Pyronaridine–artesunate real-world safety, tolerability, and effectiveness in malaria patients in 5 African countries: A single-arm, open-label, cohort event monitoring study

Abstract

Background In Phase II/III randomized controlled clinical trials for the treatment of acute uncomplicated malaria, pyronaridine–artesunate demonstrated high efficacy and a safety profile consistent with that of comparators, except that asymptomatic, mainly mild-to-moderate transient increases in liver aminotransferases were reported for some patients. Hepatic safety, tolerability, and effectiveness have not been previously assessed under real-world conditions in Africa. Methods and findings This single-arm, open-label, cohort event monitoring study was conducted at 6 health centers in Cameroon, Democratic Republic of Congo, Gabon, Ivory Coast, and Republic of Congo between June 2017 and April 2019. The trial protocol as closely as possible resembled real-world clinical practice for the treatment of malaria at the centers. Eligible patients were adults or children of either sex, weighing at least 5 kg, with acute uncomplicated malaria who did not have contraindications for pyronaridine–artesunate treatment as per the summary of product characteristics. Patients received fixed-dose pyronaridine–artesunate once daily for 3 days, dosed by body weight, without regard to food intake. A tablet formulation was used in adults and adolescents and a pediatric granule formulation in children and infants under 20 kg body weight. The primary outcome was the hepatic event incidence, defined as the appearance of the clinical signs and symptoms of hepatotoxicity confirmed by a >2× rise in alanine aminotransferase/aspartate aminotransferase (ALT/AST) versus baseline in patients with baseline ALT/AST >2× the upper limit of normal (ULN). As a secondary outcome, this was assessed in patients with ALT/AST >2× ULN prior to treatment versus a matched cohort of patients with normal baseline ALT/AST. The safety population comprised 7,154 patients, of mean age 13.9 years (standard deviation (SD) 14.6), around half of whom were male (3,569 [49.9%]). Patients experienced 8,560 malaria episodes; 158 occurred in patients with baseline ALT/AST elevations >2×ULN. No protocol-defined hepatic events occurred following pyronaridine–artesunate treatment of malaria patients with or without baseline hepatic dysfunction. Thus, no cohort comparison could be undertaken. Also, as postbaseline clinical chemistry was only performed where clinically indicated, postbaseline ALT/AST levels were not systematically assessed for all patients. Adverse events of any cause occurred in 20.8% (1,490/7,154) of patients, most frequently pyrexia (5.1% [366/7,154]) and vomiting (4.2% [303/7,154]). Adjusting for Plasmodium falciparum reinfection, clinical effectiveness at day 28 was 98.6% ([7,369/7,746] 95% confidence interval (CI) 98.3 to 98.9) in the per-protocol population. There was no indication that comorbidities or malnutrition adversely affected outcomes. The key study limitation was that postbaseline clinical biochemistry was only evaluated when clinically indicated. Conclusions Pyronaridine–artesunate had good tolerability and effectiveness in a representative African population under conditions similar to everyday clinical practice. These findings support pyronaridine–artesunate as an operationally useful addition to the management of acute uncomplicated malaria. Trial registration ClinicalTrials.gov NCT03201770.

Prospective observational study to evaluate the clinical and biological safety profile of pyronaridine–artesunate in a rural health district in Burkina Faso

“…Our findings are consistent with previous studies and most frequently observed AEs were similar to these previous studies and malaria symptoms. 13,14,16,19,28 This study supports what has been observed with PA safety up until now.…”

“…[13][14][15][16][17] The safety warning that was reported with the PA use was a transient increase of hepatic transaminases, 13,14,16,17 without any clinical signs or symptoms of hepatotoxicity. 13,18,19 Therefore, WHO recommends malaria-endemic countries to include PA in their national treatment guidelines. 12 However, this deployment should be conducted under a strong pharmacovigilance system as required for the introduction of all new medicines.…”

Effectiveness of pyronaridine-artesunate against Plasmodium malariae, Plasmodium ovale spp, and mixed-Plasmodium infections: a post-hoc analysis of the CANTAM-Pyramax trial

“… 23 However, the effects of antimalarials on the sexual stages of Plasmodium malariae and Plasmodium ovale spp, and the characteristics of those stages, have not been described conclusively so far. 12 , 24 Therefore, we cannot rule out that these submicroscopic parasitaemias were due to sexual stages of said non-falciparum parasite species that, to date, cannot be reliably distinguished from asexual stages with the available molecular methods.…”

“…We did a post-hoc analysis assessing samples collected during the CANTAM-Pyramax trial ( NCT03201770 ), which has been published in more detail elsewhere. 12 In short, the CANTAM-Pyramax trial was an open label, non-randomised, phase 3b/4, cohort event monitoring study designed to evaluate, in a real-life setting, the safety, tolerability, and efficacy of pyronaridine–artesunate therapy administered daily over 3 consecutive days in patients with uncomplicated malaria. Patients were included on the basis of a positive rapid diagnostic test (RDT) result or malaria microscopy.…”

“…For this post-hoc analysis, we analysed blood samples from the CANTAM-Pyramax real-world study, in which pyronaridine–artesunate was administered to patients with acute uncomplicated malaria, to provide a patient pool of considerable size from endemic countries with a known prevalence of P malariae and P ovale spp. 12 …”