Exploration of a Potential DOOR Endpoint for Hospital-Acquired Bacterial Pneumonia and Ventilator-Associated Bacterial Pneumonia Using Six Registrational Trials for Antibacterial Drugs.

BACKGROUND: Desirability of outcome ranking (DOOR) is an innovative approach to clinical trial design and analysis that uses an ordinal ranking system to incorporate the overall risks and benefits of a therapeutic intervention into a single measurement. Here, we derived and evaluated a disease-specific DOOR endpoint for registrational trials for hospital-acquired bacterial pneumonia and ventilator-associated bacterial pneumonia (HABP/VABP). METHODS: Through comprehensive examination of data from nearly 4,000 participants enrolled in six registrational trials for HABP/VABP submitted to the FDA between 2005-2022, we derived and applied a HABP/VABP specific endpoint. We estimated the probability that a participant assigned to the study treatment arm would have a more favorable overall DOOR or component outcome than a participant assigned to comparator. RESULTS: DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 48.3% to 52.9% and were not statistically different. There were no significant differences between treatment arms in the component analyses. Though infectious complications and serious adverse events occurred more frequently in ventilated participants compared to non-ventilated participants, the types of events were similar. CONCLUSIONS: Through a data-driven approach, we constructed and applied a potential DOOR endpoint for HABP/VABP trials. The inclusion of syndrome-specific events may help to better delineate and evaluate participant experiences and outcomes in future HABP/VABP trials and could help inform data collection and trial design.

An Electronic Algorithm to Identify Vancomycin-Associated Acute Kidney Injury.

Background: The burden of vancomycin-associated acute kidney injury (V-AKI) is unclear because it is not systematically monitored. The objective of this study was to develop and validate an electronic algorithm to identify cases of V-AKI and to determine its incidence. Methods: Adults and children admitted to 1 of 5 health system hospitals from January 2018 to December 2019 who received at least 1 dose of intravenous (IV) vancomycin were included. A subset of charts was reviewed using a V-AKI assessment framework to classify cases as unlikely, possible, or probable events. Based on review, an electronic algorithm was developed and then validated using another subset of charts. Percentage agreement and kappa coefficients were calculated. Sensitivity and specificity were determined at various cutoffs, using chart review as the reference standard. For courses ≥48 hours, the incidence of possible or probable V-AKI events was assessed. Results: The algorithm was developed using 494 cases and validated using 200 cases. The percentage agreement between the electronic algorithm and chart review was 92.5% and the weighted kappa was 0.95. The electronic algorithm was 89.7% sensitive and 98.2% specific in detecting possible or probable V-AKI events. For the 11 073 courses of ≥48 hours of vancomycin among 8963 patients, the incidence of possible or probable V-AKI events was 14.0%; the V-AKI incidence rate was 22.8 per 1000 days of IV vancomycin therapy. Conclusions: An electronic algorithm demonstrated substantial agreement with chart review and had excellent sensitivity and specificity in detecting possible or probable V-AKI events. The electronic algorithm may be useful for informing future interventions to reduce V-AKI.

Exploration of a Potential Desirability of Outcome Ranking Endpoint for Complicated Intra-Abdominal Infections Using 9 Registrational Trials for Antibacterial Drugs.

BACKGROUND: Desirability of outcome ranking (DOOR) is a novel approach to clinical trial design that incorporates safety and efficacy assessments into an ordinal ranking system to evaluate overall outcomes of clinical trial participants. Here, we derived and applied a disease-specific DOOR endpoint to registrational trials for complicated intra-abdominal infection (cIAI). METHODS: Initially, we applied an a priori DOOR prototype to electronic patient-level data from 9 phase 3 noninferiority trials for cIAI submitted to the US Food and Drug Administration between 2005 and 2019. We derived a cIAI-specific DOOR endpoint based on clinically meaningful events that trial participants experienced. Next, we applied the cIAI-specific DOOR endpoint to the same datasets and, for each trial, estimated the probability that a participant assigned to the study treatment would have a more desirable DOOR or component outcome than if assigned to the comparator. RESULTS: Three key findings informed the cIAI-specific DOOR endpoint: (1) a significant proportion of participants underwent additional surgical procedures related to their baseline infection; (2) infectious complications of cIAI were diverse; and (3) participants with worse outcomes experienced more infectious complications, more serious adverse events, and underwent more procedures. DOOR distributions between treatment arms were similar in all trials. DOOR probability estimates ranged from 47.4% to 50.3% and were not significantly different. Component analyses depicted risk-benefit assessments of study treatment versus comparator. CONCLUSIONS: We designed and evaluated a potential DOOR endpoint for cIAI trials to further characterize overall clinical experiences of participants. Similar data-driven approaches can be utilized to create other infectious disease-specific DOOR endpoints.

