Cerebral HemorrhageINTERACT3NCT03209258
The Third, Intensive Care Bundle With Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial
A study testing Care bundle of active management in people with Cerebral Hemorrhage and Stroke, run by The George Institute for Global Health, China at 1 site in China.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Cerebral Hemorrhage, Stroke, Hypertension
- What is being tested?
- Care bundle of active management
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 7,067 participants
- Where
- 1 siteChina
- Study dates
- 12 Dec 2017to 17 Nov 2022
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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.
Who cannot join
- 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.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: An Investigator Initiated and Conducted, International, Multicenter, Stepped Wedge Cluster Randomized Study of a Care Bundle of Physiological Control Strategies in Acute Intracerebral Hemorrhage
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.
Read the detailed description
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.
- Conditions
- Cerebral Hemorrhage, Stroke, Hypertension, Diabetes, Anticoagulant-induced Bleeding, Cerebral Vascular Disorder
- Being tested
- Care bundle of active management, Usual care
- Keywords
- Stroke, Intracerebral Hemorrhage, Care Bundle, Clinical Trial, Stepped-wedge Cluster, Management, Blood Pressure
- Medical subject headings
- Cerebral Hemorrhage, Stroke, Hypertension, Diabetes Mellitus, Cerebrovascular Disorders, Brain Diseases, Hemorrhage, Intracranial Hemorrhages
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Care bundle of active managementOther
Also called Early intensive BP lowing, Intensive glucose control, Early treatment of pyrexia, Reversal of anticoagulation
- Intensive BP lowering to systolic target of <140mmHg;
- Glucose control target 6.1-7.8 mmol/l for non-diabetic; 7.8-10.0 mmol/l for diabetic patients;
- Treatment of pyrexia to a target body temperature ≤37.5 ℃;
- Reversal of anticoagulation to target INR <1.5 involving use of vitamin K and prothrombin complex concentrate (PCC) or alternatively, fresh frozen plasma (FFP).
As the trial is an assessment of care bundle of physiological management, there is some flexibility in the use of particular BP lowering agents and antipyretic agents to achieve targets.
Usual careOther
Usual care decisions about the location of care delivery, investigations, monitoring, and all treatments will be made by the treating clinical team.
| Study group | Role | What they receive |
|---|---|---|
| Goal-directed care bundle | Other | 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) Receives: Other: Care bundle of active management |
| Usual care group | Other | Patients receive the usual management based on local guidelines and hospital's individual policy. Receives: Other: Usual care |
What is being measured
The primary outcome is the main question the study is designed to answer.
Shift ('improvement') in functional recovery (death or disability) defined by the modified Rankin Scale (mRS)
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)
Measured: 6 months
Secondary outcomes (7)
Shift ('improvement') in survival and neurological impairment defined by scores on the National Institutes of Health Stroke Scale (NIHSS)
measure of physical function
Measured: 7 days
Death or disability defined by scores of 3-6 on the mRS
measure of physical function
Measured: 6 months
Death
measure of vital status
Measured: 6 months
Disability defined by scores 3-5 on the mRS
measure of physical function
Measured: 6 months
Health-related quality of life (HRQoL)
measure of quality of life on the EQ5D scale
Measured: 6 months
Duration of initial hospitalization
measure of severity and service use
Measured: 6 months
Residence
measure of patient living status (e.g. home, high care)
Measured: 6 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Jul 2017
- Study start12 Dec 2017
- Primary completion12 Oct 2022
- Study completion17 Nov 2022
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (12)Papers the sponsor has linked to this study.
- Other trials for Cerebral HemorrhageStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Model description
- Stepped-wedge Cluster Randomised Trial
- Masking
- Single blind
- Who is masked
- Outcomes assessor
- Enrolment
- 7,067 participants (actual)
Sponsor and investigators
- Lead sponsor
- The George Institute for Global Health, China
- Sponsor type
- University, hospital or other
- Collaborators
- West China Hospital, Sichuan Credit Pharmaceutical Co., Ltd., Takeda, National Institute for Health Research, United Kingdom, Department for International Development, United Kingdom, UK Research and Innovation, Medical Research Council
- Responsible party
- Principal investigator, Craig Anderson, The George Institute for Global Health, China
- Investigators
- Craig S Anderson, PhD, Principal investigator, The George Institute for Global Health, ChinaChao You, PhD, Principal investigator, West China Hospital
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03209258
- Sponsor's protocol ID
- ICH-WCH&GI
- Acronym
- INTERACT3
- Status last verified
- Nov 2022
- First submitted
- 1 Jul 2017
- Last updated
- 29 Nov 2022
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- No
Publications
Ren X, Chen X, Hu X, Lin Y, Chen C, Wang J, Robinson TG, Liu L, Venturelli PM, Martins SC, Pontes-Neto OM, Qureshi AI, Song L, Anderson C, Wang X; as the INTERACT and ATACH-II Investigators. Effects of Blood Pressure Lowering by Hematoma Location in Acute Intracerebral Hemorrhage. Neurology. 2026 Nov 10;107(9):e218514. doi: 10.1212/WNL.0000000000218514. Epub 2026 Oct 8.
