Abstract
Introduction
Sepsis is a life-threatening infectious disease with increasing prevalence. Although several studies have reported high-quality evidence, therapeutic strategies still require further development to reduce the high mortality associated with sepsis. However, small effects of newly proposed treatments due to heterogeneity in sepsis hinder the feasibility of randomised controlled trials, a standard resource-demanding approach to validate benefits of therapy. This trial aims to rapidly evaluate various treatments and strategies for sepsis through an adaptive platform trial (APT) established as a semipermanent study platform.
Methods and analysis
The Evaluating Multiple Treatments and Strategies for Sepsis in Adaptive Platform (EURASSIA) trial is an APT, incorporating 11 tertiary care centres in Japan. This trial was initiated in 2024 with two domains, where two different interventions will be separately and simultaneously investigated in a randomised controlled design. Domains will be added and removed during the conduct of this semipermanent trial. The EURASSIA trial will include adult patients with sepsis who require intensive care whereas those with withheld/withdrawn care at sepsis diagnosis will be excluded. Subsequently, eligibility will be assessed for each domain, and participants will be randomly assigned to either intervention in each domain (eg, intravenous low-dose landiolol or no medication for mild tachycardia in the haemodynamic management domain and chlorhexidine-containing or usual dressing for a catheter insertion site in the infection control domain). The primary outcome is 90-day survival after intensive care initiation for sepsis; however, additional outcomes will be defined at the domain admission. The outcome will be analysed following a statistical analysis plan that will be predefined in each domain. Although reweighted response-adaptive randomisation will not be adopted, intervention-by-subtype interactions will be assessed across the domains at interim and final analyses to modify the sample size and add a stratification factor for random allocation as needed.
Ethics and dissemination
The Certified Review Board of Keio at the principal institution approved this study (approval number: N20240002). Written informed consent will be obtained from all participants or their legal representatives. The results will be disseminated via publications and presentations.
Trial registration number
jRCT1031240424.
Keywords: INFECTIOUS DISEASES, INTENSIVE & CRITICAL CARE, Randomized Controlled Trial
STRENGTHS AND LIMITATIONS OF THIS STUDY.
The Evaluating Multiple Treatments and Strategies for Sepsis in Adaptive Platform (EURASSIA) trial is a nationwide adaptive platform trial (APT) targeting patients with sepsis in Japan and will rapidly evaluate the effects of various treatments and strategies.
Multiple interventions will be simultaneously investigated as domains with the randomised controlled trial (RCT) design by sharing the funds and operation and may facilitate the participation of researchers who desire to conduct RCT in resource-limited environments.
The EURASSIA trial does not adopt the reweighted response-adaptive randomisation that is not essential but typically included in an APT to identify and drop ineffective interventions.
Introduction
Sepsis is a life-threatening infectious disease associated with organ dysfunction, and its prevalence is increasing worldwide.1 2 Although several clinical practice guidelines have been published to disseminate evidence-based recommendations for improving sepsis outcomes,3–5 a systematic review reported a mortality rate of >20% in Europe and North America.1 Therefore, the management of patients with sepsis requires further investigation, and a high-quality clinical trial should promptly validate studies with promising results to evolve therapeutic strategies for sepsis.
