Statistical Analysis Plan for the INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4).

INTRODUCTION: Recruitment is complete in the fourth INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4) is a multicenter, prospective, randomized, open-label, blinded endpoint assessed trial of pre-hospital blood pressure (BP) lowering initiated in the ambulance for patients with a suspected acute stroke and elevated BP in China. According to the registered and published trial protocol and developed by the blinded trial Steering Committee and Operations team, this manuscript outlines a detailed statistical analysis plan for the trial prior to database lock. METHODS: Patients were randomized (1:1) to intensive (target systolic BP [SBP] 130-140 mmHg within 30 minutes) or guideline-recommended BP management (BP lowering only considered if SBP >220 mmHg) group. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale at 90 days. A modified sample size of 2320 was estimated to provide 90% power to detect a 22% reduction in the odds (common odds ratio of 0.78) of a worse functional outcome using ordinal logistic regression, on the assumption of 5% patients with missing outcome and 6% patients with a stroke mimic. CONCLUSION: The statistical analysis plan for the trial has been developed to ensure transparent, verifiable, and prespecified analysis, and to avoid potential bias in the evaluation of the trial intervention.

Correction: A Virtual Hospital Model of Care for Low Back Pain, Back@Home: Protocol for a Hybrid Effectiveness-Implementation Type-I Study.

[This corrects the article DOI: 10.2196/50146.].

Intensive Ambulance-Delivered Blood-Pressure Reduction in Hyperacute Stroke.

BACKGROUND: Treatment of acute stroke, before a distinction can be made between ischemic and hemorrhagic types, is challenging. Whether very early blood-pressure control in the ambulance improves outcomes among patients with undifferentiated acute stroke is uncertain. METHODS: We randomly assigned patients with suspected acute stroke that caused a motor deficit and with elevated systolic blood pressure (≥150 mm Hg), who were assessed in the ambulance within 2 hours after the onset of symptoms, to receive immediate treatment to lower the systolic blood pressure (target range, 130 to 140 mm Hg) (intervention group) or usual blood-pressure management (usual-care group). The primary efficacy outcome was functional status as assessed by the score on the modified Rankin scale (range, 0 [no symptoms] to 6 [death]) at 90 days after randomization. The primary safety outcome was any serious adverse event. RESULTS: A total of 2404 patients (mean age, 70 years) in China underwent randomization and provided consent for the trial: 1205 in the intervention group and 1199 in the usual-care group. The median time between symptom onset and randomization was 61 minutes (interquartile range, 41 to 93), and the mean blood pressure at randomization was 178/98 mm Hg. Stroke was subsequently confirmed by imaging in 2240 patients, of whom 1041 (46.5%) had a hemorrhagic stroke. At the time of patients' arrival at the hospital, the mean systolic blood pressure in the intervention group was 159 mm Hg, as compared with 170 mm Hg in the usual-care group. Overall, there was no difference in functional outcome between the two groups (common odds ratio, 1.00; 95% confidence interval [CI], 0.87 to 1.15), and the incidence of serious adverse events was similar in the two groups. Prehospital reduction of blood pressure was associated with a decrease in the odds of a poor functional outcome among patients with hemorrhagic stroke (common odds ratio, 0.75; 95% CI, 0.60 to 0.92) but an increase among patients with cerebral ischemia (common odds ratio, 1.30; 95% CI, 1.06 to 1.60). CONCLUSIONS: In this trial, prehospital blood-pressure reduction did not improve functional outcomes in a cohort of patients with undifferentiated acute stroke, of whom 46.5% subsequently received a diagnosis of hemorrhagic stroke. (Funded by the National Health and Medical Research Council of Australia and others; INTERACT4 ClinicalTrials.gov number, NCT03790800; Chinese Trial Registry number, ChiCTR1900020534.).

Antenatal oral glucose tolerance test abnormalities in the prediction of future risk of postpartum diabetes in women with gestational diabetes: Results from the LIVING study.

