The third Intensive Care Bundle with Blood Pressure Reduction in Acute Cerebral Haemorrhage Trial (INTERACT3): an international, stepped wedge cluster randomised controlled trial.

"Declaration of interests LS reports funding from the Medical Research Council of the UK, Sichuan Credit Pharmaceutic, and Takeda China; and speaker fees from Takeda China. CSA has received grants from the National Health and Medical Research Council and Medical Research Futures Fund of Australia, the Medical Research Council of the UK, Penumbra, and Takeda China; is also the chair of the data and safety monitoring boards for several trials; is a board member of WHO; and is the Editor-in-Chief of Cerebrovascular Disease. CY has received funding from West China Hospital. All other authors declare no competing interests."

"AcknowledgmentsThe study is supported by an award (grant reference number MR/T005009/1) jointly funded by the Department of Health and Social Care, the Foreign, Commonwealth & Development Office, the Medical Research Council, and the Wellcome Trust (all London, UK); the West China Hospital Outstanding Discipline Development 1–3-5 programme (number ZY2016102); National Health and Medical Research Council of Australia (number APP1149987); Sichuan Credit Pharmaceutical; and Takeda (China). We thank the independent members and patient representatives of the trial steering committee: Thompson Robinson (Chair, University of Leicester, Leicester, UK), J Jaime Miranda (Deputy Chair, Centro de Excelencia en Enfermedades Crónicas, Universidad Peruana Cayetano Heredia, Lima, Peru), Adrian Parry-Jones (University of Manchester, Manchester, UK), Nikola Sprigg (University of Nottingham, Nottingham, UK), Ann Bamford (Manchester, UK), Olivia Smith (Nottingham, UK), and Caroline Harris (Global Health Strategy, Medical Research Council, London, UK). We acknowledge the EuroQol Group for use of the EQ-5D-3L. CSA is a senior investigator fellow for the National Health and Medical Research Council of Australia. We thank the investigators and research staff at the participating sites of the various participating emergency departments, intensive care units, and stroke units, and neurosurgery and neurology departments (appendix pp 4–9), and executive staff at The George Institute for Global Health China for their support of the study. We also thank the participants, their relatives, and their families."

"Although two interim analyses were undertaken during the study period, given the use of a conservative Haybittle–Peto stopping rule and the negligible amount of type 1 error rate spent, the significance threshold for the primary outcome, including sensitivity analyses, was still p<0·05. For the seven secondary clinical outcomes, we controlled the family-wise error rate by applying a sequential Holm–Sidak correction to facilitate an interpretation of the findings. Between-group differences in interventional physiological variables were assessed using a repeated-measure linear mixed model with adjustments for treatment, time, and treatment-by-time interactions fixed effects, site as a random effect, and with within-patient correlations modelled using a repeated patient effect assuming a compound-symmetry structure. We used SAS Enterprise Guide (version 8.2) and R (version 4.0.0 or newer) for statistical analysis. This trial is registered with ClinicalTrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787). Methods: We performed a pragmatic, international, multicentre, blinded endpoint, stepped wedge cluster randomised controlled trial at hospitals in nine low-income and middle-income countries (Brazil, China, India, Mexico, Nigeria, Pakistan, Peru, Sri Lanka, and Viet Nam) and one high-income country (Chile). Hospitals were eligible if they had no or inconsistent relevant, disease-specific protocols, and were willing to implement the care bundle to consecutive patients (aged ≥18 years) with imaging-confirmed spontaneous intracerebral haemorrhage presenting within 6 h of the onset of symptoms, had a local champion, and could provide the required study data. Hospitals were centrally randomly allocated using permuted blocks to three sequences of implementation, stratified by country and the projected number of patients to be recruited over the 12 months of the study period. These sequences had four periods that dictated the order in which the hospitals were to switch from the control usual care procedure to the intervention implementation of the care bundle procedure to different clusters of patients in a stepped manner. To avoid contamination, details of the intervention, sequence, and allocation periods were concealed from sites until they had completed the usual care control periods. The care bundle protocol included the early intensive lowering of systolic blood pressure (target <140 mm Hg), strict glucose control (target 6·1–7·8 mmol/L in those without diabetes and 7·8–10·0 mmol/L in those with diabetes), antipyrexia treatment (target body temperature ≤37·5°C), and rapid reversal of warfarin-related anticoagulation (target international normalised ratio <1·5) within 1 h of treatment, in patients where these variables were abnormal. Analyses were performed according to a modified intention-to-treat population with available outcome data (ie, excluding sites that withdrew during the study). The primary outcome was functional recovery, measured with the modified Rankin scale (mRS; range 0 [no symptoms] to 6 [death]) at 6 months by masked research staff, analysed using proportional ordinal logistic regression to assess the distribution in scores on the mRS, with adjustments for cluster (hospital site), group assignment of cluster per period, and time (6-month periods from Dec 12, 2017). This trial is registered at Clinicaltrials.gov (NCT03209258) and the Chinese Clinical Trial Registry (ChiCTR-IOC-17011787) and is completed."