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. 2019 Apr 19;219(10):1536-1544.
doi: 10.1093/infdis/jiy578.

Evidence-Based Study Design for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia

George H Talbot  1 , Anita Das  2 , Stephanie Cush  3 , Aaron Dane  4 , Michele Wible  5 , Roger Echols  6 , Antoni Torres  7 , Sue Cammarata  8 , John H Rex  9 , John H Powers  10 , Thomas Fleming  11 , Jeffrey Loutit  12 , Steve Hoffmann  3 ; Foundation for the National Institutes of Health Biomarkers Consortium HABP/VABP Project Team
Affiliations

Evidence-Based Study Design for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia

George H Talbot et al. J Infect Dis. .

Abstract

Background: The US Food and Drug Administration solicited evidence-based recommendations to improve guidance for studies of hospital-acquired bacterial pneumonia (HABP) and ventilator-associated bacterial pneumonia (VABP).

Methods: We analyzed 7 HABP/VABP datasets to explore novel noninferiority study endpoints and designs, focusing on alternatives to all-cause mortality (ACM).

Results: ACM at day 28 differed for ventilated HABP (27.8%), VABP (18.0%), and nonventilated HABP (14.5%). A "mortality-plus" (ACM+) composite endpoint was constructed by combining ACM with patient-relevant, infection-related adverse events from the Medical Dictionary for Regulatory Activities toxic/septic shock standardized query. The ACM+ rate was 3-10 percentage points above that of ACM across the studies and treatment groups. Predictors of higher ACM/ACM+ rates included older age and elevated acute physiology and chronic health evaluation (APACHE) II score. Only patients in the nonventilated HABP group were able to report pneumonia symptom changes.

Conclusions: If disease groups and patient characteristics in future studies produce an ACM rate so low (<10%-15%) that a fixed noninferiority margin of 10% cannot be justified (requiring an odds ratio analysis), an ACM+ endpoint could lower sample size. Enrichment of studies with patients with a higher severity of illness would increase ACM. Data on symptom resolution in nonventilated HABP support development of a patient-reported outcome instrument.

Keywords: all-cause mortality; hospital-acquired bacterial pneumonia; mortality-plus endpoint; ventilator-associated bacterial pneumonia.

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Figures

Figure 1.
Figure 1.
A–D, Kaplan–Meier curves for proportion of patients surviving: all-cause mortality (ACM) vs ACM plus toxic/septic shock standardized MedDRA query adverse events (ACM+) (serious adverse events only) (all-treated population). Abbreviation: SAE, serious adverse event.
Figure 2.
Figure 2.
A–C, Improvement in clinical symptoms by study day (Pfizer Study 311). “At least number of symptoms” indicates the number of subjects with at least 1, 2, 3, 4, or 5 symptoms at baseline and with these same symptoms assessed at the specified postbaseline visit, and includes subjects who died (ie, patients who died are considered to not have had an improvement in symptoms). Abbreviations: FNIH, Foundation for the National Institutes of Health; HABP, hospital-acquired bacterial pneumonia; MITT, modified intention-to-treat; VABP, ventilator-associated bacterial pneumonia.
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References

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    1. Foundation for the National Institutes of Health Biomarkers Consortium HABP/VABP Working Group. Interim considerations for clinical trial design for the study of hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia. July 15, 2013, submission to docket #FDA-2013-N-0556 https://www.pharmamedtechbi.com/~/media/Supporting%20Documents/The%20Pin.... Accessed 2 April 2018.
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