Blinding of outcome assessors and its association with outcome in a randomized open-label stroke trial

Nadinda A.M. van der Ende*, Bob Roozenbeek, Joseph P. Broderick, Pooja Khatri, Hester F. Lingsma, Diederik W.J. Dippel

*Corresponding author for this work

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Abstract

Background: It is challenging for outcome assessors to remain blinded during outcome assessment in trials with prospective randomized open blinded endpoint (PROBE) design. If assessors are able to guess the correct treatment allocation more often than expected based on chance, the assessors may have been not properly blinded. Aims: We aimed to assess blinding of outcome assessors in a stroke trial with PROBE design and its association with outcome. Methods: We used data of the Interventional Management of Stroke (IMS) III trial. The modified Rankin Scale (mRS) at 90 days was assessed by local assessors who were unaware of treatment allocation. To assess success of blinding, each assessor was asked to guess the patient’s treatment allocation. We assessed whether the percentage of correct guesses was higher than chance (i.e. 50%). The association between correctly guessed treatment allocation and the mRS at 90 days was analyzed with ordinal logistic regression stratified by treatment allocation. We tested for interaction of correctly versus incorrectly guessed treatment allocation with actual treatment allocation on the mRS. Patients with missing data on guessed treatment allocation and patients who died prior to 90-day assessment were excluded. Results: In total, 459 patients were included in this study. The assessors guessed the correct treatment allocation significantly more often than expected (267/459, 58.2%, one-sided p = 0.0003). Correctly guessed treatment allocations were associated with better mRS scores in the intervention group (common odds ratio (cOR): 2.28, 95% confidence interval (CI): 1.50–3.48) and with worse mRS scores in the control group (cOR: 0.47, 95% CI: 0.27–0.83) (pinteraction < 0.001). Conclusions: Assessors may not always be truly blinded for treatment allocation in clinical trials, and their guesses may be associated with outcome. Although causality between the assessors’ guess and patient outcome cannot be determined, future trials with subjective outcome should make efforts to ensure blinding and should report their blinding method and the success of blinding like the IMS III trial. Clinical Trial Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00359424.

Original languageEnglish
JournalInternational Journal of Stroke
DOIs
Publication statusE-pub ahead of print - 28 Sep 2022

Bibliographical note

Funding Information:
The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: Diederik Dippel reports funding from the Dutch Heart Foundation, Brain Foundation Netherlands, The Netherlands Organisation for Health Research and Development, and Health Holland Top Sector Life Sciences & Health and unrestricted grants from Penumbra Inc., Stryker, Medtronic, Thrombolytic Science, LLC, and Cerenovus for research, all paid to institution. Pooja Khatri reports grant funding from NIH and Cerenovus and consulting fees from Lumosa, Bayer, Diamedica, and Basking Biosciences. The other authors report no conflicts.

Funding
The author(s) disclosed receipt of the following financial support
for the research, authorship, and/or publication of this article: The
IMS (Interventional Management of Stroke) III trial was funded
by National Institutes of Health and National Institute of
Neurological Disorders and Stroke: grant numbers: University of
Cincinnati (U01NS052220) and Medical University of South
Carolina (U01NS054630 and U01NS077304). Genentech supplied the study drug used for intraarterial tissue-type plasminogen
activator treatment in the endovascular group. EKOS, Concentric
Medical, and Cordis supplied study catheters during protocol versions 1 to 3. In the United States, IMS III trial investigator meeting support was provided in part by Genentech, EKOS, and
Concentric Medical. In Europe, IMS III trial investigator meeting
support was provided in part by Boehringer Ingelheim. All funding sources had no role in the study design and conduct; collection, management, analysis, and interpretation of data; preparation,
review, or approval of the article; and decision to submit the article for publication.

Publisher Copyright:
© 2022 World Stroke Organization.

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