Study details:

Research question: Patients receiving thrombolytic therapy (tissue plasminogen activator \[tPA\]) for acute ischaemic stroke (AIS), have been monitored with a high intensity schedule of vital signs and neurologic assessments, which often requires 1:1 nursing and/or admission in an intensive care unit (ICU) or similar ward for at least 24 hours after receiving tPA. Studies indicate that patients with mild degrees of AIS after tPA do not require such intensive monitoring, yet most stroke services continue to follow a practice recommended in guidelines based on the initial cautious evaluation of tPA in AIS over 20 years ago. Design: Stepped-wedge cluster randomised design.

With 3 groups and 4 phases. All groups starting with standard care and in each subsequent phase, groups I through III will switch to the intervention (low-intensity monitoring). Study centers: This is a global study.

Approximately 157 hospitals ('sites') in Australasia, Europe, South American, and North American regions, who are willing to accept the randomized intervention change and adhere to the protocol, collect a required minimum data set on patients over 7 days in hospital (or discharge or death, if sooner), and record any serious adverse event (SAE) during and at clinical outcome assessed at 90 days of follow-up of patients. Consent/randomization: Hospitals will be eligible if they are using the proposed low-intensity nursing monitoring strategy. A stepped-wedge cluster randomized design has been chosen to avoid contamination, facilitate hospital-wide implementation, and maximize adherence, as the intervention under investigation is to become usual standard of care.

The process of one direction (from control to intervention) is to facilitate the low intensity monitoring protocol being applied in clinical practice. The stepped-wedge design means that all hospitals will be randomly allocated to 3 groups: in phase 1, all hospitals will be observed under standard care 'control' conditions according to guideline recommended monitoring; in phase 2, the first cluster of hospitals (Group I) will start receiving the intervention (low-intensity), and then sequentially, Groups II and III will start receiving the interventional package in phase 3 and 4, respectively, so that by phase 4, all hospitals will have the intervention. Those hospitals in Group I are exposed to the intervention for longest time, and those in Group III, the shortest time.

In each phase, hospitals are to maintain a register of all thrombolyzed AIS patients, and to identify all those eligible for, or excluded from participating in the study. Hospitals are required to manage at minimum target of at least 10 consecutive thrombolyzed AIS patients who fulfill the eligibility criteria (presumed 50% of all thrombolyzed AIS patients) over each 4 month period. The recruitment number will vary from 10 to 30 patients, according to seasonal fluctuation and overall numbers of thrombolyzed AIS patients across hospitals.

The target number and time limits for each phase will be pre-determined and agreed to with each hospital, to ensure an orderly completion of the study. On average, for Group I, the time for initiation of the low-intensive intervention is 4 months after activation into phase 1 of the study; for Groups II and III, the time periods for initiation of the low-intensive intervention are 6 and 9 months, after activation, respectively. Data collection will occur at baseline, the first 24 hours, Day 7 (or death or time of hospital discharge, if earlier), and at 90 days (end of follow-up).

Patients will be asked to consent to being contacted at some future date to examine long-term outcomes, according to available resources. A senior executive officer at each center will act as a 'guardian', to provide consent at an institutional level for the intervention to be applied as a 'low risk' intervention to clusters of patients as part of routine care; and written informed consent is to be subsequently obtained from participants, or their approved surrogates, for collection of medical data and participation in the follow-up assessments Randomized allocation of intervention will be assigned by a statistician not otherwise involved in the study according to a statistical program stratified by the country of the site. Sample size: The sample size required to detect a plausible treatment effect on a clinical outcome in a stepped-wedge trial (3 groups, 4 phases) is 157 hospitals, each recruiting an average of 80 patients (20 per phase), for a total of 12,394 AIS patients.

The basis of this calculation is that the study is designed with 90% power (one-sided α = 0. 025) to detect non-inferiority (non-inferiority OR margin is 1. 25, presumed actual OR is 1.

0; the proportion of a bad outcome \[mRS 2-6\] is 50%) of low-intensity monitoring on the primary outcome. Assuming a stepped-wedge trial of 3 groups and 4 phases, 157 hospitals are required to be randomized into 3 groups of 53 hospitals, each recruiting an average of 16 patients per phase, for a total of 9340 subjects. Assuming 10% with missing primary endpoint data and 5% with nonadherence to randomized treatment, the overall sample size increases to an average of 20 subjects per hospital per phase (i.

e. total sample size of 12,394 AIS patients). Allowance will be made to include some very large hospitals (10%, 7) to recruit 50 patients per phase, and smaller hospitals (10%, 7) to recruit 8 patients per phase, in order to allow a broad range of hospitals with variable experience and systems of care for the management of AIS.

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