injection is
followed.
 Although still successful, the success of masking
potentially is reduced for participants who receive real
injections in 1 eye and sham injections in the other, or
receive both a sham injection and a real injection in the
same eye.
 This study did not assess the bias in measuring visual
acuity that may occur when participants receiving
intraocular injections are not masked to treatment
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assignment.