PubMed 42848972Liu T, Chen L, Liu L, Liu Y, Ma L, Billot L, Li Q, Zhao Z, Malavera A, Munoz-Venturelli P, de Silva A, Nguyen HT, Wahab KW, Pandian JD, Wasay M, Pontes-Neto OM, Jiang R, Abanto C, Arauz A, Song L, You C, Anderson CS, Hu X, Chen X; INTERACT3 Investigators. Impact of Ultra-Early Perioperative Antihypertensive Therapy in Acute Intracerebral Hemorrhage. Stroke. 2026 Jun;57(6):1549-1562. doi: 10.1161/STROKEAHA.125.053989. Epub 2026 Mar 24.
PubMed 41873543Wang X, Phan TG, Ren X, Ma HH, Li Q, Ouyang M, Delcourt C, Chen X, Wang J, Robinson TG, Arima H, Ma L, Hu X, You C, Liu L, Venturelli PM, Martins SC, Pontes-Neto OM, Chalmers JP, Song L, Qureshi AI, Anderson C. Systolic Blood Pressure Trajectory and Outcomes in Acute Intracerebral Hemorrhage: Pooled Analysis of the 4 INTERACT and ATACH-II Clinical Trials. Neurology. 2026 Apr 14;106(7):e214671. doi: 10.1212/WNL.0000000000214671. Epub 2026 Mar 19.
PubMed 41855454Ren X, Li Q, Ouyang M, Billot L, Chen X, Venturelli PM, de Silva A, Nguyen TH, Wahab KW, Pandian JD, Wasay M, Pontes-Neto OM, Abanto C, Arauz A, You C, Ma L, Hu X, Anderson C, Wang X, Song L; as the INTERACT3 Investigators. Mediation Analysis to Identify Individual Component Effects of the Care Bundle to Improve Functional Outcome After ICH in the INTERACT3 Study. Neurology. 2025 Oct;105(7):e214070. doi: 10.1212/WNL.0000000000214070. Epub 2025 Sep 12.
PubMed 40939125Hu X, Ouyang M, Xu J, Liu Y, Li X, Jiang Y, Chen X, Billot L, Li MBiostat Q, Malavera A, Venturelli PMO, de Silva A, Thang NH, Wahab KW, Pandian JD, Wasay M, Pontes-Neto OM, Abanto C, Arauz A, Li Z, Chen M, Wang X, Yang C, Xin X, Jiang D, Zheng J, Yu Z, Xiao A, Tao C, Chen L, Wu B, Li H, Anderson CS, You C, Song L, Ma L; INTERACT3 Investigators. Surgical outcomes from haematoma evacuation for intracerebral haemorrhage in the INTERACT3 study. Lancet Reg Health West Pac. 2025 Aug 28;62:101669. doi: 10.1016/j.lanwpc.2025.101669. eCollection 2025 Sep.
PubMed 40927652Wang X, Ren X, Li Q, Ouyang M, Chen C, Delcourt C, Chen X, Wang J, Robinson T, Arima H, Ma L, Hu X, You C, Li G, Jie Y, Lin Y, Billot L, Munoz-Venturelli P, Martins S, Pontes-Neto OM, Liu L, Chalmers J, Carcel C, Song L, Anderson CS; INTERACT Investigators. Effects of blood pressure lowering in relation to time in acute intracerebral haemorrhage: a pooled analysis of the four INTERACT trials. Lancet Neurol. 2025 Jul;24(7):571-579. doi: 10.1016/S1474-4422(25)00160-7.
PubMed 40541207Ouyang M, Anjum A, Mc Cawley FG, Wasay M, Ma L, Hu X, Chen X, Malavera A, Li X, Venturelli PM, Silva HA, Thang NH, Wahab KW, Pandian JD, Pontes-Neto OM, Abanto C, Cano-Nigenda V, Arauz A, You C, Jan S, Song L, Anderson CS, Liu H; INTERACT3 Investigators. Implementation of a goal-directed Care Bundle for intracerebral hemorrhage: Results of embedded process evaluation in the INTERACT3 trial. PLOS Glob Public Health. 2024 Dec 19;4(12):e0003711. doi: 10.1371/journal.pgph.0003711. eCollection 2024.
