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International Care Bundle Evaluation in Cerebral Hemorrhage Research

PHASE4NOT_YET_RECRUITING

Spontaneous intracerebral haemorrhage (ICH) accounts for approximately 10-15% of all strokes but stands for 50% of stroke-related morbidity and mortality. Approximately half of all patients with ICH have a decreased level of consciousness at hospital admission. Despite this, intensive care and neurosurgical interventions are uncommon.

A study conducted in low- and middle-income countries has demonstrated a beneficial effect of a treatment package consisting of early intensive blood pressure lowering, as well as the treatment of pyrexia and elevated blood glucose levels. The I-CATCHER team is now planning to conduct a similar study in Sweden and Australia, as well as in other high-income countries. The study has a clear focus on implementation, aiming to improve treatment and prognosis for patients with ICH within a few years.

The purpose of I-CATCHER is to investigate whether a structured treatment package (Care Bundle) improves 3-month prognosis in patients with spontaneous ICH compared to standard care.

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Study details:

Spontaneous intracerebral hemorrhage (ICH) accounts for 10 to 15% of all strokes in high-income countries (HIC), and nearly twice this number in low-income to upper-middle-income countries (LMIC) (29. 5%). It is the most devastating type of stroke given the high one-month case fatality of approximately 30-40%, and only 12-39% suffer persistent disability.

Despite several advances in the management of acute ischemic stroke supported by numerous randomized controlled trials (RCT), progress in establishing novel interventions to improve outcomes for ICH has been slow. Still today, the diagnosis of ICH evokes pessimism among treating physicians, and patients may be withheld guideline adherent treatment for this reason. This nihilistic approach is presumably due to an over-estimation of poor outcome, often influenced by the neurologically devastating features commonly present at ICH admission.

Additionally, the scarcity of RCTs providing strong evidence for treatment recommendations may contribute to a more reluctant approach in the acute setting of ICH, particularly when presenting with debilitating symptoms. The third INTEnsive care bundle with BP reduction in acute cerebral hemorrhage trial (INTERACT3) was recently published in 2023. This trial employed a stepped wedge cluster RCT design to evaluate the implementation of a Care Bundle protocol.

This comprehensive protocol included early intensive BP lowering (EIBPL), management of pyrexia and hyperglycemia, and the early reversal of OAC treatment. The design of this trial drew inspiration from a post-hoc analysis of the INTERACT2 study that showed that the scoring of abnormal baseline variables, interventions included in the future INTERACT3 Care Bundle, independently predicted a poor functional outcome following ICH. The implementation of the time sensitive bundle of care in INTERACT3 resulted in an improved functional outcome at 6 months following ICH.

However, as the trial included patients predominantly from LMIC, further studies are warranted to determine if these results are applicable to HIC with a more applicable Care Bundle for these populations. An earlier intervention study from the United Kingdom, published in 2019, studied a similar 'quality improvement' acute Care Bundle. This Care Bundle aimed to improve the speed of treatment delivery, access to acute care, and decrease case fatality following ICH.

Despite certain limitations, including a non-randomized design, this study demonstrated significantly lower mortality rates in patients receiving the Care Bundle versus the pre-implementation standard of care. I-CATCHER is an international, multicenter, batched, parallel, cluster, randomized clinical trial (RCT) to assess a multifaceted package of protocols in a broad range of patients with acute ICH. In each batch, hospitals will be randomized into two groups according to the timing of the intervention (Care Bundle) over 3 phases (phase 1: usual care, phase 2: randomized evaluation - to intervention or usual care, phase 3: post-implementation follow-up - all hospitals implement the intervention).

This design will capture consecutive patients with ICH and allow continued intervention in perpetuity as more hospitals join. Compared to a conventional stepped-wedge cluster RCT, the intervention effect in this design is less likely to be confounded by background temporal trends as only baseline and parallel comparison data (first 2 periods in bold black frame) are used to determine the effectiveness of the Care Bundle. All hospitals will be exposed to the Care Bundle which allows assessment of sustainability and integration of the intervention into routine practice.

Each batch period is 18 months (6 months per phase); whole study will be rolled out in 2. 5 years. This design involves implementation of an intervention package applied to all 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 follow-up procedures. Study site inclusion criteria: Organized systems of acute stroke care; no established comprehensive protocols for the management of ICH; suitable location, infrastructure and willingness to participate in clinical research; suitable numbers of ICH patients (at least 30 per year). Patient inclusion criteria: Adults (≥18 years) with spontaneous ICH confirmed by imaging and admitted hospital within 24 hours of the onset of symptoms.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

  • Adults (age ≥18 years)
  • Non-contrast computerized tomography (NCCT) imaging-verified diagnosis of spontaneous intracerebral haemorrhage
  • ≤24 hours from symptom onset or presumed symptom onset (last seen well)
  • Exclusion criteria

  • Previous care limitation
  • End-stage comorbidity with short life-expectancy (<6 m; e.g. terminal cancer)
  • ICH caused by brain tumor or cerebral venous thrombosis
  • Clinical signs of brain herniation at first presentation (unresponsive patient with bilaterally fixed, maximally dilated pupils)
  • Pregnant women beyond 22 weeks gestation may only be included after thorough discussion with an obstetrician to determine risks vs benefit.
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    Eligibility

