Malaria: Can clinical trials help?
Summary by: Kathryn Maitland
In 2013, ~500,000 children in sub-Saharan Africa died as a direct result of Plasmodium falciparum malaria, accounting for 90% of global malaria mortality. The scale-up of control efforts has led to some reductions in malaria incidence in parts of Africa, but countries where transmission is high malaria continues to be a major public health problem. Early optimism that the most promising malaria vaccine candidate (RTS,S) would reduce the burden of malaria proved premature since following (3-dose) vaccination since immunity rapidly wanes >20 months post-vaccination. Severe malaria remains a major cause of hospital admission and paediatric death across sSA. Nevertheless, clinical research has been fragmented, resulting in only two large Phase III clinical trials – both with landmark results. The AQUAMAT trial, enrolling 5425 children demonstrated significantly lower in-hospital mortality in those receiving artesunate (8.5%) versus quinine (10.9%) (relative risk reduction 22.5%). Second, FEAST a pragmatic trial of fluid resuscitation as a supportive treatment in 3141 African children with shock, of whom 57% had severe malaria; this trial was stopped early due to higher 48-hour mortality in bolus arms (RR increase 45%) than no bolus (control) across all sub-groups.
Even with artesunate as standard antimalarial treatment, overall mortality remains ~10%, but includes large sub-groups with substantially higher case fatalities (15-20%) with 3 key prognostic markers (coma, metabolic acidosis or a high blood urea nitrogen) and/or bacterial co-infection (CF ~24%). There seems little prospect for further reducing the substantial mortality of severe malaria within the foreseeable future without a concerted and strategic effort from funders and researchers. SMAART (a nascent consortium for research and trials) aims to catalyse and accelerate the severe malaria research agenda. SMAART will formulate and coordinate seamless Phase I/II to large multi-centre Phase III trials using efficient trial designs to inform treatment guidelines and ultimately the outcome amongst African children.