OBJECTIVES: To explore associations between type and number of abnormal glucose values on antenatal oral glucose tolerance test (OGTT) with postpartum diabetes in South Asian women diagnosed with gestational diabetes (GDM) using International Association of the Diabetes and Pregnancy Study Groups criteria. METHODS: This post-hoc evaluation of the Lifestyle Intervention IN Gestational Diabetes (LIVING) study, a randomized controlled trial, was conducted among women with GDM in the index pregnancy, across 19 centers in Bangladesh, India, and Sri Lanka. Postpartum diabetes (outcome) was defined on OGTT, using American Diabetes Association (ADA) criteria. RESULTS: We report data on 1468 women with GDM, aged 30.9 (5.0) years, and with median (interquartile range) follow-up period of 1.8 (1.4-2.4) years after childbirth following the index pregnancy. We found diabetes in 213 (14.5%) women with an incidence of 8.7 (7.6-10.0)/100 women-years. The lowest incidence rate was 3.8/100 women years, in those with an isolated fasting plasma glucose (FPG) abnormality, and highest was 19.0/100 women years in participants with three abnormal values. The adjusted hazard ratios for two and three abnormal values compared to one abnormal value were 1.73 (95% confidence interval [CI], 1.18-2.54; p = .005) and 3.56 (95% CI, 2.46-5.16; p < .001) respectively. The adjusted hazard ratio for the combined (combination of fasting and postglucose load) abnormalities was 2.61 (95% CI, 1.70-4.00; p < .001), compared to isolated abnormal FPG. CONCLUSIONS: Risk of diabetes varied significantly depending upon the type and number of abnormal values on antenatal OGTT. These data may inform future precision medicine approaches such as risk prediction models in identifying women at higher risk and may guide future targeted interventions.

Synergetic Exterior and Interfacial Approaches by Colloidal Carbon Quantum Dots for More Stable Perovskite Solar Cells Against UV.

The achievement of both efficiency and stability in perovskite solar cells (PSCs) remains a challenging and actively researched topic. In particular, among different environmental factors, ultraviolet (UV) photons play a pivotal role in contributing to device degradation. In this work, by harvesting simultaneously both the optical and the structural properties of bottom-up-synthesized colloidal carbon quantum dots (CQDs), a cost-effective means is provided to circumvent the UV-induced degradation in PSCs without scarification on their power conversion efficiencies (PCEs). By exploring and optimizing the number of CQDs and the different locations/interfaces of the solar cells where CQDs are applied, a synergetic configuration is achieved where the photovoltaic performance drop due to optical loss is completely compensated by the increased perovskite crystallinity due to interfacial modification. As a result, on the optimized configurations where CQDs are applied both on the exterior front side as an optical layer and at the interface between the electron transport layer and the perovskite absorber, unencapsulated PSCs with PCEs >20% are fabricated which can maintain up to ≈94% of their initial PCE after 100 h of degradation in ambient air under continuous UV illumination (5 mW cm-2).

Individual patient data meta-analysis of the effects of fluoxetine on functional outcomes after acute stroke.

