## Protocol Section
### Identification Module
**NCT ID:** NCT06429332

**Acronym:** I-CATCHER

**Brief Title:** 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

#### Organization Study ID Info
**ID:** 2024-02523-01
#### Organization
**Class:** OTHER
**Full Name:** Region Skane
### Status Module
#### Completion Date
**Date:** 2027-03-31

**Type:** ESTIMATED

#### Expanded Access Info
#### Last Update Post Date
**Date:** 2024-05-24

**Type:** ACTUAL

**Last Update Submit Date:** 2024-05-20

**Overall Status:** NOT_YET_RECRUITING

#### Primary Completion Date
**Date:** 2026-10-01

**Type:** ESTIMATED

#### Start Date
**Date:** 2024-09-01

**Type:** ESTIMATED

**Status Verified Date:** 2024-04

#### Study First Post Date
**Date:** 2024-05-24
**Type:** ACTUAL
**Study First Submit Date:** 2024-05-14
**Study First Submit QC Date:** 2024-05-20
### Sponsor Collaborators Module

#### Collaborators

**Class:** OTHER

**Name:** The George Institute for Global Health, Australia

#### Lead Sponsor

**Class:** OTHER

**Name:** Region Skane

#### Responsible Party

**Type:** SPONSOR

### Oversight Module

**Is FDA Regulated Device:** False

**Is FDA Regulated Drug:** False

**Oversight Has DMC:** True

### Description Module

**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.

### Conditions Module

**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

### Design Module

#### Design Info

**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

##### Masking Info

**Masking:** SINGLE

**Masking Description:** Treatment allocation is on a site-level and not on an individual level. The allocation is not blinded. Follow-up clinical outcome assessors, who have no prior association with the study and are unaware of the patients' allocation to either the intervention or control arm, will contact the participant by telephone at 6 months. At the initiation of contact, study subjects will be urged not to disclose their treatment allocation.

**Who Masked:**

- OUTCOMES_ASSESSOR

**Primary Purpose:** TREATMENT

#### Enrollment Info

**Count:** 3500

**Type:** ESTIMATED

**Phases:**

- PHASE4

**Study Type:** INTERVENTIONAL

### Arms Interventions Module

#### Arm Group 1

**Description:** 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

**Intervention Names:**

- 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

**Label:** Intervention group

**Type:** ACTIVE_COMPARATOR

#### Arm Group 2

**Description:** 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.

**Intervention Names:**

- Other: Standard care

**Label:** Usual care

**Type:** PLACEBO_COMPARATOR

### Interventions

#### Intervention 1

**Arm Group Labels:**

- Intervention group

**Description:** 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.

**Name:** Reversal of Oral anticoagulation within 30 minutes

**Other Names:**

- OAC reversal

**Type:** OTHER

#### Intervention 2

**Arm Group Labels:**

- Intervention group

**Description:** A systolic blood pressure (BP) target of 130-140 mmHg within 30 minutes of commencing treatment is strived for, and to maintain this BP level for the first 7 days (for patients presenting with blood pressure \<200 mmHg). If blood pressure ≥200 and \<220, a target BP of 160 mmHg should be targeted at 30 minutes, and 130-140 mmHg should be achieved in 60 minutes. If BP ≥220, target BP of 160 mmHg and should be achieved in 60 minutes.

**Name:** Early intensive blood pressure lowering

**Type:** OTHER

#### Intervention 3

**Arm Group Labels:**

- Intervention group

**Description:** To achieve a body temperature target \<37.5 °C

**Name:** Treatment of pyrexia

**Type:** OTHER

#### Intervention 4

**Arm Group Labels:**

- Intervention group

**Description:** To maintain a blood glucose level 7-10 mmol/L

**Name:** Hyperglycemia treatment

**Type:** OTHER

#### Intervention 5

**Arm Group Labels:**

- Intervention group

**Description:** Refrain from the use of DNR or withdrawal of care orders for 48 hours

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

**Type:** OTHER

#### Intervention 6

**Arm Group Labels:**

- Intervention group

**Description:** Immediate (\<30 min) referral to intensive care if airway, breathing and/or circulation are compromized

**Name:** Referral to Intensive Care

**Type:** OTHER

#### Intervention 7

**Arm Group Labels:**

- Intervention group

**Description:** Immediate (\<30 min) referral to neurosurgery if any of the following criteria are fulfilled:

* Large and/or rapidly evolving supratentorial ICH (\>20 ml volume)
* Any intraventricular extension
* Posterior fossa bleed, irrespective of volume
* Suspicion of a vascular malformation, independent of volume or location
* Reduction in reaction to sensory stimulation or drowsiness

**Name:** Referral to Neurosurgery

**Type:** OTHER

#### Intervention 8

**Arm Group Labels:**

- Intervention group

**Description:** Repeat 6-12-hour brain imaging with the physicians choice of modality, preferably computed tomography (CT), if clinical deterioration or the patient received OAC reversal treatment

**Name:** Repeat brain imaging

**Type:** DIAGNOSTIC_TEST

#### Intervention 9

**Arm Group Labels:**

- Usual care

**Description:** 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.

**Name:** Standard care

**Type:** OTHER

### Outcomes Module

#### Primary Outcomes

**Description:** The 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 \[death\]).

**Measure:** Evaluation of functional outcome based on the Utility Weighted modified Rankin Scale score

**Time Frame:** 180±30 days

#### Secondary Outcomes

**Description:** The assessment of shifts in the distribution of mRS scores through the evaluation of scores in ordinal groups

