Randomized Noninferiority Trial of Dihydroartemisinin-Piperaquine Compared with Sulfadoxine-Pyrimethamine plus Amodiaquine for Seasonal Malaria Chemoprevention in Burkina Faso

Abstract

The WHO recommends that children living in areas of highly seasonal malaria transmission in the Sahel subregion should receive seasonal malaria chemoprevention (SMC) with sulfadoxine-pyrimethamine plus amodiaquine (SPAQ). We evaluated the use of dihydroartemisinin-piperaquine (DHAPQ) as an alternative drug that could be used if SPAQ starts to lose efficacy. A total of 1,499 children 3 to 59 months old were randomized to receive SMC with SPAQ or DHAPQ over 3 months. The primary outcome measure was the risk of clinical malaria (fever or a history of fever with a parasite density of at least 3,000/μl). A cohort of 250 children outside the trial was followed up as a control group. Molecular markers of drug resistance were assessed. The risk of a malaria attack was 0.19 in the DHAPQ group and 0.15 in the SPAQ group, an odds ratio of 1.33 (95% confidence interval [CI], 1.02 to 1.72). Efficacy of SMC compared to the control group was 77% (67% to 84%) for DHAPQ and 83% (74% to 89%) for SPAQ. pfdhfr and pfdhps mutations associated with antifolate resistance were more prevalent in parasites from children who received SPAQ than in children who received DHAPQ. Both regimens were highly efficacious and well tolerated. DHAPQ is a potential alternative drug for SMC. (This trial is registered at ClinicalTrials.gov under registration no. NCT00941785.).

FIG 1

Trial profile. Twelve allocation errors occurred (7 children randomized to SPAQ received DHAPQ in error, 2 randomized to SPAQ received mixed treatments, and 3 randomized to DHAPQ received mixed treatments), leaving 754 who received DHAPQ and 740 who received SPAQ in the ATP analysis. At enrollment, 9.4% (70/742) and 9.5% (72/757) of children in the SPAQ and DHAPQ groups, respectively, did not receive SMC because they had clinical malaria. These proportions were 7.5% (55/738) and 8.1% (61/756) in September and 8.3% (61/737) and 8.8% (66/754) in October. Ninety-seven percent (1,454/1,499) of randomized children were seen at the survey at the end of the transmission season.

FIG 2

Cumulative hazard of malaria (fever or history of fever with any parasitemia) in children who received SMC with DHA-PQ or SP-AQ on three occasions in August, September, and October. A cohort of untreated children were recruited as a control group, at the time the main cohorts received the second round of SMC. The y axis shows the mean number of episodes per child since the start of surveillance. Malaria episodes were detected by passive detection, and at cross-sectional surveys performed just before each round of SMC.

FIG 3

Duration of protection (malaria with any parasitemia). A smoothed estimate of the hazard ratio was obtained using regression splines using the method of Lambert and Royston (32), and the efficacy (1-hazard ratio) with 95% confidence band is plotted against time since the final round of SMC.

FIG 4

(Top) Kaplan-Meier estimates of the proportion of children with an episode of malaria. (Bottom) Diagram showing the 90% and 95% confidence intervals for the odds ratios for ATP and ITT analyses for the primary endpoint (malaria with parasitemia above 3,000/μl) and for the secondary endpoint (malaria with parasitemia at any density). An odds ratio of 1.64 was specified as the noninferiority margin. The 90% and 95% CIs cross this margin for some analyses but are entirely above 1, so we are confident that SPAQ is superior to DHAPQ and are somewhat less confident in our conclusion that the DHAPQ is not inferior to SPAQ.

FIG 5

Relationship between dose of piperaquine administered and plasma concentration on day 7.

FIG 6

Cumulative hazard of malaria in children who received DHAPQ, according to the dose of piperaquine administered.

FIG 7

Incidence of mild adverse events during each SMC round.