BACKGROUND: Three large randomized controlled trials of fluoxetine for stroke recovery have been performed. We performed an individual patient data meta-analysis (IPDM) on the combined data. METHODS: Fixed effects meta-analyses were performed on the combined data set, for the primary outcome (modified Rankin scale (mRS) at 6 months), and secondary outcomes common to the individual trials. As a sensitivity analysis, summary statistics from each trial were created and combined. FINDINGS: The three trials recruited a combined total of 5907 people (mean age 69.5 years (SD 12.3), 2256 (38%) females, 2-15 days post-stroke) from Australia, New Zealand, United Kingdom, Sweden, and Vietnam; and randomized them to fluoxetine 20 mg daily or matching placebo for 6 months. Data on 5833 (98.75%) were available at 6 months. The adjusted ordinal comparison of mRS was similar in the two groups (common OR 0.96, 95% CI 0.87 to 1.05, p = 0.37). There were no statistically significant interactions between the minimization variables (baseline probability of being alive and independent at 6 months, time to treatment, motor deficit, or aphasia) and pre-specified subgroups (including age, pathological type, inability to assess mood, proxy or patient consent, baseline depression, country). Fluoxetine increased seizure risk (2.64% vs 1.8%, p = 0.03), falls with injury (6.26% vs 4.51%, p = 0.03), fractures (3.15% vs 1.39%, p < 0.0001) and hyponatremia (1.22% vs 0.61%, p = 0.01) but reduced new depression (10.05% vs 13.42%, p < 0.0001). At 12 months, there was no difference in adjusted mRS (n = 5760; common OR 0.98, 95% CI 0.89 to 1.07). Sensitivity analyses gave the same results. INTERPRETATION: Fluoxetine 20 mg daily for 6 months did not improve functional recovery. It increased seizures, falls with injury, and bone fractures but reduced depression frequency at 6 months.

Therapeutic Inertia With Initial Low-Dose Quadruple Combination Therapy for Hypertension: Results From the QUARTET Trial.

BACKGROUND: Low-dose combinations are a promising intervention for improving blood pressure (BP) control but their effects on therapeutic inertia are uncertain. METHODS: Analysis of 591 patients randomized to an ultra-low-dose quadruple pill or initial monotherapy. The episode of therapeutic inertia was defined as a patient visit with a BP of >140/90 mm Hg without intensification of antihypertensive treatment. We compared the frequency of therapeutic inertia episodes between Quadpill and initial monotherapy as a proportion of the total population (intention-to-treat analysis with the denominator being all participants randomized) and as a proportion of people with uncontrolled BP (with the denominator being participants with uncontrolled BP). RESULTS: Therapeutic inertia occurred in fewer participants randomized to Quadpill compared with monotherapy. For example, among the 390 participants with a 6-month follow-up, therapeutic inertia according to unattended BP was 21/192 (11%) versus 45/192 (23%), P=0.002. There were similar rates of therapeutic inertia among those with uncontrolled unattended BP in each group (all P>0.4). Consistent observations were seen with the use of attended office BP measures. The major determinants of not intensifying treatment during follow-up were BP readings that were close to target and large improvements in BP compared with the previous visit. CONCLUSIONS: Among all treated individuals, low-dose Quadpill reduced the number of therapeutic inertia episodes compared with initial monotherapy. After the first follow-up visit, most high BP values did not lead to treatment intensification in both groups. Education is needed about the importance of treatment intensification despite a significant improvement in BP or BP being close to target. REGISTRATION: URL: https://anzctr.org.au/Trial/Registration/TrialReview.aspx?ACTRN=ACTRN12616001144404; Unique identifier: ACTRN12616001144404.

How should a cluster randomized trial be analyzed?

In cluster randomized trials, individuals from the same cluster tend to have more similar outcomes than individuals from different clusters. This correlation must be taken into account in the analysis of every cluster trial to avoid incorrect inferences. In this paper, we describe the principles guiding the analysis of cluster trials including how to correctly account for intra-cluster correlations as well as how to analyze more advanced designs such as stepped-wedge and cluster cross-over trials. We then describe how to handle specific issues such as small sample sizes and missing data.

Practical and methodological challenges when conducting a cluster randomized trial: Examples and recommendations.

The use of cluster randomized trial design to answer research questions is increasing. This design and associated variants such as the cluster randomized crossover and stepped wedge are useful to assess complex interventions in a pragmatic way but when adopting such designs, one may face specific implementation challenges. This article summarizes common challenges faced when conducting cluster randomized trials, cluster randomized crossover trials, and stepped wedge trials, and provides recommendations.

Overcoming silos in health care systems through meso-level organisations - a case study of health reforms in New South Wales, Australia.