Although the conventional randomised controlled trial (RCT) is the standard approach for investigating benefits and harms of a potential therapy, implementation of RCT often massively necessitates human, financial and time resources, thereby restraining the feasibility of new trials.6 7 Furthermore, as newly proposed treatments typically exert minimal beneficial effects on heterogeneous patients with sepsis,8 studies with large sample sizes and extended durations were more likely to be planned with strict eligibility criteria, further impeding the rapid generation of clinical evidence.9 Notably, although some studies have suggested novel therapeutic interventions based on the pathophysiology of sepsis or observational studies,10 11 a substantial number of inconclusive results has been reported owing to small sample sizes in previous RCTs.8 12
Adaptive platform trial (APT) is an RCT design that has been developed in the last decade, where multiple interventions for targeted diseases can be simultaneously investigated and hypothesised intervention can be added or ended during the course of the semipermanent study platform.12–14 Considering that APTs have efficiently generated scientific knowledge in malignant and infectious diseases,15–17 including coronavirus disease 2019,18 this novel design is highly anticipated to facilitate sepsis management investigations. Moreover, sharing the funds and operation of RCTs in APT may facilitate the participation of researchers who desire to conduct RCT in resource-limited environments.19
Accordingly, the Evaluating Multiple Treatments and Strategies for Sepsis in Adaptive Platform (EURASSIA) trial, an adaptive platform for trials targeting sepsis, has been established and initiated in 2024 with two domains. The initial two domains were determined based on the controversy surrounding the beneficial effects of β1-selective blockers in reducing new-onset arrhythmias and the uncertainty regarding the preventive effects of chlorhexidine-containing dressing in decreasing catheter-related infection among patients with sepsis (online supplemental materials 1 and 2).20–25 The EURASSIA trial aims to rapidly evaluate the effects of various treatments and strategies for patients with sepsis and to eventually incorporate this semipermanent study platform of sepsis into clinical practice as a learning health system. The current protocol describes the scheme of general EURASSIA trial, with the two first domains presented as examples.
Methods and analysis
Trial design and setting
The EURASSIA trial is an APT targeting patients with sepsis, encompassing 11 tertiary care centres, including academic and community hospitals, in Japan (Keio University Hospital, Tsuchiura Kyodo General Hospital, Center Hospital of the National Center for Global Health and Medicine, Hokkaido University Hospital, Wakayama Medical University Hospital, Tohoku University Hospital, Jikei University Hospital, Osaka Medical and Pharmaceutical University Hospital, Osaka General Medical Center, Sapporo Medical University Hospital and Chiba University Hospital). In this trial, each intervention will be investigated in a randomised controlled design, which is defined as an APT domain. While each domain will be operated as a conventional RCT, patients will be enrolled in the adaptive platform; therefore, the same patient will be simultaneously randomised across multiple domains. Some patients may, in theory, be randomised only to experimental or control groups across domains within the platform.
At the launch of the EURASSIA trial in 2024, two domains were initiated, including low-dose beta blocker for mild tachycardia and chlorhexidine-containing dressing for a catheter insertion site, and another domain regarding short-duration corticosteroid use for septic shock will be added in 2026. These domains will be completed when the required sample sizes have been reached, and additional domains will be introduced on the basis of the scientific and feasibility considerations, as determined by the steering committee of the EURASSIA trial. Potential new domains will be proposed by the investigators of the EURASSIA trial, and they will be discussed and refined by the steering committee. However, novel domains anticipated to exhibit an obvious interaction with ongoing domains will not be added to the EURASSIA trial to prevent increasing the sample size of ongoing domains.
As the EURASSIA trial employs an adaptive design, assessment of potential clinically relevant subgroup effects between interventions in ongoing domains will be performed in interim analyses of each domain, potentially providing the adjustments of sample size or stratification factors of domains; however, reweighted response-adaptive randomisation will not be adopted in the EURASSIA trial because accrual of patient outcome data is considered slow and accurate pretrial simulation is difficult.19
Participants
The flowchart of the patient enrolment process is depicted in figure 1. The following are the inclusion criteria for the EURASSIA trial: (1) patients aged ≥18 years, (2) those diagnosed as sepsis based on the Sepsis-3 criteria (presence of organ dysfunction due to infection as demonstrated by an increased Sequential Organ Failure Assessment score of ≥2 points), (3) those necessitating intensive care and (4) those in whom written consent has been obtained from the participant or proxy. Patients will be included regardless of the infection site, causative organism and presence of bacteraemia.
Figure 1. Flowchart of the patient enrolment process. Sepsis diagnosis is based on the Sepsis-3 criteria; presence of organ dysfunction caused by a dysregulated host response to infection as demonstrated by an increased Sequential Organ Failure Assessment score of ≥2 points. EURASSIA, Evaluating Multiple Treatments and Strategies for Sepsis in Adaptive Platform.
The following are the exclusion criteria: (1) patients participating in another clinical trial requiring a treatment intervention that may interact with any of the trial domains; (2) those with withheld/withdrawn care at sepsis diagnosis; (3) detainees in correctional facilities and/or immigration detention centres; (4) those ineligible for, or not participating in, any domains of this trial; and (5) those in whom a treating physician considers study participation inappropriate.
