TY - JOUR
T1 - Development of standard clinical endpoints for use in dengue interventional trials
AU - Tomashek, Kay M.
AU - Wills, Bridget
AU - See Lum, Lucy Chai
AU - Thomas, Laurent
AU - Durbin, Anna
AU - Leo, Yee Sin
AU - de Bosch, Norma
AU - Rojas, Elsa
AU - Hendrickx, Kim
AU - Erpicum, Martin
AU - Agulto, Liane
AU - Jaenisch, Thomas
AU - Tissera, Hasitha
AU - Suntarattiwong, Piyarat
AU - Collers, Beth Ann
AU - Wallace, Derek
AU - Schmidt, Alexander C.
AU - Precioso, Alexander
AU - Narvaez, Federico
AU - Thomas, Stephen J.
AU - Edelman, Robert
AU - Siqueira, João Bosco
AU - Cassetti, M. Cristina
AU - Dempsey, Walla
AU - Gubler, Duane J.
N1 - Publisher Copyright:
© 2018, Public Library of Science. All rights reserved. https://creativecommons.org/publicdomain/zero/1.0/.
PY - 2018/10
Y1 - 2018/10
N2 - 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.
AB - 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.
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U2 - 10.1371/journal.pntd.0006497
DO - 10.1371/journal.pntd.0006497
M3 - Article
C2 - 30286085
AN - SCOPUS:85054460664
SN - 1935-2727
VL - 12
JO - PLoS neglected tropical diseases
JF - PLoS neglected tropical diseases
IS - 10
M1 - e0006497
ER -