Fragmented care delivery is a barrier to improving health system performance worldwide. Investment in meso-level organisations is a potential strategy to improve health system integration, however, its effectiveness remains unclear. In this paper, we provide an overview of key international and Australian integrated care policies. We then describe Collaborative Commissioning - a novel health reform policy to integrate primary and hospital care sectors in New South Wales (NSW), Australia and provide a case study of a model focussed on older person's care. The policy is theorised to achieve greater integration through improved governance (local stakeholders identifying as part of one health system), service delivery (communities perceive new services as preferable to status quo) and incentives (efficiency gains are reinvested locally with progressively higher value care achieved). If effectively implemented at scale, Collaborative Commissioning has potential to improve health system performance in Australia and will be of relevance to similar reform initiatives in other countries.

A Virtual Hospital Model of Care for Low Back Pain, Back@Home: Protocol for a Hybrid Effectiveness-Implementation Type-I Study.

BACKGROUND: Low back pain (LBP) was the fifth most common reason for an emergency department (ED) visit in 2020-2021 in Australia, with >145,000 presentations. A total of one-third of these patients were subsequently admitted to the hospital. The admitted patient care accounts for half of the total health care expenditure on LBP in Australia. OBJECTIVE: The primary aim of the Back@Home study is to assess the effectiveness of a virtual hospital model of care to reduce the length of admission in people presenting to ED with musculoskeletal LBP. A secondary aim is to evaluate the acceptability and feasibility of the virtual hospital and our implementation strategy. We will also investigate rates of traditional hospital admission from the ED, representations and readmissions to the traditional hospital, demonstrate noninferiority of patient-reported outcomes, and assess cost-effectiveness of the new model. METHODS: This is a hybrid effectiveness-implementation type-I study. To evaluate effectiveness, we plan to conduct an interrupted time-series study at 3 metropolitan hospitals in Sydney, New South Wales, Australia. Eligible patients will include those aged 16 years or older with a primary diagnosis of musculoskeletal LBP presenting to the ED. The implementation strategy includes clinician education using multimedia resources, staff champions, and an "audit and feedback" process. The implementation of "Back@Home" will be evaluated over 12 months and compared to a 48-month preimplementation period using monthly time-series trends in the average length of hospital stay as the primary outcome. We will construct a plot of the observed and expected lines of trend based on the preimplementation period. Linear segmented regression will identify changes in the level and slope of fitted lines, indicating immediate effects of the intervention, as well as effects over time. The data will be fully anonymized, with informed consent collected for patient-reported outcomes. RESULTS: As of December 6, 2023, a total of 108 patients have been cared for through Back@Home. A total of 6 patients have completed semistructured interviews regarding their experience of virtual hospital care for nonserious back pain. All outcomes will be evaluated at 6 months (August 2023) and 12 months post implementation (February 2024). CONCLUSIONS: This study will serve to inform ongoing care delivery and implementation strategies of a novel model of care. If found to be effective, it may be adopted by other health districts, adapting the model to their unique local contexts. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/50146.

Efficacy of decentralised home-based antihypertensive treatment in older adults with multimorbidity and polypharmacy (ATEMPT): an open-label randomised controlled pilot trial.

