Presentation on theme: "Sponsored by the National Eye Institute,"— Presentation transcript:
1 Sponsored by the National Eye Institute, An Evaluation of Study Participant Masking of Intraocular Injections in a Randomized Clinical TrialSponsored 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 designRandomization alone does not ensure unbiased experimentTypes of Bias:Non-differential bias: Noise affecting outcomes of treatment groups equallyDifferential bias: Systematic differences in outcomes between treatment groups2
3 Minimizing Differential Bias BackgroundMinimizing Differential BiasParticipant masking is one method of minimizing differential biasThe decision on whether to mask study participants to treatment should be based on:Subjectivity of trial outcomesType of treatmentDisease type
4 PurposeDescribe a trial design which attempted to mask participants to treatment allocationDiscuss rationale for masking in the trialEvaluate 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 LaserRanibizumab Injection+Prompt LaserRanibizumab Injection+Deferred LaserTriamcinolone Injection+Prompt LaserVisits every 4 weeks through 52 weeks52 Week Visit Primary Outcome
6 Study DesignParticipants with 1 study eye; randomized to 1 of 4 treatment groupsParticipants with 2 study eyes; one eye randomized to 1 of the 3 study drug groups and sham+prompt laser in the otherSham + LaserRanibizumab + Prompt LaserRanibizumab + Deferred LaserTriamcinolone + Laser*Injection Intervals (Weeks)4WTriam: 16WSham: 4W-intermittentlyInjection TypeAlways ShamAlways RealSometimes sham and sometimes realMedian (Quartiles)# of injections/13 possible11 (8,13)8 (6, 10)9 (6, 11)Triam: 3 (2, 4) Sham: 5 (3, 7)
7 MaskingParticipants were masked through the 1-year primary outcome except those in the ranibizumab + deferred laser group in either eyeDRCR.net investigators believed that a successful sham laser treatment was not feasible.Investigators were not masked.
8 Injection ProcedurePre/post injection procedures for sham and intraocular injections were identicalProvidone iodine prep of the conjunctivaPre-, 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 timeOnly pre-injection 9% vs. 12% of the timeOnly post-injection 21% vs. 14% of the timeFor sham, the hub of a syringe without a needle was pressed against the conjunctival surface
10 Why MaskVisual 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 receivedImproving 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 measureInvestigators believed masking would work10
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, orsometimes real and sometimes sham?
12 Results: Masking Questionnaire Participants with 1 Study Eye Sham + LaserN=105Ran + Prompt LaserRan + Deferred LaserN=112Triam + LaserN=118Refused to answer question4%5%2%ResponseN=101N=100N=106N=116Always Real72%88%90%55%Sometimes real/ sometimes sham18%12%7%44%Always Sham10%1%
13 Results: Masking Questionnaire Participants with 2 Study Eyes Ranibizumab + Prompt LaserN=42Ranibizumab + Deferred LaserTriamcinolone + LaserN=37Refused to answer question4%21%5%N=44N=33N=35Injected eyeCorrect response84%88%31%Incorrect response16%12%69%Sham eye30%27%14%70%73%86%
14 Results - SubgroupsCorrectness of response within treatment group did not appear to differ by:Prior injection for DMEPrior laser for DMEBaseline visual acuityAgeGenderRace and ethnicity
15 Relationship of Masking and Visual Acuity – Sham + Laser Group Change in Visual AcuityBelieved Sham Injections Always GivenBelieved Real Injections were Always or Sometimes GivenDistribution of visual acuity changeImproved ≥ 5 letters (≥ 1 line): N=6010%90%Changed ± 4 letters: N=297%93%Worsened ≥ 5 letters (≥ 1 line): N=1217%83%Mean ± Standard Deviation3.6 ± 8.16.0 ± 9.4
16 DiscussionThe 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 SummaryCompared 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 ConclusionSham 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.