Comparison of the safety and efficacy of fixed-dose combination of arterolane maleate and piperaquine phosphate with chloroquine in acute, uncomplicated Plasmodium vivax malaria: a phase III, multicentric, open-label study

Abstract

BackgroundChloroquine has been the treatment of choice for acute vivax malaria for more than 60 years. Malaria caused by Plasmodium vivax has recently shown resistance to chloroquine in some places. This study compared the efficacy and safety of fixed dose combination (FDC) of arterolane maleate and piperaquine phosphate (PQP) with chloroquine in the treatment of uncomplicated vivax malaria.MethodsPatients aged 13–65 years with confirmed mono-infection of P. vivax along with fever or fever in the previous 48 h were included. The 317 eligible patients were randomly assigned to receive FDC of arterolane maleate and PQP (n = 159) or chloroquine (n = 158) for 3 days. Primaquine was given as an anti-relapse measure on day 3 and continued for 14 consecutive days. Primary efficacy analysis included assessment of the proportion of aparasitaemic and afebrile patients at 72 h. Safety endpoints were analysis of adverse events, vital signs, laboratory data, and abnormalities on electrocardiograph. Patients participated in the study for at least 42 days.ResultsIn per protocol population, the proportion of aparasitaemic and afebrile patients at 72 h was 100 % (140/140) in the FDC of arterolane maleate and PQP group, and 99.3 % (145/146) in the chloroquine group (Fisher, p > 0.9999). In intent to treat population, the corresponding value was reported to be 96.9 % (154/159) in the FDC of arterolane maleate and PQP group and 98.7 % (156/158) in the chloroquine group (Fisher, p = 0.4479). The median parasite clearance time was 24 h in FDC of arterolane maleate and PQP group and 26 h in chloroquine group (Log-rank, p = 0.2264). Similarly, median fever clearance time was 24 h in both the groups (Log-rank, p = 0.7750). In PP population, day 28 cure rates were 100 % in both the groups (95 % CI (96.52, 100.0 for FDC of arterolane maleate and PQP and 96.73, 100.0 in chloroquine group)). Incidence of adverse events was 82.4 % in the FDC of arterolane maleate and PQP group and 85.4 % in the chloroquine group. Most of the adverse events were mild to moderate in intensity. The commonly reported clinical adverse events in the FDC of arterolane maleate and PQP versus chloroquine group were vomiting (5.0 vs 5.1 %), headache (1.3 vs 3.2 %) and prolonged QT (1.9 vs 3.2 %). No deaths were reported. The pharmacokinetic analysis indicates that arterolane maleate is well absorbed and has a relatively short t1/2 of 3.2 h. Piperaquine is also well absorbed after oral administration with a t1/2 of about 228.33 h.ConclusionsThe study showed that FDC of arterolane maleate and PQP effectively cured vivax malaria and attained acceptable level of cure up to day 28. Both the groups showed similar safety profile.Trial Registration Clinical Trial Registry India: CTRI/2011/11/002129Electronic supplementary materialThe online version of this article (doi:10.1186/s12936-016-1084-1) contains supplementary material, which is available to authorized users.

High-Dose Chloroquine for Uncomplicated Plasmodium falciparum Malaria Is Well Tolerated and Causes Similar QT Interval Prolongation as Standard-Dose Chloroquine in Children

“…Thereafter, QTc gradually decreased with declining chloroquine concentrations. In line with this, the mean QTcF (Fridericia correction) increase was 11 ms on day 2 in malaria-infected adults taking standard doses of chloroquine (21). The 12-ms median QTc 0.4 increase from baseline to before the third dose and the 26-ms increase corresponding to the peak concentration after the 3rd dose seen in the current study is thus in line with previous data.…”

“…To further support this normal daily variation, QTc 0.4 decreased by up to 58 ms on day 1 in other patients. In other studies, the maximum QTc (Bazett correction) prolongation was 63 ms in one healthy volunteer after intake of 1,200 mg chloroquine base and more than 60 ms (Fridericia correction) in five (3.2% of patients) between day 0 and day 2 after intake of standard-dose chloroquine for malaria treatment (19,21). This again suggests that the doses used in this study are as unlikely as standard-dose chloroquine to cause cardiac arrhythmias.…”

Inhibition of Human Coronaviruses by Antimalarial Peroxides

“…The 3 h day 0 and day 6 mean plasma concentrations ranged from 8–40 ng/mL to 14–68 ng/mL, respectively. The reported C max of OZ277 is ∼60 ng/mL, 40 which translates to an in vitro concentration of 0.1 μM. The AUC 3745 (last) and 1100 (48–72 h) ng*h/mL are calculated as the in vitro concentrations of 13 μM and 4 μM, respectively.…”

Two successful decades of Swiss collaborations to develop new anti-malarials

“…The goal was to find a new molecule that was as active as artesunate (an injectable artemisinin derivative), with a fully synthetic scheme, allowing a low cost of goods, and also the potential to increase the duration of action of the treatment. The first compound to emerge from this highly fruitful collaboration was OZ277 (arterolane; [ 15 , 16 ]). This was taken into full clinical development, and then partnered with the Indian company Ranbaxy.…”