BACKGROUND: Older patients with multimorbidity and polypharmacy have been under-represented in clinical trials. We aimed to assess the effect of different intensities of antihypertensive treatment on changes in blood pressure, major safety outcomes, and patient-reported outcomes in this population. METHODS: ATEMPT was a decentralised, two-armed, parallel-group, open-label randomised controlled pilot trial conducted in the Thames Valley area, South East England. Individuals aged 65 years or older with multimorbidity (three or more chronic conditions) or polypharmacy (five or more types of medications) and a systolic blood pressure of 115-165 mm Hg were eligible for inclusion. Participants were identified through a search of national hospital discharge databases, identification of patients registered with an online pharmacy, and via targeted advertising on social media platforms. Participants were randomly assigned to receive up to two more classes versus up to two fewer classes of antihypertensive medications. Apart from routine home visits for conducting the baseline assessment, all communication, monitoring, and management of participants by the trial team was conducted remotely. The primary outcome was change in home-measured blood pressure. FINDINGS: Between Dec 15, 2020, and Aug 31, 2022, 230 participants were randomly assigned (n=126 to more vs n=104 to fewer antihypertensive medications). The frequency of serious adverse events was similar across both groups; no cardiovascular events occurred in the more antihypertensive drugs group, compared with six in the fewer antihypertensive drugs group, of which two were fatal. Over a 13-month follow-up period, the mean systolic blood pressure in the group allocated to receive more antihypertensive medications decreased from 134·5 mm Hg (SD 10·7) at baseline to 122·1 mm Hg (10·5). By contrast, in the group allocated to receive fewer antihypertensive medications, it remained relatively unchanged, moving from 134·8 mm Hg (SD 11·2) at baseline to 132·9 mm Hg (15·3); this corresponded to a mean difference of -10·7 mm Hg (95% CI -17·5 to -4·0). INTERPRETATION: Remotely delivered antihypertensive treatment substantially reduced systolic blood pressure in older adults who are often less represented in trials, with no increase in the risk of serious adverse events. The results of this trial will inform a larger clinical trial focusing on assessing major cardiovascular events, safety, physical functioning, and cognitive function that is currently in the planning stages. These results also underscore the efficiency of decentralised trial designs, which might be of broader interest in other settings. FUNDING: National Institute for Health Research Oxford Biomedical Research Centre and the Oxford Martin School.

Selective digestive tract decontamination in critically ill adults with acute brain injuries: a post hoc analysis of a randomized clinical trial.

PURPOSE: The aim of this study was to determine whether selective decontamination of the digestive tract (SDD) reduces in-hospital mortality in mechanically ventilated critically ill adults admitted to the intensive care unit (ICU) with acute brain injuries or conditions. METHODS: We carried out a post hoc analysis from a crossover, cluster randomized clinical trial. ICUs were randomly assigned to adopt or not to adopt a SDD strategy for two alternating 12-month periods, separated by a 3-month inter-period gap. Patients in the SDD group (n = 2791; 968 admitted to the ICU with an acute brain injury) received a 6-hourly application of an oral paste and administration of a gastric suspension containing colistin, tobramycin, and nystatin for the duration of mechanical ventilation, plus a 4-day course of an intravenous antibiotic with a suitable antimicrobial spectrum. Patients in the control group (n = 3191; 1093 admitted to the ICU with an acute brain injury) received standard care. The primary outcome was in-hospital mortality within 90 days. There were four secondary clinical outcomes: death in ICU, ventilator-, ICU- and hospital-free days to day 90. RESULTS: Of 2061 patients with acute brain injuries (mean age, 55.8 years; 36.4% women), all completed the trial. In patients with acute brain injuries, there were 313/968 (32.3%) and 415/1093 (38%) in-hospital deaths in the SDD and standard care groups (unadjusted odds ratio [OR], 0.76, 95% confidence interval [CI] 0.63-0.92; p = 0.004). The use of SDD was associated with statistically significant improvements in the four clinical secondary outcomes compared to standard care. There was no significant heterogeneity of treatment effect between patients with and without acute brain injuries (interaction p = 0.22). CONCLUSIONS: In this post hoc analysis of a randomized clinical trial in critically ill patients with acute brain injuries receiving mechanical ventilation, the use of SDD significantly reduced in-hospital mortality in patients compared to standard care without SDD. These findings require confirmation.

REVISE: re-evaluating the inhibition of stress erosions in the ICU-statistical analysis plan for a randomized trial.

