Publication: Defining surrogate endpoints for clinical trials in severe falciparum malaria
Issued Date
2017-01-01
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ISSN
19326203
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2-s2.0-85008414445
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Mahidol University
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SCOPUS
Bibliographic Citation
PLoS ONE. Vol.12, No.1 (2017)
Suggested Citation
Atthanee Jeeyapant, Hugh W. Kingston, Katherine Plewes, Richard J. Maude, Josh Hanson, M. Trent Herdman, Stije J. Leopold, Thatsanun Ngernseng, Prakaykaew Charunwatthana, Nguyen Hoan Phu, Aniruddha Ghose, M. Mahtab Uddin Hasan, Caterina I. Fanello, Md Abul Faiz, Tran Tinh Hien, Nicholas P.J. Day, Nicholas J. White, Arjen M. Dondorp Defining surrogate endpoints for clinical trials in severe falciparum malaria. PLoS ONE. Vol.12, No.1 (2017). doi:10.1371/journal.pone.0169307 Retrieved from: https://repository.li.mahidol.ac.th/handle/20.500.14594/41620
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Title
Defining surrogate endpoints for clinical trials in severe falciparum malaria
Author(s)
Atthanee Jeeyapant
Hugh W. Kingston
Katherine Plewes
Richard J. Maude
Josh Hanson
M. Trent Herdman
Stije J. Leopold
Thatsanun Ngernseng
Prakaykaew Charunwatthana
Nguyen Hoan Phu
Aniruddha Ghose
M. Mahtab Uddin Hasan
Caterina I. Fanello
Md Abul Faiz
Tran Tinh Hien
Nicholas P.J. Day
Nicholas J. White
Arjen M. Dondorp
Hugh W. Kingston
Katherine Plewes
Richard J. Maude
Josh Hanson
M. Trent Herdman
Stije J. Leopold
Thatsanun Ngernseng
Prakaykaew Charunwatthana
Nguyen Hoan Phu
Aniruddha Ghose
M. Mahtab Uddin Hasan
Caterina I. Fanello
Md Abul Faiz
Tran Tinh Hien
Nicholas P.J. Day
Nicholas J. White
Arjen M. Dondorp
Abstract
© 2017 Jeeyapant et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Background Clinical trials in severe falciparum malaria require a large sample size to detect clinically meaningful differences in mortality. This means few interventions can be evaluated at any time. Using a validated surrogate endpoint for mortality would provide a useful alternative allowing a smaller sample size. Here we evaluate changes in coma score and plasma lactate as surrogate endpoints for mortality in severe falciparum malaria. Methods Three datasets of clinical studies in severe malaria were re-evaluated: studies from Chittagong, Bangladesh (adults), the African 'AQUAMAT' trial comparing artesunate and quinine (children), and the Vietnamese 'AQ' study (adults) comparing artemether with quinine. The absolute change, relative change, slope of the normalization over time, and time to normalization were derived from sequential measurements of plasma lactate and coma score, and validated for their use as surrogate endpoint, including the proportion of treatment effect on mortality explained (PTE) by these surrogate measures. Results Improvements in lactate concentration or coma scores over the first 24 hours of admission, were strongly prognostic for survival in all datasets. In hyperlactataemic patients in the AQ study (n = 173), lower mortality with artemether compared to quinine closely correlated with faster reduction in plasma lactate concentration, with a high PTE of the relative change in plasma lactate at 8 and 12 hours of 0.81 and 0.75, respectively. In paediatric patients enrolled in the 'AQUAMAT' study with cerebral malaria (n = 785), mortality was lower with artesunate compared to quinine, but this was not associated with faster coma recovery. Conclusions The relative changes in plasma lactate concentration assessed at 8 or 12 hours after admission are valid surrogate endpoints for severe malaria studies on antimalarial drugs or adjuvant treatments aiming at improving the microcirculation. Measures of coma recovery are not valid surrogate endpoints for mortality.