**Measure:** Ordinal shift analysis of mRS

**Time Frame:** 180 days±30 days

**Description:** 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).

**Measure:** Assessment of health-related quality of life (HRQoL)

**Time Frame:** 180 days±30 days

**Description:** Binary 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.

**Measure:** Poor outcome defined as mRS 3-6

**Time Frame:** 180 days±30 days

**Description:** Binary 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.

**Measure:** Separate outcomes for death and disability

**Time Frame:** 180 days±30 days

### Eligibility Module

**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.

**Minimum Age:** 18 Years

**Sex:** ALL

**Standard Ages:**

- ADULT

- OLDER_ADULT

### Contacts Locations Module

#### Central Contacts

**Contact 1:**

**Email:** i-catcher@med.lu.se

**Name:** Teresa Ullberg, MD, PhD

**Phone:** 0046175057

**Role:** CONTACT

#### Locations

**Location 1:**

**City:** Sydney

**Contacts:**

***Contact 1:***

- **Email:** mouyang@georgeinstitute.org.au

- **Name:** Menglu Ouyang, PhD, MPH

- **Phone:** 0061280524808

- **Role:** CONTACT

***Contact 2:***

- **Name:** Menglu Ouyang, PhD, MPH

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** Australia

**Facility:** The George Institute for Global Health

**Zip:** NSW 2000

**Location 2:**

**City:** Malmö

**Contacts:**

***Contact 1:***

- **Email:** i-catcher@med.lu.se

- **Name:** Teresa Ullberg, MD, PhD

- **Phone:** +4646175057

- **Role:** CONTACT

***Contact 2:***

- **Name:** Trine Apostolaki-Hansson, MD PhD

- **Role:** PRINCIPAL_INVESTIGATOR

***Contact 3:***

- **Name:** Fredrik Buchwald, MD PhD

- **Role:** PRINCIPAL_INVESTIGATOR

**Country:** Sweden

**Facility:** Region Skåne, Skåne University Hospital in Malmö, Department of Neurology

**Zip:** 20502

### IPD Sharing Statement Module

**IPD Sharing:** NO

### References Module

#### 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.

**PMID:** 34487721

**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.

**PMID:** 11346811

**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.

**PMID:** 20056489

**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.

**PMID:** 31291031

**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.

**PMID:** 15044768

**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.

**PMID:** 11274312

**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.

**PMID:** 17502545

**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.

**PMID:** 34930428

## Derived Section

### Condition Browse Module - Ancestors

- ID: D000010335

- Term: Pathologic Processes

- ID: D000020300

- Term: Intracranial Hemorrhages

- ID: D000001927

- Term: Brain Diseases

- ID: D000002493

- Term: Central Nervous System Diseases

- ID: D000009422

- Term: Nervous System Diseases

- ID: D000014652

- Term: Vascular Diseases

- ID: D000002318

- Term: Cardiovascular Diseases

### Condition Browse Module - Browse Branches

- Abbrev: BC23

- Name: Symptoms and General Pathology

- Abbrev: All

- Name: All Conditions

- Abbrev: BC10

- Name: Nervous System Diseases

- Abbrev: BC14

- Name: Heart and Blood Diseases

### Condition Browse Module - Browse Leaves

- ID: M9556

- Name: Hemorrhage

- Relevance: HIGH

- As Found: Hemorrhage

- ID: M22306

- Name: Stroke

- Relevance: LOW

- As Found: Unknown

- ID: M5792

- Name: Cerebral Hemorrhage

- Relevance: HIGH

- As Found: Intracerebral Hemorrhage

- ID: M5810

- Name: Cerebrovascular Disorders

- Relevance: HIGH

- As Found: Cerebrovascular Disease

- ID: M11910

- Name: Mitral Valve Insufficiency

- Relevance: LOW

- As Found: Unknown

- ID: M22113

- Name: Intracranial Hemorrhages

- Relevance: LOW

- As Found: Unknown

- ID: M5204

- Name: Brain Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M5742

- Name: Central Nervous System Diseases

- Relevance: LOW

- As Found: Unknown

- ID: M17400

- Name: Vascular Diseases

- Relevance: LOW

- As Found: Unknown

### Condition Browse Module - Meshes

- ID: D000002543

- Term: Cerebral Hemorrhage

- ID: D000002561

- Term: Cerebrovascular Disorders

- ID: D000006470

- Term: Hemorrhage

### Intervention Browse Module - Browse Branches

- Abbrev: Infe

- Name: Anti-Infective Agents

- Abbrev: All

- Name: All Drugs and Chemicals

- Abbrev: AnCoag

- Name: Anticoagulants

- Abbrev: Coag

- Name: Coagulants

- Abbrev: CNSDep

- Name: Central Nervous System Depressants

- Abbrev: Ot

- Name: Other Dietary Supplements

### Intervention Browse Module - Browse Leaves

- ID: M11767

- Name: Metronidazole

- Relevance: LOW

- As Found: Unknown

- ID: M17602

- Name: Warfarin

- Relevance: LOW

- As Found: Unknown

- ID: M4244

- Name: Anticoagulants

- Relevance: LOW

- As Found: Unknown

- ID: M16676

- Name: Thrombin

- Relevance: LOW

- As Found: Unknown

- ID: M4854

- Name: Benzocaine

- Relevance: LOW

- As Found: Unknown

- ID: T433

- Name: Tannic Acid

- Relevance: LOW

- As Found: Unknown

### Misc Info Module

- Version Holder: 2024-05-31
