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Minimal sufficient balance randomization for sequential randomized controlled trial designs: results from the ESCAPE trial

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      We describe the implementation of minimal sufficient balance randomization, a covariate-adaptive randomization technique, used for the “Endovascular treatment for Small Core and Anterior circulation Proximal occlusion with Emphasis on minimizing CT to recanalization times” (ESCAPE) trial.


      The ESCAPE trial is a prospective, multicenter, randomized clinical trial that enrolled subjects with the following main inclusion criteria: less than 12 h from symptom onset, age 18 years or older, baseline NIHSS score > 5, ASPECTS score > 5 and computed tomography angiography (CTA) evidence of carotid T/L or M1-segment middle cerebral artery (MCA) occlusion, and at least moderate collaterals by CTA. Patients were randomized using a real-time, dynamic, Internet-based, minimal sufficient balance randomization method that balanced the study arms with respect to baseline covariates including age, sex, baseline NIHSS score, site of arterial occlusion, baseline ASPECTS score and treatment with intravenously administered alteplase.


      Permutation-based tests of group differences confirmed group balance across several baseline covariates including sex ( p = 1.00), baseline NIHSS score ( p = 0.95), site of arterial occlusion ( p = 1.00), baseline ASPECTS score ( p = 0.28), treatment with intravenously administered alteplase ( p = 0.31), and age ( p = 0.67).


      Results from the ESCAPE trial demonstrate the feasibility and the benefit of this covariate adaptive randomization scheme in small-sample trials and for data monitoring endeavors.

      Trial registration

      ESCAPE trial – NCT01778335 – at Registered on 29 January 2013.

      Electronic supplementary material

      The online version of this article (doi:10.1186/s13063-017-2264-1) contains supplementary material, which is available to authorized users.

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      Most cited references 22

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      Randomized assessment of rapid endovascular treatment of ischemic stroke.

       Oh Young Bang,  ,  D. Hill (2015)
      Among patients with a proximal vessel occlusion in the anterior circulation, 60 to 80% of patients die within 90 days after stroke onset or do not regain functional independence despite alteplase treatment. We evaluated rapid endovascular treatment in addition to standard care in patients with acute ischemic stroke with a small infarct core, a proximal intracranial arterial occlusion, and moderate-to-good collateral circulation. We randomly assigned participants to receive standard care (control group) or standard care plus endovascular treatment with the use of available thrombectomy devices (intervention group). Patients with a proximal intracranial occlusion in the anterior circulation were included up to 12 hours after symptom onset. Patients with a large infarct core or poor collateral circulation on computed tomography (CT) and CT angiography were excluded. Workflow times were measured against predetermined targets. The primary outcome was the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days. A proportional odds model was used to calculate the common odds ratio as a measure of the likelihood that the intervention would lead to lower scores on the modified Rankin scale than would control care (shift analysis). The trial was stopped early because of efficacy. At 22 centers worldwide, 316 participants were enrolled, of whom 238 received intravenous alteplase (120 in the intervention group and 118 in the control group). In the intervention group, the median time from study CT of the head to first reperfusion was 84 minutes. The rate of functional independence (90-day modified Rankin score of 0 to 2) was increased with the intervention (53.0%, vs. 29.3% in the control group; P<0.001). The primary outcome favored the intervention (common odds ratio, 2.6; 95% confidence interval, 1.7 to 3.8; P<0.001), and the intervention was associated with reduced mortality (10.4%, vs. 19.0% in the control group; P=0.04). Symptomatic intracerebral hemorrhage occurred in 3.6% of participants in intervention group and 2.7% of participants in control group (P=0.75). Among patients with acute ischemic stroke with a proximal vessel occlusion, a small infarct core, and moderate-to-good collateral circulation, rapid endovascular treatment improved functional outcomes and reduced mortality. (Funded by Covidien and others; ESCAPE number, NCT01778335.).
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        Sequential treatment assignment with balancing for prognostic factors in the controlled clinical trial.

        In controlled clinical trials there are usually several prognostic factors known or thought to influence the patient's ability to respond to treatment. Therefore, the method of sequential treatment assignment needs to be designed so that treatment balance is simultaneously achieved across all such patients factor. Traditional methods of restricted randomization such as "permuted blocks within strata" prove inadequate once the number of strata, or combinations of factor levels, approaches the sample size. A new general procedure for treatment assignment is described which concentrates on minimizing imbalance in the distributions of treatment numbers within the levels of each individual prognostic factor. The improved treatment balance obtained by this approach is explored using simulation for a simple model of a clinical trial. Further discussion centers on the selection, predictability and practicability of such a procedure.
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          Issues in outcomes research: an overview of randomization techniques for clinical trials.

          To review and describe randomization techniques used in clinical trials, including simple, block, stratified, and covariate adaptive techniques. Clinical trials are required to establish treatment efficacy of many athletic training procedures. In the past, we have relied on evidence of questionable scientific merit to aid the determination of treatment choices. Interest in evidence-based practice is growing rapidly within the athletic training profession, placing greater emphasis on the importance of well-conducted clinical trials. One critical component of clinical trials that strengthens results is random assignment of participants to control and treatment groups. Although randomization appears to be a simple concept, issues of balancing sample sizes and controlling the influence of covariates a priori are important. Various techniques have been developed to account for these issues, including block, stratified randomization, and covariate adaptive techniques. Athletic training researchers and scholarly clinicians can use the information presented in this article to better conduct and interpret the results of clinical trials. Implementing these techniques will increase the power and validity of findings of athletic medicine clinical trials, which will ultimately improve the quality of care provided.

            Author and article information

            [1 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Department of Community Health Sciences and O’Brien Institute for Public Health, Cumming School of Medicine, , University of Calgary, ; Calgary, AB Canada
            [2 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Department of Clinical Neurosciences, , Cumming School of Medicine, University of Calgary, ; 3300 Hospital Drive NW, Calgary, AB T2N 4N1 Canada
            [3 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Clinical Research Unit, Cumming School of Medicine, , University of Calgary, ; Calgary, AB Canada
            [4 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Hotchkiss Brain Institute, Cumming School of Medicine, , University of Calgary, ; Calgary, AB Canada
            [5 ]ISNI 0000 0004 1936 7697, GRID grid.22072.35, Department of Radiology, Cumming School of Medicine, , University of Calgary, ; Calgary, AB Canada
            +1 403 944 8065 ,
            BioMed Central (London )
            2 November 2017
            2 November 2017
            : 18
            29096678 5667454 2264 10.1186/s13063-017-2264-1
            © The Author(s). 2017

            Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.

            Funded by: FundRef, Covidien;
            Funded by: FundRef, Alberta Innovates - Health Solutions;
            Funded by: Heart and Stroke Foundation Alberta
            Funded by: FundRef, Institute of Circulatory and Respiratory Health;
            Funded by: FundRef, Alberta Health Services;
            Funded by: FundRef, Hotchkiss Brain Institute, University of Calgary;
            Funded by: FundRef, University of Calgary;
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            © The Author(s) 2017


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