MICA: The third, Intensive care bundle with blood pressure reduction in acute cerebral haemorrhage (INTERACT3) trial

The context of the research
Acute intracerebral haemorrhage (ICH) is the most severe type of stroke, which affects millions people in the world each year. The incidence of ICH is high in low- and middle- income countries (LMICs), particularly because prevalence of hypertension is high. ICH has a grave prognosis, with at least two thirds of the patients either dying or left with disability. Given the complex and serious nature of ICH, reliable evidence is required to guide health care delivery and policy making. However, the progress has been slow in established clear evidence of benefit for specific management strategies in this condition. However, there is good pre-clinical and observational data indicating that outcomes can be improved through early strict management of several key physiological parameters. Moreover, audits of hospital administrative data for stroke indicate there is widespread poor adherence to many evidence-based recommendations.

Aims and objectives
INTERACT3 (The third, INTEnsive care bundle with blood pressure Reduction in Acute Cerebral haemorrhage Trial) is an investigator initiated and conducted, international, multicentre, randomised cluster clinical trial. The study aims to determine the effectiveness of early intensive care bundle (BP lowering, glycaemic control, treatment of pyrexia, and reversal of anticoagulation).
The overall objectives include: (i) to solve persistent uncertainties of the most appropriate medical management of acute ICH; (ii) to understand the patterns of usual care for ICH in LMIC, in particular in relation to the use of local protocols, pathways and implementation of current national and international guidelines; (iii) to explore the barriers to implementation and adherence to a complex intervention; and (iv) to explore how best to adopt and integrate evidence-based recommendations into routine health care practice in LMICs.

Potential applications and benefits
This study will provide reliable evidence on the acute management of ICH and assist decision makings by professionals, service developers, and policy makers in health sectors. Reliable data on ICH management and outcomes could improve quality of care and reduce the high burden of ICH in LMIC. Clinical practice in the care of stroke patients, particularly those with ICH, and adherence to guidelines, could improve outcomes through participation in a high quality clinical trial conducted across multiple hospitals in LMICs. Moreover, the result could have a widely generalizable benefit, since evaluation of the intervention will be in a broad range of patients, including those severe ICH and/or who undergo surgery, who have been excluded from conventional individual patient randomised trials to date.

INTERACT3 is an international, multicentre, stepped-wedge, cluster randomised, blinded outcome assessed, clinical trial (Phase III-IV). The objective is to determine the effectiveness of a goal-directed care bundle of active management involving intensive BP lowering, glycaemic control, early treatment of pyrexia, and reversal of anticoagulation, against a practice of usual care, on the standard clinical outcome of functional recovery in patients with acute spontaneous ICH. The primary outcome measure is an ordinal shift analysis of all 7-levels (scores) on the modified Rankin scale (mRS, categories 0 to 6: 0=no symptoms, 1=no significant disability, 2=slight disability, 3= moderate disability, 4=moderate severe disability, 5=severe disability, 6=death) at 6 months. Secondary outcomes include early functional neurological recovery (according to a shift analysis of scores on the National Institutes of Health stroke scale [NIHSS] at 7 days), health-related quality of life (HRQoL) using the EuroQoL Group 5-Dimension self-report questionnaire (EQ-5D) at 6 months, duration of hospitalisation, and residence.
This research will be conducted through a global network of investigators from nine LMICs. The stepped-wedge cluster randomised design has been chosen to avoid contamination, facilitate hospital-wide implementation, and maximise adherence as the complex intervention under investigation becomes usual standard of care. A consecutive recruiting approach is involved to minimise bias in patient selection into the study. A mixed consent process is proposed according to local/national rules and regulations. Besides an individual standard consent for the data collection and follow-up, a cluster guardian consent is required for patients to receive the randomised care bundle to be implemented for acute ICH patients across multiple wards as a systems of care approach.

Academic impact
There is limited studies of ICH in large sample size and diverse population, the study will solve the uncertainties of ICH management and supply reliable evidence for guidelines development, which will assist physicians to make decisions and solve concerns. The methodology involved in the study, such as stepped-wedge design and mixed process of inform consents will provide opportunities for researchers to develop similar research in different field.
Investigator meetings, workshops and multi-model training will be given to participating investigators in order to enhance their engagement in clinical research as well as spread advanced knowledge in this field. Particularly most of the participants in this study are from secondary or rural hospitals with low medical resources and settings in LMIC, who have very rare research experience. The implementation of guideline-recommended care bundle in INTERACT3 will be evaluated by process evaluation. Relevant health system issues and barriers in knowledge, attitude and behaviour of clinicians that might facilitate or impede the evidence-based practice will be explored in the study. The contextual factors that affect implementation will be essential to health policy makers and health department at higher level to promote present health systems. This study will also assist in standardising and integrating those evidence-based recommendations into the system clinical routine for ICH management in the low settings of LMIC. The international and multiple institutions collaboration promotes exchanges and cooperation among investigators in stroke field. Moreover, the study requires the engagement of researchers from multiple disciplines, not only stroke unit or ward, but emergency department, metabolic department, Intensive Care Unit and Imaging Department. The international multidisciplinary collaboration is favourable for the generalization of the result, making contribution to build specialized pathway for acute ICH management, and providing opportunities to spread the benefit broadly into different facilities and multi-disciplines across LMIC.

Economical and societal impact
ICH is the most severe type of stroke, with almost half of ICH patients having a bad outcome (death or major disability), which causes a great burden to the whole society. The proportion of ICH of stroke in LMIC is greatly higher than that in high-income countries. We assume the long-term outcomes including quality of life in ICH patients can be improved through the guideline-recommended interventions. In this study, the 5.6% absolute improvement is a relatively larger effect size compared to other ICH trials which can be translated that one out of 18 patients treated with the care bundle, will have a favourable outcome avoiding death or major disability. We believe ICH patients will have their health wellbeing and quality of life improved through the studies. Society and economic benefit will be obtained through decreasing huge disease burden caused by ICH at country level and community level. As to achieve this aim, the study will provide information about the value judgements of patients to health policy makers, clinicians and health care managers, in decision making through economic evaluations. The study will provide some first-hand data to help world health or charity organisations to understand the real status of health services and facilities in LMICs through this study conduction in 9 LMIC countries. We also aim to provide a platform for the investigators, physicians and policy makers to formulate a better pathway to maximize the efficiency of health care delivery and minimize costs in ICH management. The study also aim to impact on non-academic community to improve the public engagement. The public is usually lack of the awareness and basic knowledge of ICH. Relevant reports and lectures of main results will be provided to the patients and public to advocate better treatment in ICH.