The Third, Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial
The Third, Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial
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).

 Study design: An international, multicentre, stepped wedge, cluster randomized 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.

 Process Evaluation: Mixed methods were used to explore how the care bundle, a complex
 intervention, is implemented, as well as to understand clinicians' perspectives, a
 prospective process evaluation will be conducted alongside the trial implementation.
 Intervention fidelity, reach, dose, adaption, feasibility and appropriateness of the
 goal-directed care bundle will be evaluated within the trial.

 Economic Evaluation: A multi-country within-trial economic evaluation will be conducted, from
 each healthcare system's perspective. Healthcare utilisation costs incurred within the
 initial hospital visit will be estimated using administratively collected hospital records.

 Statistical considerations: We anticipate recruiting a minimum of 110 sites in a
 stepped-wedge design consisting of 3 groups and 4 phases. Each group would therefore include
 approximately 36-37 sites. We assume an interclass correlation coefficient (ICC) of 0.044
 between sites which is similar to that found in the INTERACT2 and recently completed Head
 Position in Acute Stroke Trial (HeadPoST) trials across Chinese sites. To demonstrate a
 treatment effect with 90% power and a 2-sided type-I error rate of 5%, each site would need
 to recruit an average of 18 patients per phase for a total sample size of 7,920 patients.
 Assuming that 5% of patients will have a missing outcome, each site would need to target an
 average of 19 patients per phase per site for a total sample size of 8,360 patients. To allow
 for variability in the number of patients recruited at each site, with very large hospitals
 expected to recruit up to 50 patients per phase and smaller hospitals recruiting as little as
 1 patient per phase in order to allow a broad range of hospitals with variable experience and
 systems of care for the management of ICH. The sample size would need to be inflated by a
 factor of approximately 1.3; thus leading to a sample size of up to 25 patients per site per
 phase (11,000 patients in total). Assuming the worst case scenario for the effect of cluster
 size variability on power, this sample size would still provide at least 80% power. 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). 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.

 Ethics consideration: 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/withdraw 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.

 Data management: 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.

 Data collection: 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.

 Collarboration: 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 110 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.
Inclusion Criteria:

 -  Aged ≥18 years

 -  Acute stroke syndrome that is due to presumed spontaneous ICH, confirmed by clinical
 history and a CT scan within 6 hours of stroke onset without/without contrast, and if
 an CT angiogram is also undertaken as part of routine care.

 -  Presentation to hospital within 6 hours of stroke onset.

 Exclusion Criteria:

 -  Definite evidence that the ICH is secondary to a structural abnormality in the brain
 (eg an AVM, intracranial aneurysm, tumour, trauma, or previous cerebral infarction) or
 previous thrombolysis.

 -  A high likelihood that the patient will not adhere to the study treatment and
 follow-up regimen. In each case, the decision about the patient's eligibility will be
 based on the attending clinician's interpretation of the above eligibility criteria.