PubMed 39700102Ma L, Hu X, Song L, Chen X, Ouyang M, Billot L, Li Q, Malavera A, Li X, Munoz-Venturelli P, de Silva A, Thang NH, Wahab KW, Pandian JD, Wasay M, Pontes-Neto OM, Abanto C, Arauz A, Shi H, Tang G, Zhu S, She X, Liu L, Sakamoto Y, You S, Han Q, Crutzen B, Cheung E, Li Y, Wang X, Chen C, Liu F, Zhao Y, Li H, Liu Y, Jiang Y, Chen L, Wu B, Liu M, Xu J, You C, Anderson CS; INTERACT3 Investigators. The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial. Lancet. 2023 Jul 1;402(10395):27-40. doi: 10.1016/S0140-6736(23)00806-1. Epub 2023 May 25.
PubMed 37245517Billot L, Song L, Hu X, Ma L, Ouyang M, Chen X, You C, Anderson CS; INTERACT3 Investigators. Statistical Analysis Plan for the INTEnsive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial: A Stepped-Wedge Cluster Randomized Controlled Trial. Cerebrovasc Dis. 2023;52(3):251-254. doi: 10.1159/000526384. Epub 2022 Sep 5.
PubMed 36063792Ouyang M, Anderson CS, Song L, Malavera A, Jan S, Cheng G, Chu H, Hu X, Ma L, Chen X, You C, Liu H. Process Evaluation of an Implementation Trial: Design, Rationale, and Early Lessons Learnt From an International Cluster Clinical Trial in Intracerebral Hemorrhage. Front Med (Lausanne). 2022 Jun 15;9:813749. doi: 10.3389/fmed.2022.813749. eCollection 2022.
PubMed 35783649Song 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.
PubMed 34930428Ouyang M, Anderson CS, Song L, Jan S, Sun L, Cheng G, Chu H, Hu X, Ma L, Chen X, You C, Liu H. Implementing a Goal-Directed Care Bundle after Acute Intracerebral Haemorrhage: Process Evaluation for the Third INTEnsive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial Study in China. Cerebrovasc Dis. 2022;51(3):373-383. doi: 10.1159/000520669. Epub 2021 Dec 20.
PubMed 34929690
Study at a glance
From the registry record, last updated by the sponsor on 29 Nov 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- An Investigator Initiated and Conducted, International, Multicenter, Stepped Wedge Cluster Randomized Study of a Care Bundle of Physiological Control Strategies in Acute Intracerebral Hemorrhage
- ClinicalTrials.gov ID
- NCT03209258
- Acronym / sponsor ID
- INTERACT3 / ICH-WCH&GI
- Conditions
- Cerebral Hemorrhage, Stroke, Hypertension, Diabetes, Anticoagulant-induced Bleeding, Cerebral Vascular Disorder
- Keywords
- Stroke, Intracerebral Hemorrhage, Care Bundle, Clinical Trial, Stepped-wedge Cluster, Management, Blood Pressure
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 7,067 participants (actual)
- Lead sponsor
- The George Institute for Global Health, ChinaUniversity, hospital or other
- Collaborators
- West China Hospital, Sichuan Credit Pharmaceutical Co., Ltd., Takeda, National Institute for Health Research, United Kingdom, Department for International Development, United Kingdom, UK Research and Innovation, Medical Research Council
- Study start
- 12 Dec 2017 (actual)
- Primary completion
- 12 Oct 2022 (actual)
- Study completion
- 17 Nov 2022 (actual)
- First posted
- 6 Jul 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Sequential
- Masking
- Single blind (outcomes assessor)
- Number of arms
- 2
- Model description
- Stepped-wedge Cluster Randomised Trial
| Arm | Type | Receives |
|---|---|---|
| Goal-directed care bundle | Other | Other: Care bundle of active managementManagement 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) |
| Usual care group | Other | Other: Usual carePatients receive the usual management based on local guidelines and hospital's individual policy. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (3 listed)
- 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.
