title: Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria.
abstract: 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.
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Atthanee
authors.initials: A
authors.lastname: Jeeyapant
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Charles Darwin University, Darwin, Northern Territory, Australia.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Hugh W
authors.initials: HW
authors.lastname: Kingston
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Katherine
authors.initials: K
authors.lastname: Plewes
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Maude
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Global Health Division, Menzies School of Health Research, Darwin, Australia.
authors.forename: Josh
authors.initials: J
authors.lastname: Hanson
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|University College, Oxford, United Kingdom.
authors.forename: M Trent
authors.initials: MT
authors.lastname: Herdman
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Stije J
authors.initials: SJ
authors.lastname: Leopold
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.
authors.forename: Thatsanun
authors.initials: T
authors.lastname: Ngernseng
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Department of Clinical Tropical Medicine, Faculty of Tropical Medicine, Mahidol Unversity,Bangkok,Thailand.
authors.forename: Prakaykaew
authors.initials: P
authors.lastname: Charunwatthana
authors.affiliation: Oxford University Clinical Research Unit. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Nguyen Hoan
authors.initials: NH
authors.lastname: Phu
authors.affiliation: Department of Medicine, Chittagong Medical College Hospital, Chittagong, Bangladesh.
authors.forename: Aniruddha
authors.initials: A
authors.lastname: Ghose
authors.affiliation: Department of Medicine, Chittagong Medical College Hospital, Chittagong, Bangladesh.
authors.forename: M Mahtab Uddin
authors.initials: MM
authors.lastname: Hasan
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Kinshasa School of Public Health, University of Kinshasa, Kinshasa, Democratic Republic of the Congo.
authors.forename: Caterina I
authors.initials: CI
authors.lastname: Fanello
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Malaria Research Group, Dev Care Foundation, Dhaka, Bangladesh.
authors.forename: Md Abul
authors.initials: MA
authors.lastname: Faiz
authors.affiliation: Oxford University Clinical Research Unit. Hospital for Tropical Diseases, Ho Chi Minh City, Vietnam.
authors.forename: Tran Tinh
authors.initials: TT
authors.lastname: Hien
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas P J
authors.initials: NP
authors.lastname: Day
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: White
authors.affiliation: Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.|Centre for Tropical Medicine and Global Health, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, United Kingdom.
authors.forename: Arjen M
authors.initials: AM
authors.lastname: Dondorp
mesh_terms: D000328:Adult; D019540:Area Under Curve; D000077549:Artemether; D037621:Artemisinins / Q000627:therapeutic use; D001459:Bangladesh; D015415:Biomarkers; D002648:Child; D002986:Clinical Trials as Topic; D003128:Coma / Q000150:complications; D019992:Databases as Topic; D015600:Glasgow Coma Scale; D006801:Humans; D007773:Lactates / Q000097:blood; D016778:Malaria, Falciparum / Q000097:blood / Q000175:diagnosis* / Q000188:drug therapy / Q000401:mortality; D011803:Quinine / Q000627:therapeutic use; D012372:ROC Curve; D015203:Reproducibility of Results
chemical_list: D037621:Artemisinins; D015415:Biomarkers; D007773:Lactates; D011803:Quinine; D000077549:Artemether