Efficacy and Tolerability Outcomes of a Phase II, Randomized, Open-Label, Multicenter Study of a New Water-Dispersible Pediatric Formulation of Dihydroartemisinin-Piperaquine for the Treatment of Uncomplicated Plasmodium falciparum Malaria in African Infants

Nicola Gargano, Lola Madrid, Giovanni Valentini, Umberto D'Alessandro, Tinto Halidou, Sodiomon Sirima, Antoinette Tshefu, Ali Mtoro, Samwel Gesase, Eurartesim Dispersible Study Group, Quique Bassat, Silvia Pace, Antonio Sitoe, Helio Mucavele, Esperança Sevene, Helder Bulo, Suzanne Anderson, Chukwuemeka Onwuchekwa, Moussa Lingani, Toussaint Rouamba, Innocent Valea, Dieudonne Bidashimwa, Jeff Atibu, Salim Abdulla, Edwin Liheluka, Rosauro Varo, Nicola Gargano, Lola Madrid, Giovanni Valentini, Umberto D'Alessandro, Tinto Halidou, Sodiomon Sirima, Antoinette Tshefu, Ali Mtoro, Samwel Gesase, Eurartesim Dispersible Study Group, Quique Bassat, Silvia Pace, Antonio Sitoe, Helio Mucavele, Esperança Sevene, Helder Bulo, Suzanne Anderson, Chukwuemeka Onwuchekwa, Moussa Lingani, Toussaint Rouamba, Innocent Valea, Dieudonne Bidashimwa, Jeff Atibu, Salim Abdulla, Edwin Liheluka, Rosauro Varo

Abstract

Artemisinin combination therapies are considered the mainstay of malaria treatment, but pediatric-friendly formulations for the treatment of infants are scarce. We sought to evaluate the efficacy and safety of a new dispersible-tablet formulation of dihydroartemisinin/piperaquine phosphate (DHA/PQP) in comparison to the marketed tablet (Eurartesim) in the treatment of infants with uncomplicated Plasmodium falciparum malaria. Reported here are the results of a large phase II, randomized, open-label, multicenter trial conducted in African infants (6 to 12 months of age) from Mozambique, Burkina Faso, The Gambia, the Democratic Republic of the Congo, and Tanzania. Primary efficacy endpoint was the PCR-corrected adequate clinical and parasitological response (ACPR) at day 28. Analysis was performed for the intention-to-treat (ITT) and per-protocol (PP) populations. A total of 201 patients received the dispersible-tablet formulation, and 99 received the conventional one administered as crushed tablets. At day 28, the PCR-corrected ACPRs were 86.9% (ITT) and 98.3% (PP) in the dispersible-tablet group and 84.9% (ITT) and 100% (PP) in the crushed-tablet group. At day 42, these values were 85.9% (ITT) and 96.5% (PP) in the dispersible-tablet group and 82.8% (ITT) and 96.4% (PP) in the crushed-tablet group. The comparison between survival curves for time to new infections showed no statistically significant differences (P = 0.409). The safety and tolerability profile for the two groups was similar in terms of type and frequency of adverse events and was consistent with that expected in African infants with malaria. A standard 3-day treatment with the new dispersible DHA/PQP formulation is as efficacious as the currently used tablet in African infants and has a comparable safety profile. (This trial was registered at ClinicalTrials.gov under registration no. NCT01992900.).

Keywords: Africa; antimalarial agents; dihydroartemisinin-piperaquine; infants; malaria.

Copyright © 2017 Gargano et al.

Figures

FIG 1
FIG 1
Flow chart of study participants with uncomplicated P. falciparum malaria treated with a 3-day course of either dispersible or crushed tablets of dihydroartemisinin-piperaquine (DHA/PQP). *, Two patients randomized in the dispersible treatment group were excluded from all analysis due to unconfirmed malaria diagnosis at day 0 (classified as “Other”) and informed consent withdrawal before first study drug administration.
FIG 2
FIG 2
ACPR at days 28 and 42 of treatment with dispersible and crushed DHA/PQP formulations administered to infant patients with uncomplicated P. falciparum malaria.
FIG 3
FIG 3
Time to new infections: survival analysis. A Kaplan-Meyer curve shows the cumulative risk of developing new infections in infants (ITT population) treated with either a dispersible- or a crushed-tablet formulation during a 42-day follow-up period.

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