Development of standard clinical endpoints for use in dengue interventional trials

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.

Severe dengue categories as research endpoints—Results from a prospective observational study in hospitalised dengue patients

“…Previously, statistical evidence for a distinct overall moderate severity group has not been corroborated [8]. The moderate disease definitions per category used in this analysis ( Table 2) were based on previous work using this data [33], as well as on the endpoints suggested recently by an expert working group [7]. However, some of the variables listed in their moderate disease endpoint definitions-e.g.…”

“…In a second step, we expanded the analysis of the overlap beyond severe Numbers represent the frequency (%) for binary and categorical variables and the median (interquartile range) for continuous variables. disease and included less severe measures of vascular leakage, bleeding, and organ dysfunction in the severe patients, using the "moderate severity" definitions presented in Table 2, which were adapted from the definitions recently suggested by Tomashek et al [7]. The reason for adapting the definitions was that this data set was collected before these definitions became available and therefore did not include certain information as for example if local interventions for bleeding (e.g.…”

“…In a recent effort to define standard clinical endpoints for use in dengue intervention trials, criteria for moderate disease severity as well as severe disease endpoints were suggested by an expert group, using a structured Delphi consensus method. The authors conclude by saying that the endpoints suggested should be validated, ideally using existing large prospective datasets [7].…”

“…The objective of the analysis presented here was to respond to the need for validation of standardized endpoints, and to investigate the potential of the severe dengue categories to represent distinct clinical endpoints for intervention or pathophysiology research in dengue. This also led to further exploration of the candidate definitions for moderate severity, which were adapted from the definitions recently suggested by the expert group [7], considering the availability of the proposed criteria/laboratory information in the DENCO dataset.…”

Primary Dengue Infection in Patients Requiring Hospitalization During an Outbreak in a Low Incidence Mexican Region

“…Clinical and Laboratory Parameters of Hospitalized Patients with Primary Versus Secondary Dengue from the Valley of Atlixco-Izucar de Matamoros, Puebla, México Normal hematocrit values at altitude970-1923/masl (Trompetero-González et al 2015. According toTomashek et al (2018). ALT, alanine transaminase; AST, aspartate transaminase; masl, meters above sea level.…”