A Regulatory Review Approach for Evaluation of Micafungin for Treatment of Neonatal Candidiasis.

Pathogenesis of neonatal candidiasis (NC) is distinct from systemic candidiasis in adults and older pediatric patients due to the significant incidence of central nervous system involvement in neonates. Thus, although adequate and well-controlled trials in NC are often unfeasible due to difficulty enrolling patients, extrapolation of efficacy from antifungal drug trials in adults is generally not appropriate. However, treatment of NC is an area of great unmet need. We describe a regulatory review approach that combined the assessment of limited clinical efficacy, pharmacokinetics, and safety data from neonates and young infants along with microbiology outcomes and pharmacokinetic data from relevant nonclinical models of candidemia/invasive candidiasis to inform the use of micafungin in pediatric patients younger than 4 months, while communicating areas of remaining uncertainty in labeling.

Concordance of Early and Late End Points for Community-acquired Bacterial Pneumonia Trials.

BACKGROUND: While there are ongoing regulatory convergence efforts, differences remain in primary end points recommended for community-acquired bacterial pneumonia (CABP) trials. The US Food and Drug Administration (FDA) recommends assessing CABP symptom resolution at an early time point (3-5 days after randomization). Other regulatory agencies recommend assessing overall clinical response at a later time point (5-10 days after therapy ends). METHODS: We analyzed participant-level data from 6 recent CABP trials submitted to the FDA (n = 4645 participants) to evaluate concordance between early and late end-point outcomes. We used multivariate logistic regression to identify factors associated with discordance. RESULTS: Early and late end-point outcomes were concordant for 85.6% of participants. The proportions of early end-point responders that ultimately failed and early end-point nonresponders that ultimately succeeded were similar (6.0% vs 8.4%, respectively). Early end-point response was highly predictive of late end-point success (positive predictive value, 92.9%). Multivariate logistic regression identified early end-point responders/late end-point failures as less likely to be obese and more likely to be infected with Chlamydophila pneumoniae or Staphylococcus aureus, have received antibacterial drug therapy prior to randomization, and have severe chest pain at baseline. The most common investigator-provided reasons for failure among early end-point responders/late end-point failures were receipt of nonstudy antibacterial drug therapy and loss to follow-up. CONCLUSIONS: Early and late end-point outcomes were highly concordant. These data may be useful in the continuing efforts to reach international regulatory convergence on CABP clinical trial design recommendations.

Designing a Low-Cost Multifunctional Infant Incubator.

Every year, an unacceptably large number of infant deaths occur in developing nations, with premature birth and asphyxia being two of the leading causes. A well-regulated thermal environment is critical for neonatal survival. Advanced incubators currently exist, but they are far too expensive to meet the needs of developing nations. We are developing a thermodynamically advanced low-cost incubator suitable for operation in a low-resource environment. Our design features three innovations: (1) a disposable baby chamber to reduce infant mortality due to nosocomial infections, (2) a passive cooling mechanism using low-cost heat pipes and evaporative cooling from locally found clay pots, and (3) insulated panels and a thermal bank consisting of water that effectively preserve and store heat. We developed a prototype incubator and visited and presented our design to our partnership hospital site in Mysore, India. After obtaining feedback, we have determined realistic, nontrivial design requirements and constraints in order to develop a new prototype incubator for clinical trials in hospitals in India.

Filarial/human immunodeficiency virus coinfection in urban southern India.

The disease course of human immunodeficiency virus (HIV) is often altered by existing or newly acquired coinfections. Treatment or prevention of these concomitant infections often improves the quality and duration of life of HIV-infected persons. The impact of helminth infections on infections with HIV is less clear. However, HIV is frequently most problematic in areas where helminth infections are common. In advance of the widespread distribution of drugs for elimination of lymphatic filariasis, we assessed the prevalence of active Wuchereria bancrofti infection among HIV-positive patients in Chennai, India at two time points separated by four years. We found that the overall prevalence of W. bancrofti infections among HIV-positive persons was 5-9.5%, and there were no quantitative differences in circulating filarial antigen levels between HIV-positive and HIV-negative filarial-infected patients.