Treating physicians at the emergency department and intensive care unit (ICU) will perform participant screening, after which trial investigators will approach eligible patients. All potential trial participants will be assessed for eligibility to each domain by investigators. Once eligibility is confirmed, consent for participation in each domain will be obtained. The investigators will explain the study verbally and in writing and will provide the consent form (online supplemental material 3) to trial participants or their legally authorised representatives. Participants are required to provide consent for participation in the EURASSIA trial. However, they may deny enrolment into a particular domain despite fulfilling the eligibility criteria of all domains, which is clearly recorded in the consent form. The eligibility criteria of each domain will be presented in the respective domain protocol, not in this core protocol of the EURASSIA trial.
Intervention
The platform of the EURASSIA trial does not have any interventions. Detailed descriptions of the domain interventions are not provided in this general EURASSIA trial protocol, and they are provided in the respective domain protocols. Following consent obtainment, participants will be randomly assigned to one of interventions in each domain; therefore, multiple interventions from different domains can be assigned. The design and analysis of each domain will consider potential interactions between interventions across domains. Treating physicians will follow any of clinical practice management guidelines of sepsis and provide all treatments other than trial interventions of domains, and investigators will provide trial interventions. While the interventions in each domain will be outlined in detail in their respective protocols, summaries of the two initial domains are provided in the current manuscript as examples.
Haemodynamic management domain
The scientific backgrounds, rationale and hypothesis of this domain are summarised in online supplemental material 1. Effects of low-dose beta blockers for mild tachycardia will be investigated in patients with mild tachycardia (heart rate, 95–129 bpm) within 72 hours following intensive care initiation. Participants will receive either continuous intravenous administration of landiolol at 2 mcg/kg/min with a target heart rate of 80–129 bpm (intervention) or no medication for controlling heart rate (control) for 48 hours or until ICU discharge, whichever comes earlier. In both groups, when the heart rate becomes <40 bpm or ≥140 bpm, any treatments, including medications, will be initiated as appropriate by a treating physician.
Infection control domain with antibiotic-containing dressing
The scientific backgrounds, rationale and hypothesis of this domain are summarised in online supplemental material 2. Effects of chlorhexidine-containing dressing will be investigated in patients with newly inserted central venous or arterial catheters. Participants will be treated with either a chlorhexidine-containing dressing (intervention) or a dressing without disinfectant/antibacterial properties (control) for covering the catheter insertion site until catheter removal. In both groups, the dressing will be replaced at 7-day intervals or when the dressing is malfunctioning within 7 days. Another newly inserted catheter during intensive care for sepsis will also follow the initial assigned treatment.
Outcome measures
The primary outcome will be 90-day survival from intensive care initiation for sepsis. The secondary outcomes will encompass hospital-free, ICU-free, ventilator-free and renal replacement therapy-free days within 90 days from intensive care initiation for sepsis and 30-day survival.
Alongside these outcome measures of the EURASSIA trial, each domain can add their own outcomes. Although domain protocols will show outcome details, some unique outcomes are as follows: newly developed arrhythmia within 30 days and ischaemic/thrombotic major vascular event within 30 days for the haemodynamic management domain; and catheter colonisation, incidence of major catheter-related infections and length of antibiotic use for the infection control domain with antibiotic-containing dressing.
Random assignment of interventions and participant timeline
After enrolment at the EURASSIA trial, random assignments will be independently performed in each domain using an electronic data capture (EDC) system. Therefore, depending on their eligibility, participants may be concurrently but separately randomised across multiple domains. The study site is used as a stratification factor, and further stratification factors can be defined in the domains. The random sequence will be permuted block randomisation, where it will be concealed to the patients, treating physicians and research personnel. The administrator will implement random sequence in the EDC system, and allocation will be determined on patient enrolment in each domain at the EDC system. Blinding of allocation will be separately determined in each domain. Allocation is not blinded to participants or treating clinicians in the two currently initiated domains; however, statisticians performing the analysis will remain blinded to the allocation.
