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.

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

Cerebral Hemorrhage

Stroke

Hypertension

Diabetes

Anticoagulant-induced Bleeding

Cerebral Vascular Disorder

Brain Disorder

Hemorrhage

Intracranial Hemorrhages

Cardiovascular Diseases

Central Nervous System Diseases

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
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.

Care bundle of active management

Usual care

An Investigator Initiated and Conducted, International, Multicenter, Stepped Wedge Cluster Randomized Study of a Care Bundle of Physiological Control Strategies in Acute Intracerebral Hemorrhage

modified Rankin Scale is a measure of physical function at 6 months, analyzed as an
ordinal outcome (categories scored as 0 'no symptoms' to 5 as 'fully dependent, and 6 as
death)

Executive Director

measure of quality of life on the EQ5D scale

measure of patient living status (e.g. home, high care)

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)

Patients receive the usual management based on local guidelines and hospital's individual
policy.

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

About this trial

Study ID

Status

Type

Phase

Placebo

Accepting

Not accepting

Trial Timing

What is this trial about?

What are the participation requirements?

Locations

Location

Status