Key exclusion criteria (2 listed)
- 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.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Care bundle of active managementAlso: Early intensive BP lowing, Intensive glucose control, Early treatment of pyrexia, Reversal of anticoagulation1. Intensive BP lowering to systolic target of <140mmHg; 2. Glucose control target 6.1-7.8 mmol/l for non-diabetic; 7.8-10.0 mmol/l for diabetic patients; 3. Treatment of pyrexia to a target body temperature ≤37.5 ℃; 4. Reversal of anticoagulation to target INR <1.5 involving use of vitamin K and prothrombin complex concentrate (PCC) or alternatively, fresh frozen plasma (FFP). As the trial is an assessment of care bundle of physiological management, there is some flexibility in the use of particular BP lowering agents and antipyretic agents to achieve targets. | Other | Goal-directed care bundle |
| Usual careUsual care decisions about the location of care delivery, investigations, monitoring, and all treatments will be made by the treating clinical team. | Other | Usual care group |
Primary outcome
Shift ('improvement') in functional recovery (death or disability) defined by the modified Rankin Scale (mRS)
Time frame: 6 months
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)
7 secondary outcomes
Shift ('improvement') in survival and neurological impairment defined by scores on the National Institutes of Health Stroke Scale (NIHSS)
Time frame: 7 days
Death or disability defined by scores of 3-6 on the mRS
Time frame: 6 months
Death
Time frame: 6 months
Disability defined by scores 3-5 on the mRS
Time frame: 6 months
Health-related quality of life (HRQoL)
Time frame: 6 months
Duration of initial hospitalization
Time frame: 6 months
Residence
Time frame: 6 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 29 Nov 2022.
- Derived from this study: PubMed 42848972Ren X, Chen X, Hu X, Lin Y, Chen C, Wang J, Robinson TG, Liu L, Venturelli PM, Martins SC, Pontes-Neto OM, Qureshi AI, Song L, Anderson C, Wang X; as the INTERACT and ATACH-II Investigators. Effects of Blood Pressure Lowering by Hematoma Location in Acute Intracerebral Hemorrhage. Neurology. 2026 Nov 10;107(9):e218514. doi: 10.1212/WNL.0000000000218514. Epub 2026 Oct 8.
- Derived from this study: PubMed 41873543Liu T, Chen L, Liu L, Liu Y, Ma L, Billot L, Li Q, Zhao Z, Malavera A, Munoz-Venturelli P, de Silva A, Nguyen HT, Wahab KW, Pandian JD, Wasay M, Pontes-Neto OM, Jiang R, Abanto C, Arauz A, Song L, You C, Anderson CS, Hu X, Chen X; INTERACT3 Investigators. Impact of Ultra-Early Perioperative Antihypertensive Therapy in Acute Intracerebral Hemorrhage. Stroke. 2026 Jun;57(6):1549-1562. doi: 10.1161/STROKEAHA.125.053989. Epub 2026 Mar 24.
- Derived from this study: PubMed 41855454Wang X, Phan TG, Ren X, Ma HH, Li Q, Ouyang M, Delcourt C, Chen X, Wang J, Robinson TG, Arima H, Ma L, Hu X, You C, Liu L, Venturelli PM, Martins SC, Pontes-Neto OM, Chalmers JP, Song L, Qureshi AI, Anderson C. Systolic Blood Pressure Trajectory and Outcomes in Acute Intracerebral Hemorrhage: Pooled Analysis of the 4 INTERACT and ATACH-II Clinical Trials. Neurology. 2026 Apr 14;106(7):e214671. doi: 10.1212/WNL.0000000000214671. Epub 2026 Mar 19.
- Derived from this study: PubMed 40939125Ren X, Li Q, Ouyang M, Billot L, Chen X, Venturelli PM, de Silva A, Nguyen TH, Wahab KW, Pandian JD, Wasay M, Pontes-Neto OM, Abanto C, Arauz A, You C, Ma L, Hu X, Anderson C, Wang X, Song L; as the INTERACT3 Investigators. Mediation Analysis to Identify Individual Component Effects of the Care Bundle to Improve Functional Outcome After ICH in the INTERACT3 Study. Neurology. 2025 Oct;105(7):e214070. doi: 10.1212/WNL.0000000000214070. Epub 2025 Sep 12.
- Derived from this study: PubMed 40927652Hu X, Ouyang M, Xu J, Liu Y, Li X, Jiang Y, Chen X, Billot L, Li MBiostat Q, Malavera A, Venturelli PMO, de Silva A, Thang NH, Wahab KW, Pandian JD, Wasay M, Pontes-Neto OM, Abanto C, Arauz A, Li Z, Chen M, Wang X, Yang C, Xin X, Jiang D, Zheng J, Yu Z, Xiao A, Tao C, Chen L, Wu B, Li H, Anderson CS, You C, Song L, Ma L; INTERACT3 Investigators. Surgical outcomes from haematoma evacuation for intracerebral haemorrhage in the INTERACT3 study. Lancet Reg Health West Pac. 2025 Aug 28;62:101669. doi: 10.1016/j.lanwpc.2025.101669. eCollection 2025 Sep.
