***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Background New antimalarials are needed for P. vivax and P. falciparum malaria . This study compared the efficacy and safety of pyronaridine-artesunate with that of chloroquine for the treatment of uncomplicated P. vivax malaria . Methods and Findings This phase III r and omized , double-blind , non-inferiority trial included five centers across Cambodia , Thail and , India , and Indonesia . In a double-dummy design , patients ( aged > 3–≤60 years ) with microscopically confirmed P. vivax mono-infection were r and omized ( 1∶1 ) to receive pyronaridine-artesunate ( target dose 7.2∶2.4 mg/kg to 13.8∶4.6 mg/kg ) or chloroquine ( st and ard dose ) once daily for three days . Each treatment group included 228 r and omized patients . Outcomes for the primary endpoint , Day-14 cure rate in the per- protocol population , were 99.5 % , ( 217/218 ; 95%CI 97.5 , 100 ) with pyronaridine-artesunate and 100 % ( 209/209 ; 95%CI 98.3 , 100 ) with chloroquine . Pyronaridine was non-inferior to chloroquine : treatment difference −0.5 % ( 95%CI −2.6 , 1.4 ) , i.e. , the lower limit of the 2-sided 95%CI for the treatment difference was greater than −10  % . Pyronaridine-artesunate cure rates were non-inferior to chloroquine for Days 21 , 28 , 35 and 42 . Parasite clearance time was shorter with pyronaridine-artesunate ( median 23.0 h ) versus chloroquine ( 32.0 h ; p<0.0001 ) , as was fever clearance time ( median 15.9 h and 23.8 h , respectively ; p = 0.0017 ) . Kaplan-Meier estimates of post-baseline P. falciparum infection incidence until Day 42 were 2.5 % with pyronaridine-artesunate , 6.1 % with chloroquine ( p = 0.048 , log-rank test ) . Post-baseline P. vivax or P. falciparum infection incidence until Day 42 was 6.8 % and 12.4 % , respectively ( p = 0.022 , log rank test ) . There were no deaths . Adverse events occurred in 92/228 ( 40.4 % ) patients with pyronaridine-artesunate and 72/228 ( 31.6 % ) with chloroquine . Mild and transient increases in hepatic enzymes were observed for pyronaridine-artesunate . Conclusion Pyronaridine-artesunate efficacy in acute uncomplicated P. vivax malaria was at least that of chloroquine . As pyronaridine-artesunate is also efficacious against P. falciparum malaria , this combination has potential utility as a global antimalarial drug . Trial registration Clinical trials.gov Summary Background Sparse data on the safety of pyronaridine-artesunate after repeated treatment of malaria episodes restrict its clinical use . We therefore compared the safety of pyronaridine-artesunate after treatment of the first episode of malaria versus re-treatment in a sub study analysis . Methods This planned sub study analysis of the r and omised , open-label West African Network for Clinical Trials of Antimalarial Drugs ( WANECAM ) phase 3b/4 trial was done at six health facilities in Mali , Burkina Faso , and Guinea in patients ( aged ≥6 months and bodyweight ≥5 kg ) with uncomplicated microscopically confirmed Plasmodium spp malaria ( parasite density < 200 000 per μL blood ) and fever or history of fever . The primary safety endpoint was incidence of hepatotoxicity : alanine aminotransferase of greater than five times the upper limit of normal ( ULN ) or Hy 's criteria ( alanine aminotransferase or aspartate aminotransferase greater than three times the ULN and total bilirubin more than twice the ULN ) after treatment of the first episode of malaria and re-treatment ( ≥28 days after first treatment ) with pyronaridine-artesunate . Pyronaridine-artesunate efficacy was compared with artemether-lumefantrine with the adequate clinical and parasitological response ( ACPR ) in an intention-to-treat analysis . WANECAM is registered with PACTR.org , number PACTR201105000286876 . Findings Following first treatment , 13 ( 1 % ) of 996 patients  had hepatotoxicity ( including one [ < 1 % ] possible Hy 's law case ) versus two ( 1 % ) of 311 patients on re-treatment ( neither a Hy 's law case ) . No evidence was found that pyronaridine-artesunate re-treatment increased safety risk based on laboratory values , reported adverse event frequencies , or electrocardiograph findings . For all first treatment or re-treatment episodes , pyronaridine-artesunate ( n=673 ) day 28 crude ACPR was 92·7 % ( 95 % CI 91·0–94·3 ) versus 80·4 % ( 77·8–83·0 ) for artemether-lumefantrine ( n=671 ) . After exclusion of patients with PCR-confirmed new infections , ACPR was similar on treatment and re-treatment and greater than 95 % at day 28 and greater than 91 % at day 42 in both treatment groups . Interpretation The findings that pyronaridine-artesunate safety and efficacy were similar on first malaria treatment versus re-treatment of subsequent episodes lend support for the wider access to pyronaridine-artesunate as an alternative artemisinin-based combination treatment for malaria in sub-Saharan Africa . Funding European and Developing Countries Clinical Trial Partnership , Medicines for Malaria Venture ( Geneva , Switzerl and ) , UK Medical Research Council , Swedish International Development Cooperation Agency , German Ministry for Education and Research , University Claude Bernard ( Lyon , France ) , Malaria Research and Training Centre ( Bamako , Mali ) , Centre National de Recherche et de Formation sur le Paludisme ( Burkina Faso ) , Institut de Recherche en Sciences de la Santé ( Bobo-Dioulasso , Burkina Faso ) , and Centre National de Formation et de Recherche en Santé Rurale ( Republic of Guinea ) BACKGROUND Artemisinin-based combination therapies are the recommended first-line treatments of falciparum malaria in all countries with endemic disease . There are recent concerns that the efficacy of such therapies has declined on the Thai-Cambodian