The schedule of enrolment, interventions and assessments is presented in figure 2. All data will be recorded using the EDC system. Trial monitoring experts, who are independent of trial conduct, will ensure that investigator-reported data are being accurately collected to validate the integrity and reliability of the data. Participants will be followed up for 90 days following intensive care initiation for sepsis unless a particular domain will mandate a longer follow-up duration. When follow-up is challenging at the study institution for a participant, the investigators will contact him/her via telephone to obtain relevant information.
Figure 2. Schedule of enrolment, interventions and assessments of trial participants. The participants will be followed up for 90 days following intensive care initiation for sepsis. ICU, intensive care unit; RRT, renal replacement therapy.
Statistical methods
The hypothesis will be defined in each domain, and sample size calculation will also be conducted in each domain based on the frequentist statistical approaches rather than Bayesian inference models.26 Regarding within-trial learning and adaptations, reweighted response-adaptive randomisation will not be implemented in the EURASSIA trial.27 Interim analyses will be routinely performed within each domain according to prespecified plans to proactively test potential clinically relevant subgroup effects and unexpected interactions between domains, using heterogeneity, subgroup, interaction or other analyses as appropriate. Findings from these analyses may inform adjustments to trial design, including sample size or stratification factors, as specified in the domain-specific protocols.19 Response-adaptive randomisation will not be implemented because accrual of patient outcome data is considered slow and accurate pretrial simulation is difficult.
A comprehensive statistical analysis plan (SAP) will be developed for each domain, describing analysis datasets, handling of missing data, description of interim analyses and hypothesis testing procedures. Furthermore, the SAP of each domain will encompass a description of the major design assumptions with simulation-based evaluations of statistical power and/or type I error under plausible scenarios relevant to each domain. The alpha level and power for sample size calculation will be set as, but not limited to, 0.05 and 0.80, respectively. Preliminary statistical plans for the initial two domains are summarised in online supplemental materials 1 and 2.
Oversight and monitoring
The steering committee comprises four clinical researchers who will supervise the trial implementation, monitor the suitability of new domain admission and examine its progress. This committee designed this trial under the support of the Japanese Association for Acute Medicine. Contract research organisations that developed the clinical trial data management system and academic research organisation at the principal institution of the EURASSIA trial will monitor protocol adherence according to approved monitoring plans, independent from the funding sources. The monitoring plans include pretrial monitoring of appropriate procedures for documentation and records of processes; midtrial monitoring of optimal eligibility, informed consent, adherence to protocol and reporting adverse events; and posttrial monitoring of proper archive of data. The Data and Safety Monitoring Committee (DSMC) comprises three clinical researchers from different institutions who are independent from the sponsor and have no competing interests. The DSMC will monitor the trial to ensure its reliability in terms of human rights protection and participant safety and welfare. To evaluate the safety of continuing the trial, the DSMC will hold a meeting at least every year.
Patient and public involvement
A patient with a previous history of sepsis is involved in the study design. The patient subsequently provides input on outcome selection, intervention and study procedures, and informed consent sheet, and plays a critical role in the associated decision-making process. During the feasibility stage, the Certified Review Board at the principal institution includes a patient as members of the board.
Ethics and dissemination
This trial will be conducted in accordance with the principles of the Declaration of Helsinki and the Clinical Trials Act enacted by the Japanese National Diet. The approval process was initiated in March 2024. Finally, in October 2024, the Certified Review Board of Keio at the principal institution approved the study protocol (approval number: N20240002). Only one certified review board can approve the trial according to the Clinical Trials Act enacted by the Japanese National Diet. Following the Clinical Trials Act, the trial protocol and related information were registered at the Japan Registry of Clinical Trials (registration number: jRCT1031240424). All participants or their legally acceptable representatives will provide written informed consent to participate. The insurance company will offer compensation to trial participants who may experience health issues associated with the flaws in the trial protocol during the first year following their trial participation.
The steering committee will initially discuss the necessity for protocol changes, including domain addition and removal, followed by a meeting that will include representatives from all participating institutions. When a decision is reached to change the protocol, the Certified Review Board will discuss the revised protocol at the principal institution. After obtaining approval from the Certified Review Board, the revised protocol will be promptly disseminated to relevant parties. The trial registry will also reflect any modifications.
