10.2. Research Question 1: Does "QCA" Decrease Mortality in Children with Severe Malaria?

According to a report released in 2003 by the World Health Organization, malaria remains one of the world's foremost health problems, killing at least one million people annually, mostly children under five years old in sub-Saharan Africa. Lactic acidosis (toxic levels of lactic acid in the blood) is a frequent complication in severe malaria and is an incremental statistical predictor ("independent risk factor") of death. Moreover, a plausible biological rationale supports the hypothesis that lactic acidosis is a contributing cause of death.

Dr. Peter Stacpoole of the University of Florida has spent decades investigating the safety and efficacy of dichloroacetate (DCA) for treating lactic acidosis in genetic and acquired diseases. In 1997–99, he collaborated with Dr. Sanjeev Krishna of the University of London to lead a team that conducted a small, randomized, double-blind, controlled trial of quinine-only versus quinine+DCA in treating lactic acidosis in Ghanaian children with severe malaria (Agbenyega et al., 2003). They concluded that a single infusion of DCA was well-tolerated, did not appear to interfere with quinine, and, as hypothesized, reduced blood lactate levels. The sample size of N = 62 + 62 was much too small to support comparing mortality rates. The authors concluded that a large prospective study was warranted.

From now on the story is fictionalized. Suppose "quadcholoracetate" (QCA) has the same molecular structure as DCA at the active biological site, and has now been shown in large animal and human studies to be clinically equivalent to DCA in quickly reducing abnormally high blood lactate levels. However, QCA is less expensive to produce (about US$1dose) and has a longer shelf-life, especially in tropical climates.

"Dr. Sol Capote" heads the malaria research group at "Children's Health International (CHI)," and he and his colleagues are now designing a large clinical trial to be coordinated from "Jamkatnia" in West Africa, Dr. Capote is an experienced investigator, so he knows that substantial thought, effort, and experience must go into developing the sample-size analysis and the rest of the statistical considerations.

The CHI study will use a randomized, double-blind design to compare usual care only (UCO) versus usual care plus a single dose of QCA. After reviewing all previous human studies of both DCA and QCA, the CHI team is convinced that a single dose of QCA is very likely to be safe. Accordingly, after consulting with Jamkatnian health officials and a bioethicist, they decide that two-thirds of the subjects should get QCA.