- Derived from this study: PubMed 40541207Wang X, Ren X, Li Q, Ouyang M, Chen C, Delcourt C, Chen X, Wang J, Robinson T, Arima H, Ma L, Hu X, You C, Li G, Jie Y, Lin Y, Billot L, Munoz-Venturelli P, Martins S, Pontes-Neto OM, Liu L, Chalmers J, Carcel C, Song L, Anderson CS; INTERACT Investigators. Effects of blood pressure lowering in relation to time in acute intracerebral haemorrhage: a pooled analysis of the four INTERACT trials. Lancet Neurol. 2025 Jul;24(7):571-579. doi: 10.1016/S1474-4422(25)00160-7.
- Derived from this study: PubMed 39700102Ouyang M, Anjum A, Mc Cawley FG, Wasay M, Ma L, Hu X, Chen X, Malavera A, Li X, Venturelli PM, Silva HA, Thang NH, Wahab KW, Pandian JD, Pontes-Neto OM, Abanto C, Cano-Nigenda V, Arauz A, You C, Jan S, Song L, Anderson CS, Liu H; INTERACT3 Investigators. Implementation of a goal-directed Care Bundle for intracerebral hemorrhage: Results of embedded process evaluation in the INTERACT3 trial. PLOS Glob Public Health. 2024 Dec 19;4(12):e0003711. doi: 10.1371/journal.pgph.0003711. eCollection 2024.
- Derived from this study: PubMed 37245517Ma L, Hu X, Song L, Chen X, Ouyang M, Billot L, Li Q, Malavera A, Li X, Munoz-Venturelli P, de Silva A, Thang NH, Wahab KW, Pandian JD, Wasay M, Pontes-Neto OM, Abanto C, Arauz A, Shi H, Tang G, Zhu S, She X, Liu L, Sakamoto Y, You S, Han Q, Crutzen B, Cheung E, Li Y, Wang X, Chen C, Liu F, Zhao Y, Li H, Liu Y, Jiang Y, Chen L, Wu B, Liu M, Xu J, You C, Anderson CS; INTERACT3 Investigators. The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial. Lancet. 2023 Jul 1;402(10395):27-40. doi: 10.1016/S0140-6736(23)00806-1. Epub 2023 May 25.
- Derived from this study: PubMed 36063792Billot L, Song L, Hu X, Ma L, Ouyang M, Chen X, You C, Anderson CS; INTERACT3 Investigators. Statistical Analysis Plan for the INTEnsive Care Bundle with Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial: A Stepped-Wedge Cluster Randomized Controlled Trial. Cerebrovasc Dis. 2023;52(3):251-254. doi: 10.1159/000526384. Epub 2022 Sep 5.
- Derived from this study: PubMed 35783649Ouyang M, Anderson CS, Song L, Malavera A, Jan S, Cheng G, Chu H, Hu X, Ma L, Chen X, You C, Liu H. Process Evaluation of an Implementation Trial: Design, Rationale, and Early Lessons Learnt From an International Cluster Clinical Trial in Intracerebral Hemorrhage. Front Med (Lausanne). 2022 Jun 15;9:813749. doi: 10.3389/fmed.2022.813749. eCollection 2022.
- Derived from this study: PubMed 34930428Song 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.
- Derived from this study: PubMed 34929690Ouyang M, Anderson CS, Song L, Jan S, Sun L, Cheng G, Chu H, Hu X, Ma L, Chen X, You C, Liu H. Implementing a Goal-Directed Care Bundle after Acute Intracerebral Haemorrhage: Process Evaluation for the Third INTEnsive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial Study in China. Cerebrovasc Dis. 2022;51(3):373-383. doi: 10.1159/000520669. Epub 2021 Dec 20.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Craig S Anderson, PhD principal investigator
The George Institute for Global Health, China
Chao You, PhD principal investigator
West China Hospital
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing Care bundle of active management in people with Cerebral Hemorrhage and Stroke, run by The George Institute for Global Health, China at 1 site in China.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 3 inclusion and 2 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 29 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in China. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Shift ('improvement') in functional recovery (death or disability) defined by the modified Rankin Scale (mRS) (time frame: 6 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03209258, which also lists 12 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 29 Nov 2022.