Continued uncertainty exists over benefits of early intensive blood pressure (BP) lowering in acute intracerebral hemorrhage (ICH), related to the non-significant primary outcomes, patient selection, and discordant results of INTERACT2 and ATACH-II. We designed INTERACT3 to determine the effectiveness of a goal-directed care bundle of active management (intensive BP lowering, glycemic control, treatment of pyrexia and reversal of anticoagulation) vs. usual care in ICH.
INTERACT3 is a large-scale pragmatic clinical trial to provide reliable evidence over the effectiveness of a widely applicable goal-directed care bundle in acute ICH.
Objectives: To determine the effectiveness of a goal-directed care bundle of active management involving early physiological control (intensive blood pressure [BP] lowering, glycemic control, early treatment of pyrexia, and rapid reversal of anticoagulation), versus usual standard of care, on functional outcome (defined by a shift in scores on the modified Rankin scale [mRS] in patients with acute spontaneous intracerebral hemorrhage (ICH).
A cluster clinical trial design involves implementation of a guideline-recommended intervention package applied to patients with ICH as part of routine care. Patients are only excluded if they refuse to have details of their management included and/or participate in the follow-up procedures.
Study site inclusion criteria: Organized systems of acute stroke care; no established comprehensive protocols for the management of patients with ICH; suitable location, infrastructure and willingness to participate in clinical research; large volume of ICH patients (approx. 100 per year). The hospitals will have training, prior to their activation and commencement of the intervention. Data collection at baseline,Day 1, discharge/ Day 7, and 6-month (end of follow-up), will be captured through a web database. 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.
Assuming a stepped-wedge trial of 3 groups and 4 phases, one needs 75 hospitals randomized into 3 groups of 25 hospitals, each recruiting an average of 27 patients per phase, for a total of 8147 subjects. Assuming 5% with missing endpoint data, the overall sample size increases to 29 subjects per hospital per phase, i.e. a total sample size of 8,621 subjects. 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 10 patients per phase, in order to allow a broad range of hospitals with variable experience and systems of care for the management of ICH. This sample size provides 90% power to determine a treatment effect of a 5.6% absolute improvement in the proportion of patients experiencing a bad outcome (modified Rankin scale [mRS] scores of 3-6), from 55.6% down to 50%. This also translates to a 10% relative risk reduction (relative risk of 0.90). Various assumptions have been made including an interclass correlation coefficient (ICC) of 0.044 between sites. All analyses will be undertaken at the patient level on an intention-to-treat basis at each center using Generalised Estimating Equations (GEE) or random-effects regression to account for clustering.
A mixed consent process is proposed, according to local/national rules and regulations, for the following protocol:
Cluster Guardian consent or appropriate approval (e.g. signed by General Manager or Chief Executive of hospital, or Head of Neurology/Stroke Department) for the goal-directed care bundle to be the new usual management for patients with ICH;
With one of the following:
(i). Individual standard consent for the collection of data through in-person assessment and data extraction from medical records during the hospital stay and follow-up, and for release of personalized information for research purposes to allow centralized follow-up at 6-month after admission, or (ii). Opt-out consent for collection of data through in-person assessment and data extraction from medical records during the hospital stay and follow-up, and for release of personalized information for research purposes to allow centralized follow-up at 90 days after admission.
The internet based data management system is managed at the George Institute for Global Health, which has extensive experience in clinical trial data capture and security. The George Institute has in place system security SOP with VeriSign SSL digital certification and encrypted HTTPS connection. Only staff listed in the delegation log will be given unique individual password to access the internet-based data management system.
Paper CRFs will be provided for sites preferring to use these for the initial collection of data. These forms will be used as source document and will need to be signed and dated by the investigator completing the form.
All computerized forms will be electronically signed (by use of the unique password) by the authorized study staff and all changes made following the initial entry will have an electronic dated audit trail. It is the requirement that the collection of data and transfer of information for the 90 day follow-up assessment has to be approved by the local IRB for each site.
Central international coordination is from GI, China and together with regional coordinating centers established and located in Sydney, and Santiago, Chile, the study will be overseen by an International Steering Committee comprised of world experts in the fields of stroke, neurocritical care, neurology, geriatrics, cardiovascular epidemiology and clinical trials. The investigators of the 75 participating hospitals (see study organisational chart) will be administratively tied through a structure designed to enhance effective communication, collaboration and study monitoring by maintaining operations through adherence to a common protocol.
Data Safety & Monitoring Board (DSMB): The DSMB will review the safety, ethics and outcomes of the study.The DSMB will be governed by a charter that will outline their responsibilities, procedures and confidentiality.
- Cardiovascular Diseases
- Intracranial Hemorrhages
- Cerebral Hemorrhage
- Brain Disorder
- Central Nervous System Diseases
- Cerebral Vascular Disorder
- Anticoagulant-induced Bleeding
- Usual care Behavioral
Intervention Desc: Usual care decisions about the location of care delivery, investigations, monitoring, and all treatments will be made by the treating clinical team. ARM 1: Kind: Experimental Label: Usual care group Description: Patients receive the usual management based on local guidelines and hospital's individual policy.
- Care bundle of active management Other
Other Names: Early intensive BP lowing; Intensive glucose control; Early treatment of pyrexia; Reversal of anticoagulation Intervention Desc: Intensive BP lowering to systolic target of <140mmHg; Glucose control target 6.1-7.8 mmol/l for non-diabetic; 7.8-10.0 mmol/l for diabetic patients; Treatment of pyrexia to a target body temperature ≤37.5 ℃; Reversal of anticoagulation to target INR <1.5 involving use of vitamin K and prothrombin complex concentrate (PCC) or alternatively, fresh frozen plasma (FFP). As the trial is an assessment of care bundle of physiological management, there is some flexibility in the use of particular BP lowering agents and antipyretic agents to achieve targets. ARM 1: Kind: Experimental Label: Goal-directed care bundle Description: Management policy to receive a goal-directed care bundle that involves the rapid correction (<1 hour) of physiological variables as soon as the abnormality is recognised and for the control to be maintained in patients for 7 days or hospital discharge (or death, if sooner)
|Type||Measure||Time Frame||Safety Issue|
|Primary||Shift ('improvement') in functional recovery (death or disability) defined by the modified Rankin Scale (mRS)||6 months|
|Secondary||Shift ('improvement') in survival and neurological impairment defined by scores on the National Institutes of Health Stroke Scale (NIHSS)||7 days|
|Secondary||Death or disability defined by scores of 3-6 on the mRS||6 months|
|Secondary||Disability defined by scores 3-5 on the mRS||6 months|
|Secondary||Health-related quality of life (HRQoL)||6 months|
|Secondary||Duration of initial hospitalization||6 months|