The data registered in the EDC system do not contain personal information. After completing all planned analyses of each domain, the findings will be presented at relevant scientific meetings and disseminated through publications in peer-reviewed journals. After completing all ancillary analyses by the trial group, the statistical codes for the domain will be available from the corresponding author of the domain and the steering committee of the EURASSIA trial. The trial data are not publicly available. Requests for data access based on a clear and reasonable justification will be reviewed by the steering committee of the EURASSIA trial and the corresponding author of the domain. If approved, access will be granted in accordance with applicable laws and regulations.
Discussion
This APT will simultaneously investigate the efficacy of various treatments and strategies for intensive care-requiring patients with sepsis. With the two initial domains evaluating effects of low-dose beta blockers for mild tachycardia and chlorhexidine-containing dressing for central venous and/or arterial catheters, additional domains will be added, facilitating the development of potential therapeutic strategies through this trial.
There are several strengths in the context of this trial design. First, the simultaneous inclusion of patients with sepsis into different hypothesised interventions will significantly enhance RCTs with greater efficacy.12 15 Although previous studies have indicated potential survival benefits of low-dose beta blockers and reduction of catheter-related infections by chlorhexidine-containing dressing,22 23 the calculated sample size suggests the need of more than a few years of study period for each intervention. APT facilitates the validation of such treatments with minimal effects without hindering other trials on sepsis. Second, the clinical outcomes of participants only assigned with control interventions will be archived at the EURASSIA trial with a clear definition of core protocol, potentially providing physicians with a general clinical consequence of sepsis following usual care.19 28 The baseline risks of patients with sepsis should represent pivotal information for another study and patient care. Third, accumulating human and financial resources into this trial may promote engagement and communication among various specialists, including clinicians, researchers, statisticians, regulators and healthcare companies. As a previous review for existing APTs revealed that an APT can be embedded in clinical practice and incorporate evidence generation into patient care,19 the maturation of this trial with a rapid turnover of domains will have a potential to develop a learning health system for patients with sepsis.29
This trial has some limitations. First, the EURASSIA trial does not adopt the reweighted response-adaptive randomisation. However, interim analyses for intervention-by-subtype interactions may guide sample size and/or stratification factor adjustments, and known or possible interactions between domains will also be assessed for the initial sample size calculation of a new domain. Second, Bayesian inference models are not used in the EURASSIA trial primarily because frequentist hypothesis testing provides straightforward interpretability for clinical practitioners and regulatory authorities, while avoiding the challenges of specifying prior distributions for diverse critical care interventions. Consequently, early termination of domains showing a non-effective tendency may not be as efficiently identified as in Bayesian adaptive trials.12 30 However, clear stopping boundaries will be prespecified at domain initiation based on frequentist interim analyses to balance trial efficiency and statistical rigour.
Trial status
On 2 October 2024, the trial protocol V.1.2 was approved (approval number: N20240002) that included the two domains (haemodynamic management and infection control domains), with the approval process initiated in March 2024. The latest protocol is V.1.5, which is currently under evaluation since April 2026, including the new entry of the third domain, minor revisions regarding the changes in the representatives at some participating hospitals and clarifications on the protocol statements. In November 2024, the first participant was recruited at the principal institution. The trial is ongoing with 10–15 recruitments per month, and approximately 200 patients will be enrolled by the end of 2026. The potential challenge of the trial will be the difficulty in institutional participation due to the complexity of APT in multiple and simultaneous randomised interventions that will be changing by the initiation of new domains and completion of existing domains. To mitigate these operational challenges, presentations at academic congresses and member communications will be used to provide institutions with practical support, such as standardised operational toolkits, visual workflow guides and EDC algorithms. In addition, these forums will serve to establish direct consultation channels with the steering committee.
The estimated completion date of the EURASSIA trial is not prespecified as it is a semipermanent study platform. New domains will be added by investigators at any participating institutions of the EURASSIA trial at the triannual meeting, and the EURASSIA trial will continue until no more domains are proposed. The corresponding authors of new domains will become members of the steering committee at the initiation of the domain and stay in the role for an extended period even after the completion of the domain.
Supplementary material
Footnotes
Funding: This trial is partially funded by the Japanese Association for Acute Medicine and the Japan Society for the Promotion of Science (JSPS KAKENHI Grant Number 25K02843).