BACKGROUND: The REVISE (Re-Evaluating the Inhibition of Stress Erosions in the ICU) trial will evaluate the impact of the proton pump inhibitor pantoprazole compared to placebo in invasively ventilated critically ill patients. OBJECTIVE: To outline the statistical analysis plan for the REVISE trial. METHODS: REVISE is a randomized clinical trial ongoing in intensive care units (ICUs) internationally. Patients ≥ 18 years old, receiving invasive mechanical ventilation, and expected to remain ventilated beyond the calendar day after randomization are allocated to either 40 mg pantoprazole intravenously or placebo while mechanically ventilated. RESULTS: The primary efficacy outcome is clinically important upper GI bleeding; the primary safety outcome is 90-day mortality. Secondary outcomes are ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine concentration, and duration of mechanical ventilation, ICU, and hospital length of stay. Following an interim analysis of results from 2400 patients (50% of 4800 target sample size), the data monitoring committee recommended continuing enrolment. CONCLUSIONS: This statistical analysis plan outlines the statistical analyses of all outcomes, sensitivity analyses, and subgroup analyses. REVISE will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION: www. CLINICALTRIALS: gov NCT03374800. November 21, 2017.

Update on the INTEnsive ambulance-delivered blood pressure Reduction in hyper-ACute stroke Trial (INTERACT4): progress and baseline features in 2053 participants.

BACKGROUND AND AIMS: Uncertainty persists over the effects of blood pressure (BP) lowering in acute stroke. The INTEnsive ambulance-delivered blood pressure Reduction in hyper-Acute stroke Trial (INTERACT4) aims to determine efficacy and safety of hyperacute intensive BP lowering in patients with suspected acute stroke. Given concerns over the safety of this treatment in the pre-hospital setting, particularly in relation to patients with intracerebral hemorrhage, we provide an update on progress of the study and profile of participants to date. METHODS: INTERACT4 is an ongoing multicentre, ambulance-delivered, randomized, open-label, blinded endpoint trial of pre-hospital BP lowering in patients with suspected acute stroke and elevated BP in China. Patients are randomized via a mobile phone digital system to intensive (target systolic BP [SBP] <140mmHg within 30 min) or guideline-recommended BP management. Primary outcome is an ordinal analysis of the full range of scores on the modified Rankin scale scores at 90 days. RESULTS: Between March 2020 and April 2023, 2053 patients (mean age 70 years, female 39%) were recruited with a mean BP 178/98 mmHg in whom 45% have a diagnosis of primary intracerebral hemorrhage upon arrival at hospital. At the time of presentation to hospital, the mean SBP was 160 and 170mmHg in the intensive and control groups (Δ10 mmHg), respectively. The independent data and safety monitoring board has not identified any safety concerns and recommended continuation of the trial. The sample size was reduced from 3116 to 2320 after meetings in August 2022 as the stroke mimic rate was persistently lower than initially estimated (6% vs 30%). The study is expected to be completed in late 2023 and the results announced in May 2024. CONCLUSIONS: INTERACT4 is on track to provide reliable evidence of the effectiveness of ambulance-delivered intensive BP lowering in patients with suspected acute stroke. TRIAL REGISTRATION: ClinicalTrials.gov NCT03790800 ; registered on 2 January 2019. Chinese Trial Registry ChCTR1900020534 , registered on 7 January 2019.

REVISE: Re-Evaluating the Inhibition of Stress Erosions in the ICU: a randomised trial protocol.

