Randomised placebo-controlled study of atovaquone plus proguanil for malaria prophylaxis in children

Abstract

Background: The combination of atovaquone and proguanil is highly effective and safe for the treatment of Plasmodium falciparum malaria. We aimed in this randomised, double-blind, placebo-controlled study to assess the efficacy and safety of this combination for malaria prophylaxis.

Methods: 320 children who lived in a hyperendemic area for P falciparum malaria were stratified by weight and randomly assigned atovaquone plus proguanil or placebo once daily for 12 weeks. All children received initial curative treatment with atovaquone and proguanil before the start of chemosuppression. We recorded adverse events daily and collected thick blood smears once a week. The primary endpoint was a positive blood smear.

Findings: 25 of 140 children in the placebo group and none of the 125 children in the atovaquone plus proguanil group had positive smears during chemosuppression (p<0.001). Adverse events during the chemosuppression phase did not differ between the groups.

Interpretation: The combination of atovaquone plus proguanil is a highly effective and well-tolerated chemosuppressive antimalarial in children. This drug combination could replace current regimens.

PIP: The efficacy and safety of combined atovaquone and proquanil as a chemosuppressive antimalarial were investigated in a randomized placebo-control study of 315 schoolchildren 4-16 years of age from Lambarene, Gabon--an area where Plasmodium falciparum malaria is endemic and parasites are highly resistant to chloroquine. The children were categorized on the basis of weight (11-20, 21-30, 31-40, and 41 kg and over). At baseline, 115 children (37%) had a positive blood smear for malaria. In the initial phase of the study, all 315 children received the combined treatment. After 3 days of curative treatment, P. falciparum and P. malariae were still detected in 5 and 11 children, respectively. After 1 week of curative treatment, all children with these parasites had negative blood smears. Of the 265 children who completed the initial curative phase, 125 were assigned the combined treatment (dose adjusted for weight) and 140 received a placebo. During a total of 28 person-years of observation in the atovaquone and proquanil group, protective efficacy was 100%. In the 28 person-years of observation accumulated among untreated controls, positive blood smears were detected in 25 children; parasites began to emerge 4 weeks after the initial curative phase. During the 4-week follow-up period, during which time neither group received treatment, positive blood smears were found in 12 controls and 3 cases (emerging only in the last 4 observation days). Although gastrointestinal symptoms were reported, the rate did not differ significantly between cases and controls. These findings suggest that the combination of atovaquone and proquanil could replace current antimalarial regimens if donated supplies were available.