Elaboration of Consensus Clinical Endpoints to Evaluate Antimicrobial Treatment Efficacy in Future Hospital-acquired/Ventilator-associated Bacterial Pneumonia Clinical Trials

Abstract

Background: Randomized clinical trials (RCTs) in hospital-acquired and ventilator-associated bacterial pneumonia (HABP and VABP, respectively) are important for the evaluation of new antimicrobials. However, the heterogeneity in endpoints used in RCTs evaluating treatment of HABP/VABP may puzzle clinicians. The aim of this work was to reach a consensus on clinical endpoints to consider in future clinical trials evaluating antimicrobial treatment efficacy for HABP/VABP.

Methods: Twenty-six international experts from intensive care, infectious diseases, and the pharmaceutical industry were polled using the Delphi method.

Results: The panel recommended a hierarchical composite endpoint including, by priority order, (1) survival at day 28, (2) mechanical ventilation-free days through day 28, and (3) clinical cure between study days 7 and 10 for VABP; and (1) survival (day 28) and (2) clinical cure (days 7-10) for HABP. Clinical cure was defined as the combination of resolution of signs and symptoms present at enrollment and improvement or lack of progression of radiological signs. More than 70% of the experts agreed to assess survival and mechanical ventilation-free days though day 28, and clinical cure between day 7 and day 10 after treatment initiation. Finally, the hierarchical order of endpoint components was reached after 3 Delphi rounds (72% agreement).

Conclusions: We provide a multinational expert consensus on separate hierarchical composite endpoints for VABP and HABP, and on a definition of clinical cure that could be considered for use in future HABP/VABP clinical trials.

Keywords: Delphi method; clinical cure; hierarchical composite endpoint; hospital-acquired bacterial pneumonia; multinational consensus.

Figure 1.

Iterative process followed to achieve the proposed hierarchical composite endpoint. Abbreviations: HABP, hospital-acquired bacterial pneumonia; RCT, randomized controlled trial; VABP, ventilator-associated bacterial pneumonia.

Figure 2.

Final hierarchical composite endpoint proposed. Abbreviations: HABP, hospital-acquired bacterial pneumonia; VABP, ventilator-associated bacterial pneumonia.

Figure 3.

Ranking of desirability of the outcome of 4 representative patients (P1–P4) according to the chosen primary endpoint. Patient outcomes were ranked from most desirable (first position of the podium) to least desirable (third position of the podium or even outside the podium). Classical composite endpoint: no hierarchy between components (all-cause mortality [ACM] at day 28, MV-free day from diagnosis to day 28, and clinical cure within 7–10 days of study initiation); the earliest event goes first. Hierarchical composite endpoint: ACM at day 28 is first assessed. Then, MV-free day from diagnosis to day 28 is assessed, and finally, clinical cure within 7–10 days of study initiation. Abbreviation: MV, mechanical ventilation.