Adaptive Randomization Method to Prevent Extreme Instances of Group Size and Covariate Imbalance in Stroke Trials.

BACKGROUND: A recent review of randomization methods used in large multicenter clinical trials within the National Institutes of Health Stroke Trials Network identified preservation of treatment allocation randomness, achievement of the desired group size balance between treatment groups, achievement of baseline covariate balance, and ease of implementation in practice as critical properties required for optimal randomization designs. Common-scale minimal sufficient balance (CS-MSB) adaptive randomization effectively controls for covariate imbalance between treatment groups while preserving allocation randomness but does not balance group sizes. This study extends the CS-MSB adaptive randomization method to achieve both group size and covariate balance while preserving allocation randomness in hyperacute stroke trials. METHODS: A full factorial in silico simulation study evaluated the performance of the proposed new CSSize-MSB adaptive randomization method in achieving group size balance, covariate balance, and allocation randomness compared with the original CS-MSB method. Data from 4 existing hyperacute stroke trials were used to investigate the performance of CSSize-MSB for a range of sample sizes and covariate numbers and types. A discrete-event simulation model created with AnyLogic was used to dynamically visualize the decision logic of the CSSize-MSB randomization process for communication with clinicians. RESULTS: The proposed new CSSize-MSB algorithm uniformly outperformed the CS-MSB algorithm in controlling for group size imbalance while maintaining comparable levels of covariate balance and allocation randomness in hyperacute stroke trials. This improvement was consistent across a distribution of simulated trials with varying levels of imbalance but was increasingly pronounced for trials with extreme cases of imbalance. The results were consistent across a range of trial data sets of different sizes and covariate numbers and types. CONCLUSIONS: The proposed adaptive CSSize-MSB algorithm successfully controls for group size imbalance in hyperacute stroke trials under various settings, and its logic can be readily explained to clinicians using dynamic visualization.

Large vessel occlusive stroke with milder baseline severity shows better collaterals and reduced harm from thrombectomy transfer delays.

BACKGROUND: Patients with large vessel occlusion (LVO) stroke presenting with milder baseline clinical severity are common and require endovascular thrombectomy. However, such patients are difficult to recognize using pre-hospital severity-based triage tools and therefore are likely to require a secondary inter-hospital transfer if transported to a non-thrombectomy center. Given the potential for milder severity to represent better underlying cerebrovascular collateral circulation, it is unknown whether transfer delays are still associated with poorer post-stroke outcomes in this patient group. AIMS: We primarily aimed to examine whether the harmful effect of inter-hospital transfer delay for thrombectomy was different for LVO patients with mild or severe deficits. Secondarily, we also investigated whether imaging markers of collateral circulation were different between severity groups. METHODS: Registry data from two large Australian thrombectomy centers were used to identify all directly presenting and secondarily transferred LVO patients undergoing thrombectomy, divided into those with lower (NIHSS < 10) and higher (NIHSS ⩾ 10) baseline deficits. The primary outcome was the functional independence or return to baseline defined as modified Rankin Scale 0-2 or baseline at 90 days. Patients with complete baseline CT-perfusion data were analyzed for imaging markers of collateral circulation by baseline severity group. RESULTS: A total of 1210 LVO patients undergoing thrombectomy were included, of which 273 (22.6%) had lower baseline severity. Despite similar thrombolysis and recanalization rates, transferred patients had lower odds of achieving the primary outcome compared to the primary presentation to a thrombectomy center, where baseline severity was higher (adjusted odds ratio (aOR) 0.759 (95% CI 0.576-0.999)), but not when severity was lower (aOR 1.357 (95% CI 0.764-2.409), p-interaction = 0.122). In the imaging analysis of 436 patients, those with milder severity showed smaller median ischemic core volumes (12.6 (IQR 0.0-17.9) vs 27.5 (IQR 6.5-37.1) mL, p < 0.001)), higher median perfusion mismatch ratio (10.8 (IQR 4.8-54.5) vs 6.6 (IQR 3.5-16.5), p < 0.001), and lower median hypoperfusion intensity ratio (0.25 (IQR 0.18-0.38) vs 0.40 (IQR 0.22-0.57), p < 0.001). DISCUSSION: Patients receiving secondary inter-hospital transfer for thrombectomy had poorer outcomes compared to those presenting directly to a thrombectomy center if baseline deficits were severe, but this difference was not observed when baseline deficits were milder. This result may potentially be due to our secondary findings of significantly improved collateral circulation markers in lower-severity LVO patients. As such, failure of pre-hospital screening tools to detect lower-severity LVO patients for pre-hospital bypass to a thrombectomy center may not necessarily deleteriously affect outcome. DATA ACCESS STATEMENT: Anonymized data not published within this article will be made available on request from any qualified investigator.

Reporting and analysis of process-of-care time measures in clinical trials for hyperacute stroke interventions: a scoping review protocol.