Prepub: Prepublication history and additional supplemental material for this paper are available online. To view these files, please visit the journal online (https://doi.org/10.1136/bmjopen-2026-123087).
Provenance and peer review: Not commissioned; externally peer reviewed.
Patient consent for publication: Not applicable.
Patient and public involvement: Patients and/or the public were involved in the design, or conduct, or reporting, or dissemination plans of this research. Refer to the Methods section for further details.
References
- 1.Bauer M, Gerlach H, Vogelmann T, et al. Mortality in sepsis and septic shock in Europe, North America and Australia between 2009 and 2019- results from a systematic review and meta-analysis. Crit Care. 2020;24:239. doi: 10.1186/s13054-020-02950-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Martin-Loeches I, Singer M, Leone M. Sepsis: key insights, future directions, and immediate goals. A review and expert opinion. Intensive Care Med. 2024;50:2043–9. doi: 10.1007/s00134-024-07694-z. [DOI] [PubMed] [Google Scholar]
- 3.Evans L, Rhodes A, Alhazzani W, et al. Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock 2021. Crit Care Med. 2021;49:e1063–143. doi: 10.1097/CCM.0000000000005337. [DOI] [PubMed] [Google Scholar]
- 4.Prescott HC, Antonelli M, Alhazzani W, et al. Surviving Sepsis Campaign: international guidelines for management of sepsis and septic shock 2026. Intensive Care Med. 2026;52:863–936. doi: 10.1007/s00134-026-08361-1. [DOI] [PubMed] [Google Scholar]
- 5.Shime N, Nakada T-A, Yatabe T, et al. The Japanese Clinical Practice Guidelines for Management of Sepsis and Septic Shock 2024. Acute Med Surg. 2025;12:e70037. doi: 10.1002/ams2.70037. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Bothwell LE, Greene JA, Podolsky SH, et al. Assessing the Gold Standard--Lessons from the History of RCTs. N Engl J Med. 2016;374:2175–81. doi: 10.1056/NEJMms1604593. [DOI] [PubMed] [Google Scholar]
- 7.Granholm A, Alhazzani W, Derde LPG, et al. Randomised clinical trials in critical care: past, present and future. Intensive Care Med. 2022;48:164–78. doi: 10.1007/s00134-021-06587-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Opal SM. Clinical trial design and outcomes in patients with severe sepsis. Shock. 2003;20:295–302. doi: 10.1097/01.shk.0000084343.58020.57. [DOI] [PubMed] [Google Scholar]
- 9.Harhay MO, Wagner J, Ratcliffe SJ, et al. Outcomes and statistical power in adult critical care randomized trials. Am J Respir Crit Care Med. 2014;189:1469–78. doi: 10.1164/rccm.201401-0056CP. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Demailly Z, Besnier E, Tamion F, et al. Ventriculo-arterial (un)coupling in septic shock: Impact of current and upcoming hemodynamic drugs. Front Cardiovasc Med. 2023;10:1172703. doi: 10.3389/fcvm.2023.1172703. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Yanase F, Spano S, Maeda A, et al. Mega-dose sodium ascorbate: a pilot, single-dose, physiological effect, double-blind, randomized, controlled trial. Crit Care. 2023;27:371. doi: 10.1186/s13054-023-04644-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Woodcock J, LaVange LM. Master Protocols to Study Multiple Therapies, Multiple Diseases, or Both. N Engl J Med. 2017;377:62–70. doi: 10.1056/NEJMra1510062. [DOI] [PubMed] [Google Scholar]
- 13.Berry SM, Connor JT, Lewis RJ. The platform trial: an efficient strategy for evaluating multiple treatments. JAMA. 2015;313:1619–20. doi: 10.1001/jama.2015.2316. [DOI] [PubMed] [Google Scholar]
