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Insights Into a “Negative” ICU Trial Derived From Gene Expression Profiling

Hoekstra, Mary BCmp1; Maslove, David M. MD, MS1–3; Veldhoen, Richard A. MD, MSc2; Marshall, John C. MD4,5; Muscedere, John MD1,3

doi: 10.1097/CCM.0000000000003693
Online Clinical Investigations

Objectives: Randomized controlled trials in the ICU often fail to show differences in endpoints between groups. We sought to explore reasons for this at a molecular level by analyzing transcriptomic data from a recent negative trial. Our objectives were to determine if randomization successfully balanced transcriptomic features between groups, to assess transcriptomic heterogeneity among the study subjects included, and to determine if the study drug had any effect at the gene expression level.

Design: Bioinformatics analysis of transcriptomic and clinical data collected in the course of a randomized controlled trial.

Setting: Tertiary academic mixed medical-surgical ICU.

Patients: Adult, critically ill patients expected to require invasive mechanical ventilation more than 48 hours.

Interventions: Lactoferrin or placebo delivered enterally and via an oral swab for up to 28 days.

Measurements and Main Results: We found no major imbalances in transcriptomic features between groups. Unsupervised analysis did not reveal distinct clusters among patients at the time of enrollment. There were marked differences in gene expression between early and later time points. Patients in the lactoferrin group showed changes in the expression of genes associated with immune pathways known to be associated with lactoferrin.

Conclusions: In this clinical trial, transcriptomic data provided a useful complement to clinical data, suggesting that the reasons for the negative result were less likely related to the biological efficacy of the study drug, and may instead have been related to poor sensitivity of the clinical outcomes. In larger studies, transcriptomics may also prove useful in predicting response to treatment.

1Department of Critical Care Medicine, Queen’s University, Kingston, ON, Canada.

2Department of Medicine, Queen’s University, Kingston, ON, Canada.

3Kingston Health Sciences Center, Queen’s University, Kingston, ON, Canada.

4Critical Illness and Injury Research Centre, Li Ka Shing Knowledge Institute, St. Michael’s Hospital, Toronto, ON, Canada.

5Department of Surgery, University of Toronto, Toronto, ON, Canada.

Ms. Hoekstra and Dr. Maslove are co-first authors with equal contribution to the study.

Funding for the Prevention of nosocomial infections in critically ill patients with lactoferrin (PREVAIL) study was provided by the Southeastern Ontario Academic Medical Association Innovation Fund and the John Hechte Memorial Foundation. Funding for the genomics sub-study was provided by the McLaughlin Center, University of Toronto, and the Garfield Kelly Fund, Queen’s University.

Ms. Hoekstra received funding and support for article research from Natural Sciences and Engineering Research Council of Canada (Undergraduate Student Research Award). Dr. Maslove disclosed off-label product use of lactoferrin of ICU. Dr. Muscedere’s institution received funding from Lotte and John Hechte Memorial Foundation Grant and Southeastern Academic Medical Association Grant, and he received funding from Poly-Phor Pharma. The remaining authors have disclosed that they do not have any potential conflicts of interest.

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