Pyronaridine–artesunate or dihydroartemisinin–piperaquine versus current first-line therapies for repeated treatment of uncomplicated malaria: a randomised, multicentre, open-label, longitudinal, controlled, phase 3b/4 trial

Abstract

SummaryBackgroundArtemether–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.MethodsWe did a randomised, 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 randomisation 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 assessments 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 outpatients up to day 42, receiving clinical assessments 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).FindingsBetween 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...

Efficacy and Safety of Pyronaridine-Artesunate plus Single-Dose Primaquine for Treatment of Uncomplicated Plasmodium falciparum Malaria in Eastern Cambodia

“…Duplicate thick blood films and one thin blood film were examined at screening on day 0 and on days 1, 2, and 3 or until two consecutive negative slides on two consecutive days were obtained. Parasitemia was also evaluated on days 7,14,21,28,35, and 42 or on any other day if clinically indicated. Giemsa-stained thick blood smears were examined independently by two microscopists, and the average of the two counts was recorded.…”

“…Pyronaridine-artesunate has high efficacy in uncomplicated P. falciparum malaria in Asia and Africa and is included on the World Health Organization (WHO) essential medicines list and is WHO prequalified (14)(15)(16)(17)(18)(19)(20)(21). However, in a multicenter phase 3 randomized clinical trial conducted in 2007 and 2008, among 211 patients from Pailin, the risk of recrudescence on day 42 with pyronaridine-artesunate was 10.2% (95% confidence interval [CI], 5.4 to 18.6) (17).…”

Hepatic safety of repeated treatment with pyronaridine-artesunate (PA) versus artemether-lumefantrine (AL) in patients with uncomplicated malaria: A secondary analysis of the WANECAM 1 data from Bobo-Dioulasso, Burkina Faso

“…The e cacy of pyronaridine-artesunate has been largely studied and proven elsewhere (13,14,19,23,24). In this study we aimed to assess hepatic safety over re treatment of uncomplicated malaria with pyronaridineartesunate and artemether-lumefantrine and to investigate the relationship between retreatment with study drugs and each identi ed adverse event.…”

“…This report is a secondary analysis of data from the WANECAM 1 study site of Bobo-Dioulasso, in Burkina Faso. The protocol and standard procedures of this trial were published elsewhere (18)(19)(20). Brie y, the site of Bobo-Dioulasso was part a multicenter, randomized phase IIIb / IV clinical trial which aimed to compare effectiveness and safety of repeated treatment with pyronaridine-artesunate (PA) or dihydroartemisinin-piperaquine (DHAPQ) versus artemether-lumefantrine (AL) and artesunate-amodiaquine (ASAQ) in patients with uncomplicated malaria during a 2-year follow-up period.…”

“…In addition, following a period of ultimate e cacity of ACTs against uncomplicated malaria, parasites with very prolonged elimination time were detected following the use of ACT (15); later on, con rmed resistant strains of parasites to existing ACTs were reported (8,16,17) highlighting the urgent need to evaluate the e cacy of further ACTs. In line with this urgent need of new effective ACTs and to account for the safety of repeated treatment with these drugs on patients, a clinical trial has been initiated to assess the e cacy and safety of two ACTs (pyronaridine-artesunate and dihydroartémisinine-piperaquine) versus 2 comparators (artesunate -amodiaquine and artemether-lumefantrine) in patients with uncomplicated malaria (18)(19)(20). Since e cacy of these 4 ACTs in the context of this clinical trial has been already reported (19,20), the present work aims to evaluate speci cally the hepatic safety of repeated treatment with pyronaridine-artesunate versus artemether-lumefantrine in patients presenting with uncomplicated malaria during the 2-year follow-up period in Bobo-Dioulasso, Burkina Faso.…”