Large, randomized clinical trials in sepsis have found few successful therapeutics in the past decade.
Traditional randomized trials of novel therapies, both in sepsis and in other fields, typically test a single drug or intervention in a single, and often narrowly defined, patient population, randomizing patients evenly to intervention versus control.
Newer designs in other fields have incorporated features to improve efficiency, such as the testing of multiple agents with a common control arm, the testing of a single agent within different patient subgroups, or the testing of agents within patients with different diseases but common mechanisms of action. Other features include randomization schemes that adapt over time, typically using Bayesian inference rules, to preferentially assign better performing agents within different subgroups.
These designs may be ideal to test new precision interventions in sepsis phenotypes, although rapid patient phenotyping will be required to enable more sophisticated randomization schemes.
Electronic health records found in many large healthcare systems are well-positioned to help deploy adaptive trials with point-of-care efficiency.
KeywordsDisease heterogeneity Phenotype Response-adaptive randomization Enrichment Adaptive trial Platform trial Basket trial Umbrella trial Embedded
- 22.Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF, et al. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. The Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Crit Care Med. 1997;25(7):1115–24.CrossRefGoogle Scholar
- 24.Shakoory B, Carcillo JA, Chatham WW, Amdur RL, Zhao H, Dinarello CA, et al. Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of macrophage activation syndrome: reanalysis of a prior phase III trial. Crit Care Med. 2016;44(2):275–81.CrossRefGoogle Scholar
- 33.Administration FaD. Enrichment strategies for clinical trials to support approval of human drugs and biological products. Available at: https://www.fdagov/downloads/drugs/guidancecomplianceregulatoryinformation/guidances/ucm332181pdf. 2012.
- 34.Panacek EA, Marshall JC, Albertson TE, Johnson DH, Johnson S, MacArthur RD, et al. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med. 2004;32(11):2173–82.CrossRefGoogle Scholar
- 41.Heinrich MC, Joensuu H, Demetri GD, Corless CL, Apperley J, Fletcher JA, et al. Phase II, open-label study evaluating the activity of imatinib in treating life-threatening malignancies known to be associated with imatinib-sensitive tyrosine kinases. Clin Cancer Res. 2008;14(9):2717–25.CrossRefGoogle Scholar
- 42.NIH Collaboratory. Available from: https://www.nihcollaboratory.org/Pages/Grand-Rounds-10-07-16.aspx.
- 44.Randomized embedded multifactorial adaptive platform trial in community acquired pneumonia. Available from: https://clinicaltrials.gov/ct2/show/NCT02735707.