INTRODUCTION: The Re-Evaluating the Inhibition of Stress Erosions (REVISE) Trial aims to determine the impact of the proton pump inhibitor pantoprazole compared with placebo on clinically important upper gastrointestinal (GI) bleeding in the intensive care unit (ICU), 90-day mortality and other endpoints in critically ill adults. The objective of this report is to describe the rationale, methodology, ethics and management of REVISE. METHODS AND ANALYSIS: REVISE is an international, randomised, concealed, stratified, blinded parallel-group individual patient trial being conducted in ICUs in Canada, Australia, Saudi Arabia, UK, US, Kuwait, Pakistan and Brazil. Patients≥18 years old expected to remain invasively mechanically ventilated beyond the calendar day after enrolment are being randomised to either 40 mg pantoprazole intravenously or an identical placebo daily while mechanically ventilated in the ICU. The primary efficacy outcome is clinically important upper GI bleeding within 90 days of randomisation. The primary safety outcome is 90-day all-cause mortality. Secondary outcomes include rates of ventilator-associated pneumonia, Clostridioides difficile infection, new renal replacement therapy, ICU and hospital mortality, and patient-important GI bleeding. Tertiary outcomes are total red blood cells transfused, peak serum creatinine level in the ICU, and duration of mechanical ventilation, ICU and hospital stay. The sample size is 4800 patients; one interim analysis was conducted after 2400 patients had complete 90-day follow-up; the Data Monitoring Committee recommended continuing the trial. ETHICS AND DISSEMINATION: All participating centres receive research ethics approval before initiation by hospital, region or country, including, but not limited to - Australia: Northern Sydney Local Health District Human Research Ethics Committee and Mater Misericordiae Ltd Human Research Ethics Committee; Brazil: Comissão Nacional de Ética em Pesquisa; Canada: Hamilton Integrated Research Ethics Board; Kuwait: Ministry of Health Standing Committee for Coordination of Health and Medical Research; Pakistan: Maroof Institutional Review Board; Saudi Arabia: Ministry of National Guard Health Affairs Institutional Review Board: United Kingdom: Hampshire B Research Ethics Committee; United States: Institutional Review Board of the Nebraska Medical Centre. The results of this trial will inform clinical practice and guidelines worldwide. TRIAL REGISTRATION NUMBER: NCT03374800.

Corrigendum to "Statistical analysis plan for the BLING III study: a phase 3 multicentre randomised controlled trial of continuous versus intermittent ß-lactam antibiotic infusion in critically ill patients with sepsis" [Crit Care Resusc 23(3) (2021) 273-284].

[This corrects the article DOI: 10.51893/2021.3.oa4.].

The main Optimal Post rTpa-Iv Monitoring in Ischemic Stroke Trial (OPTIMISTmain): protocol for a pragmatic, stepped wedge, cluster randomized controlled trial.

Introduction Careful monitoring of patients who receive intravenous thrombolysis (IVT) for acute ischemic stroke (AIS) is resource-intensive, and potentially less relevant in those with mild degrees of neurological impairment who are at low-risk of symptomatic intracerebral hemorrhage (sICH) and other complications. \ Methods OPTIMISTmain is an international, multicenter, prospective, stepped wedge, cluster randomized, blinded outcome assessed trial aims to determine whether a less-intensity monitoring protocol is at least as effective, safe and efficient as standard post-IVT monitoring in patients with mild deficits post-AIS. Clinically-stable adult patients with mild AIS (defined by a NIHSS <10) who do not require intensive care within 2 hours post-IVT are recruited at hospitals in Australia, Chile, China, Malaysia, Mexico, UK, US and Vietnam. An average of 15 patients recruited per period (overall 60 patient participants) at 120 sites for a total of 7200 IVT-treated AIS patients will provide 90% power (one-sided α 0.025). The initiation of eligible hospitals is based on a rolling process whenever ready, stratified by country. Hospitals are randomly allocated using permuted blocks into 3 sequences of implementation, stratified by country and the projected number of patients to be recruited over 12 months. These sequences have four periods that dictate the order in which they are to switch from control (usual care) to intervention (implementation of low intensity monitoring protocol) to different clusters of patients in a stepped manner. Compared to standard monitoring, the low-intensity monitoring protocol includes assessments of neurological and vital signs every 15 minutes for 2 hours, 2 hourly (versus every 30 minutes) for 8 hours, and 4 hourly (versus every 1 hour) until 24 hours, post-IVT. The primary outcome measure is functional recovery, defined by the modified Rankin scale (mRS) at 90 days, a seven-point ordinal scale (0 [no residual symptom] to 6 [death]). Secondary outcomes include death or dependency, length of hospital stay, and health-related quality of life, sICH and serious adverse events. Conclusion OPTIMISTmain will provide Level I evidence for the safety and effectiveness of a low-intensity post-IVT monitoring protocol in patients with mild severity of AIS.