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

Development of standard clinical endpoints for use in dengue interventional trials.

Author information

1
Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, Maryland, United States of America (USA).
2
Oxford University Clinical Research Unit, Hospital for Tropical Diseases, Ho Chi Minh City, Viet Nam.
3
Department of Paediatrics, University of Malaya, Kuala Lumpur, Malaysia.
4
Emergency Department, University Hospital of Martinique, Fort-de-France, Martinique.
5
Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America.
6
Institute of Infectious Diseases and Epidemiology, Tan Tock Seng Hospital, Singapore.
7
Universidad Central de Venezuela, Caracas, Venezuela.
8
Escuela de Medicina, Universidad Industrial de Santander, Bucaramanga, Colombia.
9
FWO Postdoctoral Fellow of the Life Sciences & Society Lab, Center for Sociological Research, KU Leuven and Research Associate of SPIRAL Research Center, University of Liège, Belgium.
10
SPIRAL Research Center, University of Liège, Belgium.
11
Department of Infectious Diseases, Heidelberg University Hospital, Heidelberg, Germany.
12
National Dengue Control Unit, Ministry of Health, Elvitigala Mawatha, Colombo, Sri Lanka.
13
Department of Pediatrics, Queen Sirikit National Institute of Child Health, Bangkok, Thailand.
14
Merck & Co. Inc., Kenilworth, New Jersey, United States of America.
15
Takeda Pharmaceutical Co. Ltd., Zurich, Switzerland.
16
GlaxoSmithKline plc (GSK) Vaccines, Rockville, Maryland, United States of America.
17
Division of Clinical Trials and Pharmacovigilance, Butantan Institute, São Paulo, Brazil.
18
Pediatrics Department of the Medical School of University of São Paulo, São Paulo, Brazil.
19
Infectious Diseases Unit, National Pediatric Reference Hospital, Hospital Infantil Manuel de Jesús Rivera, Managua, Nicaragua.
20
Division of Infectious Diseases, State University of New York, Upstate Medical University, Syracuse, New York, United States of America.
21
Center for Vaccine Development, University of Maryland School of Medicine, Baltimore, Maryland, United States of America.
22
Federal University of Goias, Brasilia, Brazil.
23
Emerging Infectious Diseases Programme, Duke-NUS Medical School, Singapore.

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.

PMID:
30286085
PMCID:
PMC6171842
DOI:
10.1371/journal.pntd.0006497
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Beth-Ann G. Coller is an employee, shareholder and patent inventor of Merck & Co., Inc., Kenilworth, New Jersey, United States of America. Robert Edelman is a paid consultant to Takeda Pharmaceutical Company vaccine trials for service as Chairman of the Data and Safety Monitoring Board (DSMB) of Takeda's Tetravalent Dengue Vaccine Program. Alexander C. Schmidt is an employee and shareholder of the GlaxoSmithKline plc (GSK), Brentford, London, United Kingdom. Stephen J. Thomas has performed both paid and unpaid consultations and safety reviews for GSK Vaccines, Merck, Takeda, Sanofi Pasteur, Chugai Pharma, Themisbio, and Primevax. Derek Wallace is an employee of Takeda Pharmaceuticals International AG, Zurich, Switzerland. Bridget Wills is a paid consultant on the DSMB for the Takeda vaccine trials. No other authors have declared that a competing interest exists.

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