Single-dose sulfadoxine–pyrimethamine plus artesunate–pyronaridine for malaria: a multicentre, randomized, controlled, assessor-blinded clinical trial

Abstract First-line artemisinin-based combination therapies retain efficacies of >90% in the treatment of malaria in clinical trials. In everyday practice their effectiveness is substantially lower, and sub-optimal treatment-adherence with multidose 3-day regimens contributes to treatment failures. Poor adherence also increases risks of selecting for drug resistances. Simplified therapeutic regimens with high efficacy can reinvigorate progress towards malaria elimination. Ideally, a single dose regimen will be most useful as it allows supervision of drug intake by healthcare personnel. Developing single-dose treatments using existing antimalarials has many potential advantages over new drug combinations. Efficacy and safety of these treatments is established, and access and cost limitations are largely addressed compared with those of new entities. We assessed a single dose therapy of two established antimalarial combinations consisting of sulfadoxine-pyrimethamine plus artesunate-pyronaridine (SPAP) in a pragmatic, non-inferiority, multi-centre, randomised, controlled clinical trial in patients with uncomplicated malaria in Gabon. The primary efficacy outcome was day 28 adequate clinical and parasitological response (ACPR). 1021 patients received SPAP (54%, 555/1021) or artemether-lumefantrine (AL) (46%, 466/1021). The modified intention to treat day 28 uncorrected ACPR were 92% (95% CI: 90, 93) in the SPAP treatment arm and 89% (95% CI: 88-90%) in the AL treatment arm (OR 1.35, 95% CI: 0.85-2.15), demonstrating non-inferiority of SPAP to AL. PCR-corrected day 28 ACPR rates were 98% (95% CI: 97-99%) in the SPAP treatment arm and 97% (95% CI: 96-98%) in the AL treatment arm (OR 1.41, 95% CI: 0.55, 3.58). The robustness of these findings was confirmed in the per protocol and sensitivity analyses. SPAP was associated with more episodes of vomiting within one hour of administration 19/555 (3.4%) than AL 3/466 (0.6%). Overall safety was comparable between regimens. Single dose SPAP is as safe and efficacious as three-day AL. Efficacy in settings with different patterns of SP resistance and optimising formulation for dosing and tolerability could accelerate development of SPAP as a readily available and affordable single-dose regimen for treating uncomplicated malaria. Registration: PACTR202405571736678. Funding: Centre de Recherches Médicales de Lambaréné (CERMEL).