- 14.Lai TL, Lavori PW, Tsang KW. Adaptive design of confirmatory trials: Advances and challenges. Contemp Clin Trials. 2015;45:93–102. doi: 10.1016/j.cct.2015.06.007. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15.The PRACTICAL, PANTHER, TRAITS, INCEPT, and REMAP-CAP investigators The Rise of Adaptive Platform Trials in Critical Care. Am J Respir Crit Care Med. 2024;209:491–6. doi: 10.1164/rccm.202401-0101CP. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Alexander BM, Ba S, Berger MS, et al. Adaptive Global Innovative Learning Environment for Glioblastoma: GBM AGILE. Clin Cancer Res. 2018;24:737–43. doi: 10.1158/1078-0432.CCR-17-0764. [DOI] [PubMed] [Google Scholar]
- 17.Heming N, Berry L, Lorenzi E, et al. Correspondence about the article “Effect of hydrocortisone on mortality in patients with severe community-acquired pneumonia: the REMAP-CAP corticosteroid domain randomized clinical trial”: author’s reply. Intensive Care Med. 2025;51:1742–3. doi: 10.1007/s00134-025-08046-1. [DOI] [PubMed] [Google Scholar]
- 18.Angus DC, Derde L, Al-Beidh F, et al. Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial. JAMA. 2020;324:1317–29. doi: 10.1001/jama.2020.17022. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Angus DC, Alexander BM, Berry S, et al. Adaptive platform trials: definition, design, conduct and reporting considerations. Nat Rev Drug Discov. 2019;18:797–807. doi: 10.1038/s41573-019-0034-3. [DOI] [PubMed] [Google Scholar]
- 20.Whitehouse T, Hossain A, Perkins GD, et al. Landiolol and Organ Failure in Patients With Septic Shock: The STRESS-L Randomized Clinical Trial. JAMA. 2023;330:1641–52. doi: 10.1001/jama.2023.20134. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21.Rehberg S, Frank S, Černý V, et al. Landiolol for heart rate control in patients with septic shock and persistent tachycardia. A multicenter randomized clinical trial (Landi-SEP) Intensive Care Med. 2024;50:1622–34. doi: 10.1007/s00134-024-07587-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Kakihana Y, Nishida O, Taniguchi T, et al. Efficacy and safety of landiolol, an ultra-short-acting β1-selective antagonist, for treatment of sepsis-related tachyarrhythmia (J-Land 3S): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. 2020;8:863–72. doi: 10.1016/S2213-2600(20)30037-0. [DOI] [PubMed] [Google Scholar]
- 23.Wei L, Li Y, Li X, et al. Chlorhexidine-impregnated dressing for the prophylaxis of central venous catheter-related complications: a systematic review and meta-analysis. BMC Infect Dis. 2019;19:429. doi: 10.1186/s12879-019-4029-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Safdar N, O’Horo JC, Ghufran A, et al. Chlorhexidine-impregnated dressing for prevention of catheter-related bloodstream infection: a meta-analysis*. Crit Care Med. 2014;42:1703–13. doi: 10.1097/CCM.0000000000000319. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Ullman AJ, Cooke ML, Mitchell M, et al. Dressings and securement devices for central venous catheters (CVC) Cochrane Database Syst Rev. 2015;2015:CD010367. doi: 10.1002/14651858.CD010367.pub2. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Wijeysundera DN, Austin PC, Hux JE, et al. Bayesian statistical inference enhances the interpretation of contemporary randomized controlled trials. J Clin Epidemiol. 2009;62:13–21. doi: 10.1016/j.jclinepi.2008.07.006. [DOI] [PubMed] [Google Scholar]
- 27.Ye X, Hu F, Ma W. Robustness of response-adaptive randomization. Biometrics. 2024;80:ujae049. doi: 10.1093/biomtc/ujae049. [DOI] [PubMed] [Google Scholar]
- 28.Saville BR, Berry DA, Berry NS, et al. The Bayesian Time Machine: Accounting for temporal drift in multi-arm platform trials. Clin Trials. 2022;19:490–501. doi: 10.1177/17407745221112013. [DOI] [PubMed] [Google Scholar]
- 29.Angus DC. Fusing Randomized Trials With Big Data: The Key to Self-learning Health Care Systems? JAMA. 2015;314:767–8. doi: 10.1001/jama.2015.7762. [DOI] [PubMed] [Google Scholar]
- 30.Wang H, Rosner GL, Goodman SN. Quantifying over-estimation in early stopped clinical trials and the “freezing effect” on subsequent research. Clin Trials. 2016;13:621–31. doi: 10.1177/1740774516649595. [DOI] [PMC free article] [PubMed] [Google Scholar]