OBJECTIVE: The objective of this scoping review is to investigate the reporting and comparison of process-of-care time measures in hyperacute stroke trials and systematic reviews of trials (subsequently referred to as "studies"). INTRODUCTION: Stroke is a leading cause of death and disability worldwide. A crucial factor in determining the effectiveness of stroke care in improving patient outcomes is time; therefore, time measures are frequently reported in studies of hyperacute stroke interventions. However, there is inconsistency in how these measures are reported and compared. Furthermore, there is a lack of clarity in how compatible the reporting methods are with the statistical analysis methods. INCLUSION CRITERIA: This scoping review will include studies that report and/or compare time measures between key events of interest in the delivery of hyperacute stroke care. Studies of thrombolytic therapy and/or thrombectomy, as well as controlled trials of mobile stroke unit interventions, will be included. METHODS: The scoping review will be conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Reviews (PRISMA-ScR) and the JBI methodology for scoping reviews. The search will be executed in MEDLINE (PubMed), Embase (Ovid), and clinical trial registries ANZCTR, ISRCTN, and ClinicalTrials.gov. Title and abstract screening will be followed by full-text screening and subsequent data extraction from eligible studies. The results from this scoping review will be presented in tables and narratively summarized. REVIEW REGISTRATION: Open Science Framework https://osf.io/y98wz.

Comparison of tenecteplase with alteplase for the early treatment of ischaemic stroke in the Melbourne Mobile Stroke Unit (TASTE-A): a phase 2, randomised, open-label trial.

BACKGROUND: Mobile stroke units (MSUs) equipped with a CT scanner reduce time to thrombolytic treatment and improve patient outcomes. We tested the hypothesis that tenecteplase administered in an MSU would result in superior reperfusion at hospital arrival, when compared with alteplase. METHODS: The TASTE-A trial is a phase 2, randomised, open-label trial at the Melbourne MSU and five tertiary hospitals in Melbourne, VIC, Australia. Patients (aged ≥18 years) with ischaemic stroke who were eligible for thrombolytic treatment were randomly allocated in the MSU to receive, within 4·5 h of symptom onset, either standard-of-care alteplase (0·9 mg/kg [maximum 90 mg], administered intravenously with 10% as a bolus over 1 min and 90% as an infusion over 1 h), or the investigational product tenecteplase (0·25 mg/kg [maximum 25 mg], administered as an intravenous bolus over 10 s), before being transported to hospital for ongoing care. The primary outcome was the volume of the perfusion lesion on arrival at hospital, assessed by CT-perfusion imaging. Secondary safety outcomes were modified Rankin Scale (mRS) score of 5 or 6 at 90 days, symptomatic intracerebral haemorrhage and any haemorrhage within 36 h, and death at 90 days. Assessors were masked to treatment allocation. Analysis was by intention-to-treat. The trial was registered with ClinicalTrials.gov, NCT04071613, and is completed. FINDINGS: Between June 20, 2019, and Nov 16, 2021, 104 patients were enrolled and randomly allocated to receive either tenecteplase (n=55) or alteplase (n=49). The median age of patients was 73 years (IQR 61-83), and the median NIHSS at baseline was 8 (5-14). On arrival at the hospital, the perfusion lesion volume was significantly smaller with tenecteplase (median 12 mL [IQR 3-28]) than with alteplase (35 mL [18-76]; adjusted incidence rate ratio 0·55, 95% CI 0·37-0·81; p=0·0030). At 90 days, an mRS of 5 or 6 was reported in eight (15%) patients allocated to tenecteplase and ten (20%) patients allocated to alteplase (adjusted odds ratio [aOR] 0·70, 95% CI 0·23-2·16; p=0·54). Five (9%) patients allocated to tenecteplase and five (10%) patients allocated to alteplase died from any cause at 90 days (aOR 1·12, 95% CI 0·26-4·90; p=0·88). No cases of symptomatic intracerebral haemorrhage were reported within 36 h with either treatment. Up to day 90, 13 serious adverse events were noted: five (5%) in patients treated with tenecteplase, and eight (8%) in patients treated with alteplase. INTERPRETATION: Treatment with tenecteplase on the MSU in Melbourne resulted in a superior rate of early reperfusion compared with alteplase, and no safety concerns were noted. This trial provides evidence to support the use of tenecteplase and MSUs in an optimal model of stroke care. FUNDING: Melbourne Academic Centre for Health.

Common scale minimal sufficient balance: An improved method for covariate-adaptive randomization based on the Wilcoxon-Mann-Whitney odds ratio statistic.

Minimal sufficient balance (MSB) is a recently suggested method for adaptively controlling covariate imbalance in randomized controlled trials in a manner which reduces the impact on randomness of allocation over other approaches by only intervening when the imbalance is sufficiently significant. Despite its improvements, the approach is unable to consider the relative clinical importance or magnitude of imbalance in each covariate weight, and ignores any imbalance which is not statistically significant, even when these imbalances may collectively justify intervention. We propose the common scale MSB (CS-MSB) method which addresses these limitations, and present simulation studies comparing our proposed method to MSB. We demonstrate that CS-MSB requires less intervention than MSB to achieve the same level of covariate balance, and does not adversely impact either statistical power or Type-I error.