Defining Surrogate Endpoints for Clinical Trials in Severe Falciparum Malaria

Abstract

BackgroundClinical 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.MethodsThree 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.ResultsImprovements 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.ConclusionsThe 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.

Lactate clearance as a prognostic marker of mortality in severely ill febrile children in East Africa

“…A recent meta-analysis [ 25 ] and a large systematic review [ 17 ] of acutely ill adults have reported a consistent lower mortality associated with LC, not limited to septic patients and regardless of the initial lactate value. Also, a recent secondary analysis of two large clinical trials on antimalarials has shown that lack of LC is an independent predictor of death in adults with severe malaria [ 26 ]. Amongst the few paediatric studies published, Krishna and colleagues measured serial lactate concentrations during 24 h in a small cohort of 115 children with severe malaria in the Gambia, concluding that sustained HL was the most powerful prognostic indicator of fatal outcome [ 21 ].…”

“…Moreover, to demonstrate an association between LC and survival in severely ill febrile children in a malaria-endemic area is relevant at least in two aspects. On one hand, LC could serve as a valid surrogate endpoint of clinical trials of malaria aiming to improve mortality, as recently demonstrated by Jeeyapant et al in a large cohort of adult patients with malaria [ 26 ]. Thus, one could hypothesise that LC might help to guide the initial resuscitation of these children in a resource-poor setting, where invasive monitoring and intensive care is mostly unavailable.…”

“…However, 169/341 children (49.6%) died before 8 h, which again could have resulted in a relevant underestimation of the study results. The key point is that we chose the 8-h correction as this could be compared to other studies [ 26 – 28 ]; given the high proportion of mortality that occurred before this time point, an early assessment of LC may be more relevant to this setting to identify high-risk patient and initial resuscitation (either at 2 or 4 h). Lastly, LC can be potentially useful when baseline HL exists, which was not the case for one third of our participants.…”

malERA: An updated research agenda for diagnostics, drugs, vaccines, and vector control in malaria elimination and eradication

“…Thus, new compounds with rapid activity against asexual blood stage parasites, suitable for parenteral administration, are needed for this critical indication (see TCP-1 specific attributes in [ 110 ]). The decline in the incidence of severe malaria in adults will require alternative development approaches, including the development of surrogate end points [ 115 ], as not enough patients will be available for large mortality studies [ 116 ]. However, sufficient safety data in adults would still be required for a phase III trial in African children with severe malaria.…”

Adjunctive therapy for severe malaria: a review and critical appraisal

“…General declines of malaria and SM burden, decreases in the CFR for malaria and difficulties in detecting reductions in mortality rates may hinder the evaluation of those interventions due to the need of recruiting large numbers of patients [ 29 ]. In this respect, it is necessary to creatively innovate in the design of clinical trials with more precise sample sizes, more accurate clinical predictors and surrogate endpoints for mortality like plasma lactate concentration [ 29 – 31 ]. It is recommended that patients with SM with signs of serious bacterial infection receive intravenous antibiotics [ 5 ].…”