INTEnsive care bundle with blood pressure reduction in acute cerebral hemorrhage trial (INTERACT3): study protocol for a pragmatic stepped-wedge cluster-randomized controlled trial

Lili Song, Xin Hu, Lu Ma, Xiaoying Chen, Menglu Ouyang, Laurent Billot, Qiang Li, Paula Muñoz-Venturelli, Carlos Abanto, Octavio Marques Pontes-Neto, Arauz Antonio, Mohammad Wasay, Asita de Silva, Nguyen Huy Thang, Jeyaraj Durai Pandian, Kolawole Wasiu Wahab, Chao You, Craig S Anderson, INTERACT3 investigators, Lili Song, Xin Hu, Lu Ma, Xiaoying Chen, Menglu Ouyang, Laurent Billot, Qiang Li, Paula Muñoz-Venturelli, Carlos Abanto, Octavio Marques Pontes-Neto, Arauz Antonio, Mohammad Wasay, Asita de Silva, Nguyen Huy Thang, Jeyaraj Durai Pandian, Kolawole Wasiu Wahab, Chao You, Craig S Anderson, INTERACT3 investigators

Abstract

Background: Early intensive blood pressure (BP) lowering remains the most promising treatment for acute intracerebral hemorrhage (ICH), despite discordant results between clinical trials and potential variation in the treatment effects by approach to control BP. As the third in a series of clinical trials on this topic, the INTEnsive care bundle with blood pressure Reduction in Acute Cerebral hemorrhage Trial (INTERACT3) aims to determine the effectiveness of a goal-directed care bundle protocol of early physiological control (intensive BP lowering, glycemic control, and pyrexia treatment) and reversal of anticoagulation, in acute ICH.

Methods: INTERACT3 is a pragmatic, international, multicenter, stepped-wedge (4 phases/3 steps), cluster-randomized controlled trial to determine the effectiveness of a multifaceted care package in adult (age ≥ 18 years) patients (target 8360) with acute ICH (< 6 h of onset) recruited from 110 hospitals (average of 19 consecutive patients per phase) in low- and middle-income countries. After a control phase, each hospital implements the intervention (intensive BP lowering, target systolic < 140 mmHg; glucose control, target 6.1-7.8 mmol/L and 7.8-10.0 mmol/L in those without and with diabetes mellitus, respectively; anti-pyrexia treatment to target body temperature ≤ 37.5 °C; and reversal of anticoagulation, target international normalized ratio < 1.5 within 1 h). Information will be obtained on demographic and baseline clinical characteristics, in-hospital management, and 7-day outcomes. Central trained blinded assessors will conduct telephone interviews to assess physical function and health-related quality of life at 6 months. The primary outcome is the modified Rankin scale (mRS) at 6 months analyzed using ordinal logistic regression. The sample size of 8360 subjects provides 90% power (α = 0.05) to detect a 5.6% absolute improvement (shift) in the primary outcome of the intervention versus control standard care, with various assumptions.

Discussion: As the largest clinical trial in acute ICH, INTERACT3 is on schedule to provide an assessment of the effectiveness of a widely applicable goal-directed care bundle for a serious condition in which a clearly proven treatment has yet to be established.

Trial registration: ClinicalTrials.gov NCT03209258. Registered on 1 July 2017. Chinese Trial Registry ChiCTR-IOC-17011787. Registered on 28 June 2017.

Keywords: Care bundle; Clinical trial; Intracerebral hemorrhage; Stepped-wedge cluster-randomized trial; Stroke; management.

Conflict of interest statement

CSA and LS declare that they received speaker fees and travel reimbursement from Takeda. The other authors declare that they have no competing interests.

© 2021. The Author(s).