border , historically a site of emerging antimalarial-drug resistance . METHODS In two open-label , r and omized trials , we compared the efficacies of two treatments for uncomplicated falciparum malaria in Pailin , western Cambodia , and Wang Pha , northwestern Thail and : oral artesunate given at a dose of 2 mg per kilogram of body weight per day , for 7 days , and artesunate given at a dose of 4 mg per kilogram per day , for 3 days , followed by mefloquine at two doses totaling 25 mg per kilogram . We assessed in vitro and in vivo Plasmodium falciparum susceptibility , artesunate pharmacokinetics , and molecular markers of resistance . RESULTS We studied 40 patients in each of the two locations . The overall median parasite clearance times were 84 hours ( interquartile range , 60 to 96 ) in Pailin and 48 hours ( interquartile range , 36 to 66 ) in Wang Pha ( P<0.001 ) . Recrudescence confirmed by means of polymerase-chain-reaction assay occurred in 6 of 20 patients ( 30 % ) receiving artesunate monotherapy and 1 of 20 ( 5 % ) receiving artesunate-mefloquine therapy in Pailin , as compared with 2 of 20 ( 10 % ) and 1 of 20 ( 5 % ) , respectively , in Wang Pha ( P=0.31 ) . These markedly different parasitologic responses were not explained by differences in age , artesunate or dihydroartemisinin pharmacokinetics , results of isotopic in vitro sensitivity tests , or putative molecular correlates of P. falciparum drug resistance ( mutations or amplifications of the gene encoding a multidrug resistance protein [ PfMDR1 ] or mutations in the gene encoding sarco-endoplasmic reticulum calcium ATPase6 [ PfSERCA ] ) . Adverse events were mild and did not differ significantly between the two treatment groups . CONCLUSIONS P. falciparum has reduced in vivo susceptibility to artesunate in western Cambodia as compared with northwestern Thail and . Resistance is characterized by slow parasite clearance in vivo without corresponding reductions on conventional in vitro susceptibility testing . Containment measures are urgently needed . ( Clinical Trials.gov number , NCT00493363 , and Current Controlled Trials number , IS RCT N64835265 . Summary Background Artemether – lumefantrine and artesunate – amodiaquine are used as first-line artemisinin-based combination therapies ( ACTs ) in west Africa .  Pyronaridine – artesunate and dihydroartemisinin – piperaquine are potentially useful for diversification of ACTs in this region , but further safety and efficacy data are required on malaria retreatment . Methods We did a r and omised , multicentre , open-label , longitudinal , controlled phase 3b/4 clinical trial at seven tertiary centres in Burkina Faso , Guinea , and Mali . Eligible participants for first malaria episode and all retreatment episodes were adults and children aged 6 months and older with microscopically confirmed Plasmodium spp malaria ( > 0 to < 200 000 parasites per μL of blood ) and fever or history of fever in the previous 24 h. Individuals with severe or complicated malaria , an alanine aminotransferase concentration of more than twice the upper limit of normal , or a QTc greater than 450 ms were excluded . Using a r and omisation list for each site , masked using sealed envelopes , participants were assigned to either pyronaridine – artesunate or dihydroartemisinin – piperaquine versus either artesunate – amodiaquine or artemether – lumefantrine . Block sizes were two or four if two treatments were allocated , and three or six if three treatments were allocated . Microscopists doing the parasitological assessment s were masked to treatment allocation . All treatments were once-daily or twice-daily tablets or granules given orally and dosed by bodyweight over 3 days at the study centre . Patients were followed up as out patients up to day 42 , receiving clinical assessment s on days 0 , 1 , 2 , 3 , 7 , 14 , 21 , 28 , 35 , and 42 . Two primary outcomes were compared for non-inferiority : the 2-year incidence rate of all microscopically confirmed , complicated and uncomplicated malaria episodes in patients in the intention-to-treat population ( ITT ; non-inferiority margin 20 % ) ; and adequate clinical and parasitological response ( ACPR ) in uncomplicated malaria across all episodes ( unadjusted and PCR-adjusted for Plasmodium falciparum and unadjusted for other Plasmodium spp ) in the per- protocol population on days 28 and 42 ( non-inferiority margin 5 % ) . Safety was assessed in all participants who received one dose of study drug . This study is registered at the Pan African Clinical Trials Registry ( PACTR201105000286876 ) . Findings Between Oct 24 , 2011 , and Feb 1 , 2016 , we assigned 4710 eligible participants to the different treatment strategies : 1342 to pyronaridine – artesunate , 967 to artemether – lumefantrine , 1061 to artesunate – amodiaquine , and 1340 to dihydroartemisinin – piperaquine . The 2-year malaria incidence rate in the ITT population was non-inferior for pyronaridine – artesunate versus artemether – lumefantrine ( 1·77 , 95 % CI 1·63–1·93 vs 1·87 , 1·72–2·03 ; rate ratio [ RR ] 1·05 , 95 % CI 0·94–1·17 ) ; and versus artesunate – amodiaquine ( 1·39 , 95 % CI 1·22–1·59 vs 1·35 , 1·18–1·54 ; RR 0·97 , 0·87–1·07 ) . Similarly , this endpoint was non-inferior for dihydroartemisinin – piperaquine versus artemether – lumefantrine ( 1·16 , 95 % CI 1·01–1· 
    Output:
    
Electrocardiograph ( ECG ) abnormalities were less common with pyronaridine‐artesunate compared to other antimalarials .
Authors ' conclusions Pyronaridine‐artesunate was efficacious against uncomplicated P falciparum malaria , achieved a PCR‐adjusted treatment failure rate of less than 5 % at days 28 and 42 , and may be at least as good as , or better than other marketed ACTs .