Development of standard clinical endpoints for use in dengue interventional trials

PLoS Negl Trop Dis. 2018 Oct 4;12(10):e0006497. doi: 10.1371/journal.pntd.0006497. eCollection 2018 Oct.

Abstract

Dengue is a major public health problem worldwide. Although several drug candidates have been evaluated in randomized controlled trials, none has been effective and at present, early recognition of severe dengue and timely supportive care are used to reduce mortality. While the first dengue vaccine was recently licensed, and several other candidates are in late stage clinical trials, future decisions regarding widespread deployment of vaccines and/or therapeutics will require evidence of product safety, efficacy and effectiveness. Standard, quantifiable clinical endpoints are needed to ensure reproducibility and comparability of research findings. To address this need, we established a working group of dengue researchers and public health specialists to develop standardized endpoints and work towards consensus opinion on those endpoints. After discussion at two working group meetings and presentations at international conferences, a Delphi methodology-based query was used to finalize and operationalize the clinical endpoints. Participants were asked to select the best endpoints from proposed definitions or offer revised/new definitions, and to indicate whether contributing items should be designated as optional or required. After the third round of inquiry, 70% or greater agreement was reached on moderate and severe plasma leakage, moderate and severe bleeding, acute hepatitis and acute liver failure, and moderate and severe neurologic disease. There was less agreement regarding moderate and severe thrombocytopenia and moderate and severe myocarditis. Notably, 68% of participants agreed that a 50,000 to 20,000 mm3 platelet range be used to define moderate thrombocytopenia; however, they remained divided on whether a rapid decreasing trend or one platelet count should be case defining. While at least 70% agreement was reached on most endpoints, the process identified areas for further evaluation and standardization within the context of ongoing clinical studies. These endpoints can be used to harmonize data collection and improve comparability between dengue clinical trials.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Antiviral Agents / therapeutic use
  • Child
  • Child, Preschool
  • Clinical Trials as Topic / methods*
  • Clinical Trials as Topic / standards
  • Dengue / diagnosis
  • Dengue / drug therapy*
  • Dengue / pathology
  • Dengue / prevention & control*
  • Dengue Vaccines / immunology
  • Endpoint Determination*
  • Female
  • Humans
  • Infant
  • Infant, Newborn
  • Male
  • Middle Aged
  • Treatment Outcome
  • Young Adult

Substances

  • Antiviral Agents
  • Dengue Vaccines

Grants and funding

This project was funded collaboratively by NIAID and PDC. The Delphi consensus component of this project was funded exclusively by PDC. NIAID and PDC had a role in the decision to publish and prepare the manuscript. The study design, data collection and analysis was conducted by Mesydel, SPIRAL Research Center, Universite de Llege in Belgium.