Figures

Fig. 1
Fig. 1
Stepped-wedge design
Fig. 2
Fig. 2
Study schema

References

    1. 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;9(2):167–176. doi: 10.1016/S1474-4422(09)70340-0.
    1. An SJ, Kim TJ, Yoon BW. Epidemiology, risk factors, and clinical features of intracerebral hemorrhage: an update. J Stroke. 2017;19(1):3–10. doi: 10.5853/jos.2016.00864.
    1. Krishnamurthi RV, Ikeda T, Feigin VL. Global, regional and country-specific burden of ischaemic stroke, intracerebral haemorrhage and subarachnoid haemorrhage: a systematic analysis of the global burden of disease study 2017. Neuroepidemiol. 2020;54(Suppl. 2):171–179. doi: 10.1159/000506396.
    1. Feigin VL, Krishnamurthi RV, Parmar P, Norrving B, Mensah GA, Bennett DA, Barker-Collo S, Moran AE, Sacco RL, Truelsen T, Davis S, Pandian JD, Naghavi M, Forouzanfar MH, Nguyen G, Johnson CO, Vos T, Meretoja A, Murray CJ, Roth GA, GBD 2013 Writing Group. GBD 2013 Stroke Panel Experts Group Update on the global burden of ischemic and hemorrhagic stroke in 1990-2013: the Global Burden of Disease 2013 study. Neuroepidemiol. 2015;45(3):161–176. doi: 10.1159/000441085.
    1. Krishnamurthi RV, Feigin VL, Forouzanfar MH, Mensah GA, Connor M, Bennett DA, Moran AE, Sacco RL, Anderson LM, Truelsen T, O'Donnell M, Venketasubramanian N, Barker-Collo S, Lawes CM, Wang W, Shinohara Y, Witt E, Ezzati M, Naghavi M, Murray C, Global Burden of Diseases, Injuries, Risk Factors Study 2010 (GBD 2010) GBD Stroke Experts Group Global and regional burden of first-ever ischaemic and haemorrhagic stroke during 1990-2010: Findings from the global burden of disease study 2010. Lancet Global Health. 2013;1(5):e259–e281. doi: 10.1016/S2214-109X(13)70089-5.
    1. Schreuder FH, Sato S, Klijn CJ, Anderson CS. Medical management of intracerebral haemorrhage. J Neurol Neurosurg Psych. 2017;88(1):76–84. doi: 10.1136/jnnp-2016-314386.
    1. Anderson CS, Heeley E, Huang Y, Wang J, Stapf C, Delcourt C, Lindley R, Robinson T, Lavados P, Neal B, Hata J, Arima H, Parsons M, Li Y, Wang J, Heritier S, Li Q, Woodward M, Simes RJ, Davis SM, Chalmers J. Rapid blood-pressure lowering in patients with acute intracerebral hemorrhage. New Engl J Med. 2013;368(25):2355–2365. doi: 10.1056/NEJMoa1214609.
    1. Al-Shahi Salman R, Frantzias J, Lee RJ, Lyden PD, Battey TWK, Ayres AM, et al. Absolute risk and predictors of the growth of acute spontaneous intracerebral haemorrhage: a systematic review and meta-analysis of individual patient data. Lancet Neurol. 2018;17(10):885–894. doi: 10.1016/S1474-4422(18)30253-9.
    1. Hemphill JC, Greenberg SM, Anderson CS, Becker K, Bendok BR, Cushman M, et al. Guidelines for the management of spontaneous intracerebral hemorrhage. Stroke. 2015;46(7):2032–2060. doi: 10.1161/STR.0000000000000069.
    1. Steiner T, Al-Shahi Salman R, Beer R, Christensen H, Cordonnier C, Csiba L, et al. European Stroke Organisation (ESO) guidelines for the management of spontaneous intracerebral hemorrhage. Int J Stroke. 2014;9(7):840–855. doi: 10.1111/ijs.12309.
    1. Qureshi AI, Palesch YY, Barsan WG, Hanley DF, Hsu CY, Martin RL, Moy CS, Silbergleit R, Steiner T, Suarez JI, Toyoda K, Wang Y, Yamamoto H, Yoon BW, ATACH-2 Trial Investigators and the Neurological Emergency Treatment Trials Network Intensive blood-pressure lowering in patients with acute cerebral hemorrhage. New Engl J Med. 2016;375(11):1033–1043. doi: 10.1056/NEJMoa1603460.
    1. Moullaali T, Wang X, Martin RH, Shipe VB, Robinson TG, Chalmers J, Suarez JI, Qureshi AI, Palesch YY, Anderson CS. Blood pressure control and clinical outcomes in acute intracerebral haemorrhage: a preplanned pooled analysis of individual participant data. Lancet Neurol. 2019;18(9):857–864. doi: 10.1016/S1474-4422(19)30196-6.
    1. Koga M, Yamagami H, Okuda S, Okada Y, Kimura K, Shiokawa Y, Nakagawara J, Furui E, Hasegawa Y, Kario K, Arihiro S, Sato S, Homma K, Matsuki T, Kinoshita N, Nagatsuka K, Minematsu K, Toyoda K, SAMURAI Study Investigators Blood glucose levels during the initial 72 h and 3-month functional outcomes in acute intracerebral hemorrhage: the SAMURAI-ICH study. J Neurol Sci. 2015;350(1-2):75–78. doi: 10.1016/j.jns.2015.02.018.
    1. Saxena A, Anderson CS, Wang X, Sato S, Arima H, Chan E, Muñoz-Venturelli P, Delcourt C, Robinson T, Stapf C, Lavados PM, Wang J, Neal B, Chalmers J, Heeley E, for the INTERACT2 Investigators Prognostic significance of hyperglycemia in acute intracerebral hemorrhage: the INTERACT2 study. Stroke. 2016;47(3):682–688. doi: 10.1161/STROKEAHA.115.011627.
