Efficacy and safety of a fixed-dose oral combination of pyronaridine-artesunate compared with artemether-lumefantrine in children and adults with uncomplicated Plasmodium falciparum malaria: a randomised non-inferiority trial.
BACKGROUND
There is a need for new artemisinin-based combination therapies that are convenient, effective, and safe. We compared the efficacy and safety of pyronaridine-artesunate with that of artemether-lumefantrine for treatment of uncomplicated P falciparum malaria.


METHODS
This phase 3, parallel-group, double-blind, randomised, non-inferiority trial was undertaken in seven sites in Africa and three sites in southeast Asia. In a double-dummy design, patients aged 3-60 years with uncomplicated P falciparum malaria were randomly assigned in a 2:1 ratio to receive pyronaridine-artesunate once a day or artemether-lumefantrine twice a day, orally for 3 days, plus respective placebo. Randomisation was done by computer-generated randomisation sequence in blocks of nine by study centre. Intervention tablets contained 180 mg pyronaridine and 60 mg artesunate; control tablets contained 20 mg artemether and 120 mg lumefantrine. Both treatments were given according to bodyweight. The primary efficacy outcome was PCR-corrected adequate clinical and parasitological response (ACPR) rate at day 28 in the per-protocol population. Non-inferiority was shown if the lower limit of the two-sided 95% CI for the difference between groups was greater than -5%. This study is registered with ClinicalTrials.gov, number NCT00422084.


RESULTS
1272 patients were randomly assigned to treatment (pyronaridine-artesunate, n=849; artemether-lumefantrine, n=423). The per-protocol population consisted of 784 patients in the pyronaridine-artesunate group and 386 patients in the artemether-lumefantrine group. PCR-corrected ACPR rate at day 28 was 99.5% (780 patients; 95% CI 98.7-99.9) in the pyronaridine-artesunate group and 99.2% (383 patients; 95% CI 97.7-99.8) in the artemether-lumefantrine group (treatment difference 0.3%, 95% CI -0.7 to 1.8; p=0.578). There were 509 (60.0%) adverse events in 849 patients assigned to pyronaridine-artesunate and 241 (57.0%) in 423 patients assigned to artemether-lumefantrine. The most frequent drug-related adverse event was eosinophilia (pyronaridine-artesunate, 53 events [6.2%]; artemether-lumefantrine 24 events [5.7%]). 21 (2.5%) patients in the pyronaridine-artesunate group and seven (1.7%) in the artemether-lumefantrine group discontinued study drugs or were withdrawn from the study. Mild and transient increases in alanine aminotransferase and aspartate aminotransferase concentrations were seen in the pyronaridine-artesunate group but not in the artemether-lumefantrine group.


CONCLUSIONS
Efficacy of pyronaridine-artesunate was non-inferior to that of artemether-lumefantrine for treatment of uncomplicated falciparum malaria. Pyronaridine-artesunate should be considered for inclusion in malaria treatment programmes.


BACKGROUND
Shin Poong Pharmaceutical and the Medicines for Malaria Venture.
Tshefu
Antoinette K
AK
Ecole de Santé Publique, Faculté de Médecine, Université de Kinshasa, Kinshasa, Democratic Republic of the Congo.
Gaye
Oumar
O
Kayentao
Kassoum
K
Thompson
Ricardo
R
Bhatt
Kirana M
KM
Sesay
Sanie S S
SS
Bustos
Dorina G
DG
Tjitra
Emiliana
E
Bedu-Addo
George
G
Borghini-Fuhrer
Isabelle
I
Duparc
Stephan
S
Shin
Chang Sik
CS
Fleckenstein
Lawrence
L
D000293:Adolescent; D000328:Adult; D000349:Africa; D000962:Antimalarials / Q000008:administration & dosage*; D000077549:Artemether; D037621:Artemisinins / Q000008:administration & dosage*; D000077332:Artesunate; D001208:Asia; D002648:Child; D002675:Child, Preschool; D004311:Double-Blind Method; D004338:Drug Combinations; D004983:Ethanolamines / Q000008:administration & dosage*; D005260:Female; D005449:Fluorenes / Q000008:administration & dosage*; D006801:Humans; D000078102:Lumefantrine; D016778:Malaria, Falciparum / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009287:Naphthyridines / Q000008:administration & dosage*; D016896:Treatment Outcome; D055815:Young Adult
D000962:Antimalarials; D037621:Artemisinins; D004338:Drug Combinations; D004983:Ethanolamines; D005449:Fluorenes; D009287:Naphthyridines; D000077332:Artesunate; D000077549:Artemether; D000078102:Lumefantrine; C027871:pyronaridine