Clinical trial NCT06429332: International Care Bundle Evaluation in Cerebral Hemorrhage Research
Official title: International Care Bundle Evaluation in Cerebral Hemorrhage Research - a Batched Parallel Cluster-randomized Trial With a Baseline Period
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Intracerebral Hemorrhage
Intracerebral Haemorrhage
Intraventricular Hemorrhage
Stroke
Cerebrovascular Disease
Keywords: intracerebral hemorrhage
oral anticoagulant
blood pressure lowering
early intensive blood pressure lowering
care bundle
implementation study
reversal treatment
outcome
UW-mRS
Modified Rankin Scale
Lead sponsor: Region Skane
Sponsor class: OTHER
Collaborators: name: The George Institute for Global Health, Australia
name: Ottawa Hospital Research Institute
First posted: 2024-05-24
Enrollment: 3500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: international multicentre, batched, cluster. Patients are not randomized, hospitals will be randomized.

In each batch, hospitals are randomized into two groups according to the timing of the intervention (Care Bundle) over 3 phases (usual care, randomized evaluation, post-implementation follow-up):

Phase 1 - baseline routine data collection, training and formative study (assess context and local resources, support adjustment of the protocol into local pathways) Phase 2 - start intervention implementation in the intervention group, data collection for comparison with usual care in the control group Phase 3 - all hospitals implement the intervention, data collection for quality improvement, assess sustainability and integration
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Evaluation of functional outcome based on the Utility Weighted modified Rankin Scale score
timeFrame: 180±30 days
Secondary outcomes:
measure: Ordinal shift analysis of mRS
timeFrame: 180 days±30 days
measure: Assessment of health-related quality of life (HRQoL)
timeFrame: 180 days±30 days
measure: Poor outcome defined as mRS 3-6
timeFrame: 180 days±30 days
measure: Separate outcomes for death and disability
timeFrame: 180 days±30 days
Other outcomes:
Locations:
city: Sydney
country: Australia
facility: The George Institute for Global Health
city: Ottawa
country: Canada
facility: Ottawa Hospital Research Institute
state: Ontario
city: Helsingborg
country: Sweden
facility: Helsingborgs Lasarett
city: Hässleholm
country: Sweden
facility: Hässleholms Sjukhus
city: Karlskrona
country: Sweden
facility: Blekingesjukhuset
city: Kristianstad
country: Sweden
facility: Centralsjukhuset Kristianstad
city: Lund
country: Sweden
facility: Skåne University Hospital Lund Neurosurgery dept
city: Lund
country: Sweden
facility: Skåne University Hospital Lund
city: Malmö
country: Sweden
facility: Region Skåne, Skåne University Hospital in Malmö, Department of Neurology
city: Sundsvall
country: Sweden
facility: Länssjukhuset Sundsvall
city: Umeå
country: Sweden
facility: Norrlands Universitetssjukhus
city: Växjö
country: Sweden
facility: Centrallasarettet Växjö
city: Ystad
country: Sweden
facility: Ystads lasarett
city: Östersund
country: Sweden
facility: Östersunds Lasarett
Study officials:
References:
citation: GBD 2019 Stroke Collaborators. Global, regional, and national burden of stroke and its risk factors, 1990-2019: a systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol. 2021 Oct;20(10):795-820. doi: 10.1016/S1474-4422(21)00252-0. Epub 2021 Sep 3.
citation: Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage. N Engl J Med. 2001 May 10;344(19):1450-60. doi: 10.1056/NEJM200105103441907. No abstract available.
citation: van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010 Feb;9(2):167-76. doi: 10.1016/S1474-4422(09)70340-0. Epub 2010 Jan 5.
citation: Parry-Jones AR, Sammut-Powell C, Paroutoglou K, Birleson E, Rowland J, Lee S, Cecchini L, Massyn M, Emsley R, Bray B, Patel H. An Intracerebral Hemorrhage Care Bundle Is Associated with Lower Case Fatality. Ann Neurol. 2019 Oct;86(4):495-503. doi: 10.1002/ana.25546. Epub 2019 Aug 16.
citation: Hemphill JC 3rd, Newman J, Zhao S, Johnston SC. Hospital usage of early do-not-resuscitate orders and outcome after intracerebral hemorrhage. Stroke. 2004 May;35(5):1130-4. doi: 10.1161/01.STR.0000125858.71051.ca. Epub 2004 Mar 25.
citation: Becker KJ, Baxter AB, Cohen WA, Bybee HM, Tirschwell DL, Newell DW, Winn HR, Longstreth WT Jr. Withdrawal of support in intracerebral hemorrhage may lead to self-fulfilling prophecies. Neurology. 2001 Mar 27;56(6):766-72. doi: 10.1212/wnl.56.6.766.
citation: Zahuranec DB, Brown DL, Lisabeth LD, Gonzales NR, Longwell PJ, Smith MA, Garcia NM, Morgenstern LB. Early care limitations independently predict mortality after intracerebral hemorrhage. Neurology. 2007 May 15;68(20):1651-7. doi: 10.1212/01.wnl.0000261906.93238.72.
citation: Song L, Hu X, Ma L, Chen X, Ouyang M, Billot L, Li Q, Munoz-Venturelli P, Abanto C, Pontes-Neto OM, Antonio A, Wasay M, Silva A, Thang NH, Pandian JD, Wahab KW, You C, Anderson CS; INTERACT3 investigators. INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): study protocol for a pragmatic stepped-wedge cluster-randomized controlled trial. Trials. 2021 Dec 20;22(1):943. doi: 10.1186/s13063-021-05881-7.