    1. Malavera A, You S, Zheng D, Delcourt C, Anderson CS, on behalf of the INTERACT2 Investigators. Prognostic significance of early pyrexia in acute intracerebral haemorrhage: the INTERACT2 study. J Neurol Sci. 2021;423:117364.
    1. Steiner T, Poli S, Griebe M, Hüsing J, Hajda J, Freiberger A, Bendszus M, Bösel J, Christensen H, Dohmen C, Hennerici M, Kollmer J, Stetefeld H, Wartenberg KE, Weimar C, Hacke W, Veltkamp R. Fresh frozen plasma versus prothrombin complex concentrate in patients with intracranial haemorrhage related to vitamin K antagonists (INCH): a randomised trial. Lancet Neurol. 2016;15(6):566–573. doi: 10.1016/S1474-4422(16)00110-1.
    1. Rincon F, Lyden P, Mayer SA. Relationship between temperature, hematoma growth, and functional outcome after intracerebral hemorrhage. Neurocritical Care. 2013;18(1):45–53. doi: 10.1007/s12028-012-9779-9.
    1. Song L, Sandset EC, Arima H, Heeley E, Delcourt C, Chen G, Yang J, Wu G, Wang X, Lavados PM, Huang Y, Stapf C, Wang J, Robinson TG, Chalmers J, Lindley RI, Anderson CS. Early blood pressure lowering in patients with intracerebral haemorrhage and prior use of antithrombotic agents: pooled analysis of the interact studies. J Neurol Neurosurg Psych. 2016;87(12):1330–1335. doi: 10.1136/jnnp-2016-313246.
    1. Middleton S, McElduff P, Ward J, Grimshaw JM, Dale S, D'Este C, Drury P, Griffiths R, Cheung NW, Quinn C, Evans M, Cadilhac D, Levi C. Implementation of evidence-based treatment protocols to manage fever, hyperglycaemia, and swallowing dysfunction in acute stroke (QASC): a cluster randomised controlled trial. Lancet. 2011;378(9804):1699–1706. doi: 10.1016/S0140-6736(11)61485-2.
    1. 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;86(4):495–503. doi: 10.1002/ana.25546.
    1. Song L, Wang X, Ouyang M, Sun L, Chen X, Arima H, Sandset EC, Delcourt C, Wang J, Chen G, Robinson T, Lindley RI, Chalmers J, Anderson CS, for the INTERACT2 Investigators Associations of an abnormal physiological score with outcomes in acute intracerebral haemorrhage: INTERACT2 study. Stroke. 2021;52(2):722–725. doi: 10.1161/STROKEAHA.120.030435.
    1. Saver JL. Optimal end points for acute stroke therapy trials: best ways to measure treatment effects of drugs and devices. Stroke. 2011;42(8):2356–2362. doi: 10.1161/STROKEAHA.111.619122.
    1. Brott T, Adams HP, Jr, Olinger CP, Marler JR, Barsan WG, Biller J, Spilker J, Holleran R, Eberle R, Hertzberg V. Measurements of acute cerebral infarction: a clinical examination scale. Stroke. 1989;20(7):864–870. doi: 10.1161/01.STR.20.7.864.
    1. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQoL group. Ann Med. 2001;33(5):337–343. doi: 10.3109/07853890109002087.
    1. Anderson CS, Arima H, Lavados P, Billot L, Hackett ML, Olavarria VV, et al. Cluster-randomized, crossover trial of head positioning in acute stroke. New Engl J Med. 2017;376(25):2437–2447. doi: 10.1056/NEJMoa1615715.
    1. Girling AJ. Relative efficiency of unequal cluster sizes in stepped wedge and other trial designs under longitudinal or cross-sectional sampling. Statistics Med. 2018;37(30):4652–4664. doi: 10.1002/sim.7943.
    1. Martin JT, Hemming K, Girling A. The impact of varying cluster size in cross-sectional stepped-wedge cluster randomised trials. BMC Med Res Methodol. 2019;19(1):123. doi: 10.1186/s12874-019-0760-6.
    1. Kerr DM, Fulton RL, Lees KR, Collaborators V. Seven-day NIHSS is a sensitive outcome measure for exploratory clinical trials in acute stroke: evidence from the virtual international stroke trials archive. Stroke. 2012;43(5):1401–1403. doi: 10.1161/STROKEAHA.111.644484.
    1. Haybittle JL. Repeated assessment of results in clinical trials of cancer treatment. Br J Radiol. 1971;44(526):793–797. doi: 10.1259/0007-1285-44-526-793.
    1. Moore GF, Audrey S, Barker M, Bond L, Bonell C, Hardeman W, Moore L, O'Cathain A, Tinati T, Wight D, Baird J. Process evaluation of complex interventions: Medical Research Council guidance. BMJ. 2015;350(mar19 6):h1258. doi: 10.1136/bmj.h1258.
    1. May C, Finch T. Implementing, embedding, and integrating practices: an outline of normalisation process theory. Sociology. 2009;43(3):535–554. doi: 10.1177/0038038509103208.

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