Defining surrogate endpoints for clinical trials in severe falciparum malaria

A.a Jeeyapant, Hugh William Fluellen Kingston, K.a c Plewes, R.J.a Maude, J.a d Hanson, M.T.a e Herdman, S.J.a Leopold, T.a Ngernseng, P.a f Charunwatthana, N.H.g Phu, A.h Ghose, M.M.U.h Hasan, C.I.a i Fanello, M.A.a j Faiz, T.T.g Hien, N.P.J.a c Day, N.J.a c White, A.M.a c Dondorp

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    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.

    Original languageEnglish
    Article numbere0169307
    Pages (from-to)1-15
    Number of pages15
    JournalPLoS One
    Volume12
    Issue number1
    DOIs
    Publication statusPublished - 4 Jan 2017

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    Falciparum Malaria
    endpoints
    malaria
    lactates
    clinical trials
    coma
    Lactic Acid
    quinine
    Quinine
    Biomarkers
    Clinical Trials
    Coma
    Mortality
    Plasmas
    Bangladesh
    Malaria
    Microcirculation
    Cerebral Malaria
    Recovery
    antimalarials

    Cite this

    Jeeyapant, A. A., Kingston, H. W. F., Plewes, K. A. C., Maude, R. J. A., Hanson, J. A. D., Herdman, M. T. A. E., ... Dondorp, A. M. A. C. (2017). Defining surrogate endpoints for clinical trials in severe falciparum malaria. PLoS One, 12(1), 1-15. [e0169307]. https://doi.org/10.1371/journal.pone.0169307
    Jeeyapant, A.a ; Kingston, Hugh William Fluellen ; Plewes, K.a c ; Maude, R.J.a ; Hanson, J.a d ; Herdman, M.T.a e ; Leopold, S.J.a ; Ngernseng, T.a ; Charunwatthana, P.a f ; Phu, N.H.g ; Ghose, A.h ; Hasan, M.M.U.h ; Fanello, C.I.a i ; Faiz, M.A.a j ; Hien, T.T.g ; Day, N.P.J.a c ; White, N.J.a c ; Dondorp, A.M.a c. / Defining surrogate endpoints for clinical trials in severe falciparum malaria. In: PLoS One. 2017 ; Vol. 12, No. 1. pp. 1-15.
    @article{377c32274f86466a8d1e9f0400028f06,
    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.",
    author = "A.a Jeeyapant and Kingston, {Hugh William Fluellen} and Plewes, {K.a c} and R.J.a Maude and Hanson, {J.a d} and Herdman, {M.T.a e} and S.J.a Leopold and T.a Ngernseng and Charunwatthana, {P.a f} and N.H.g Phu and A.h Ghose and M.M.U.h Hasan and Fanello, {C.I.a i} and Faiz, {M.A.a j} and T.T.g Hien and Day, {N.P.J.a c} and White, {N.J.a c} and Dondorp, {A.M.a c}",
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    Jeeyapant, AA, Kingston, HWF, Plewes, KAC, Maude, RJA, Hanson, JAD, Herdman, MTAE, Leopold, SJA, Ngernseng, TA, Charunwatthana, PAF, Phu, NHG, Ghose, AH, Hasan, MMUH, Fanello, CIAI, Faiz, MAAJ, Hien, TTG, Day, NPJAC, White, NJAC & Dondorp, AMAC 2017, 'Defining surrogate endpoints for clinical trials in severe falciparum malaria', PLoS One, vol. 12, no. 1, e0169307, pp. 1-15. https://doi.org/10.1371/journal.pone.0169307

    Defining surrogate endpoints for clinical trials in severe falciparum malaria. / Jeeyapant, A.a; Kingston, Hugh William Fluellen; Plewes, K.a c; Maude, R.J.a; Hanson, J.a d; Herdman, M.T.a e; Leopold, S.J.a; Ngernseng, T.a; Charunwatthana, P.a f; Phu, N.H.g; Ghose, A.h; Hasan, M.M.U.h; Fanello, C.I.a i; Faiz, M.A.a j; Hien, T.T.g; Day, N.P.J.a c; White, N.J.a c; Dondorp, A.M.a c.

    In: PLoS One, Vol. 12, No. 1, e0169307, 04.01.2017, p. 1-15.

    Research output: Contribution to journalArticleResearchpeer-review

    TY - JOUR

    T1 - Defining surrogate endpoints for clinical trials in severe falciparum malaria

    AU - Jeeyapant, A.a

    AU - Kingston, Hugh William Fluellen

    AU - Plewes, K.a c

    AU - Maude, R.J.a

    AU - Hanson, J.a d

    AU - Herdman, M.T.a e

    AU - Leopold, S.J.a

    AU - Ngernseng, T.a

    AU - Charunwatthana, P.a f

    AU - Phu, N.H.g

    AU - Ghose, A.h

    AU - Hasan, M.M.U.h

    AU - Fanello, C.I.a i

    AU - Faiz, M.A.a j

    AU - Hien, T.T.g

    AU - Day, N.P.J.a c

    AU - White, N.J.a c

    AU - Dondorp, A.M.a c

    PY - 2017/1/4

    Y1 - 2017/1/4

    N2 - 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.

    AB - 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.

    U2 - 10.1371/journal.pone.0169307

    DO - 10.1371/journal.pone.0169307

    M3 - Article

    VL - 12

    SP - 1

    EP - 15

    JO - PLoS One

    JF - PLoS One

    SN - 1932-6203

    IS - 1

    M1 - e0169307

    ER -

    Jeeyapant AA, Kingston HWF, Plewes KAC, Maude RJA, Hanson JAD, Herdman MTAE et al. Defining surrogate endpoints for clinical trials in severe falciparum malaria. PLoS One. 2017 Jan 4;12(1):1-15. e0169307. https://doi.org/10.1371/journal.pone.0169307