1. Sponsored by the National Eye Institute,
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

2. 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 2

3. Minimizing Differential Bias
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

4. 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

5. 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

6. 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
Sham + Laser
Ranibizumab + Prompt Laser
Ranibizumab + Deferred Laser
Triamcinolone + Laser*
Injection Intervals (Weeks) 4W
Triam: 16W
Sham: 4W-intermittently
Injection Type
Always Sham
Always Real
Sometimes sham and sometimes real
Median (Quartiles)
# of injections/13 possible
11 (8,13)
8 (6, 10)
9 (6, 11)
Triam: 3 (2, 4) Sham: 5 (3, 7)

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.

8. 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

10. 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 10

11. 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:
real injections into the eye,
sham injection, meaning that a needle has not been injected into the eye, or
sometimes real and sometimes sham?

12. Results: Masking Questionnaire Participants with 1 Study Eye
Sham + Laser
N=105
Ran + Prompt Laser
Ran + Deferred Laser
N=112
Triam + Laser
N=118
Refused to answer question 4% 5% 2%
Response
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% 1%

13. Results: Masking Questionnaire Participants with 2 Study Eyes
Ranibizumab + Prompt Laser
N=42
Ranibizumab + Deferred Laser
Triamcinolone + Laser
N=37
Refused to answer question 4%
21% 5%
N=44
N=33
N=35
Injected eye
Correct response
84%
88%
31%
Incorrect response
16%
12%
69%
Sham eye
30%
27%
14%
70%
73%
86%

14. 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

15. Relationship of Masking and Visual Acuity – Sham + Laser Group
Change in Visual Acuity
Believed Sham Injections Always Given
Believed Real Injections were Always or 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%
Mean ± Standard Deviation
3.6 ± 8.1
6.0 ± 9.4

16. 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.

17. 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 study).

18. 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 assignment.