    Age eligible for study : 18 and older

    Healthy volunteers accepted : No

    Gender eligible for study: All

    Things to know

    Study dates

    Study start: 2024-09-01

    Primary completion: 2026-10-01

    Study completion finish: 2027-03-31

    study type

    Study type

    TREATMENT

    phase

    Phase

      PHASE4

    trial

    Trial ID

    NCT06429332

    Intervention or treatment

    OTHER: Reversal of Oral anticoagulation within 30 minutes

    OTHER: Early intensive blood pressure lowering

    OTHER: Treatment of pyrexia

    OTHER: Hyperglycemia treatment

    OTHER: Do-not-resuscitate (DNR) or withdrawal of care

    OTHER: Referral to Intensive Care

    OTHER: Referral to Neurosurgery

    DIAGNOSTIC_TEST: Repeat brain imaging

    OTHER: Standard care

    Conditions

    • Intracerebral Hemorrhage
    • Intraventricular Hemorrhage
    • Stroke
    • Cerebrovascular Disease
    • Intracerebral Haemorrhage
    Image related to Intracerebral Hemorrhage
    • Condition: Intracerebral Hemorrhage, Intraventricular Hemorrhage and more

    • OTHER: Reversal of Oral anticoagulation within 30 minutes and other drugs

    • Sydney, Not Specified, Australia

    • Sponsor: Region Skane

    Find a site

    Closest Location:

    The George Institute for Global Health

    Research sites nearby

    Select from list below to view details:

    • The George Institute for Global Health

      Sydney, Not Specified, Australia

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    Study Plan

    This section provides details of the study plan, including how the study is designed and what the study is measuring.

    How is the study designed?

    Participant Group/ArmIntervention/Treatment
    ACTIVE_COMPARATOR: Intervention group
    • A range of implementation methods will be used to introduce an active Care Bundle with time- and target-based metrics that involve the rapid correction of abnormal physiological variables over days or hospital discharge (or death, if sooner) and referral pathways
    OTHER: Reversal of Oral anticoagulation within 30 minutes
    • In situations of either an elevated INR with the use of warfarin - treatment with either 3- or 4-factor prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) within 30 minutes of hospital arrival to reach and maintain an INR target \<1.3; or where there has been recent use (\<48 hours) of a direct oral anticoagulant (DOAC), use of an appropriate reversal agent within 30 minutes, where available, and according to local approvals.
    PLACEBO_COMPARATOR: Usual care
    • For patients in the usual-care group, decisions about the location of care delivery, investigations, monitoring, and all treatments are made by the treating clinical team. Data will be collected regarding the management of patients, including insertion of invasive monitoring devices, intravenous fluid resuscitation, BP lowering, vasoactive support, glycemic control, mechanical ventilation, neurosurgery, and other supportive therapy.
    OTHER: Standard care
    • For patients in the usual-care group, decisions about the location of care delivery, investigations, monitoring, and all treatments are made by the treating clinical team. Data will be collected regarding the management of patients, including insertion of invasive monitoring devices, intravenous fluid resuscitation, BP lowering, vasoactive support, glycemic control, mechanical ventilation, neurosurgery, and other supportive therapy.

    What is the study measuring?

    Primary outcome

    Primary Outcome MeasurePrimary Outcome DescriptionPrimary Outcome Time Frame
    Evaluation of functional outcome based on the Utility Weighted modified Rankin Scale scoreThe modified Rankin Scale (mRS) is an efficient, reliable, and simple functional outcome measure widely used as a primary endpoint in clinical trials for acute stroke. However, being an ordered categorical scale, it may not reflect potentially unequal differences in perceived quality of life associated with certain 1-point shifts vs others. Utility-weighted mRS is a score that weighs the mRS against a health utility scale, which defined as the desirability of a specific health outcome, facilitates comparisons of health-related quality of life across an array of clinical settings. Utility weights, as referred to hereafter, reflect the spectrum between perfect health (a score of 1) and outcomes worse than death (where death is a score of 0 and negative values indicate an outcome worse than death). The primary outcome is UW-mRS at 3 months and will be analyzed by means of a linear regression, with mRS as a dependent variable with 7 levels (0 \[no residual symptom\] to 6 \[death\]).180±30 days

    Secondary outcome

    Secondary Outcome MeasureSecondary Outcome DescriptionSecondary Outcome Time Frame
    Ordinal shift analysis of mRSThe assessment of shifts in the distribution of mRS scores through the evaluation of scores in ordinal groups180 days±30 days
    Assessment of health-related quality of life (HRQoL)This will be assessed using the EuroQoL Group 5-Dimension self-report questionnaire (EQ-5D). The VAS is a scale from 0 (worst imaginable health state) to 100 (best imaginable health state).180 days±30 days
    Poor outcome defined as mRS 3-6Binary secondary outcomes will be analyzed by means of standard GEE or random-effects regression with a logistic link and/or time-to-event type endpoints using the Cox model with a sandwich formula or a frailty model.180 days±30 days
    Separate outcomes for death and disabilityBinary secondary outcomes will be analyzed by means of standard GEE or random-effects regression with a logistic link and/or time-to-event type endpoints using the Cox model with a sandwich formula or a frailty model.180 days±30 days

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    References

    Clinical Trials Gov: International Care Bundle Evaluation in Cerebral Hemorrhage Research

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