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.

Conflict of interest statement

I have read the journal’s policy and the authors of this manuscript have the following competing interests: JS is an employee of Shin Poong Pharmaceuticals. IBF, SD and JSL are employees of Medicines for Malaria Venture (MMV). SA-B and RM are employees of Artemida Pharma which received funding from MMV associated with this study, and RM is the medical safety officer for Shin Poong Pharmaceutical. SJA reports personal fees from MMV during the conduct of the study and personal fees from Novartis Pharma AG outside the submitted work. S-AW is a paid consultant funded by MMV. All other authors have no conflicts of interest to disclose.

Figures

Fig 1. Screening and analysis populations.

There may have been more than 1 reason for exclusion from enrollment into the study or exclusion from a study population. Normal LFTs were ALT or AST ≤2×ULN and abnormal values were ALT or AST >2×ULN at baseline. “Patient considered to be at risk from participation” included patients that investigators considered inappropriate for trial inclusion, mainly because of low hemoglobin or an inability to draw blood for assessments. Note that no patient with clinically evident preexisting liver injury was excluded from the screening population. ALT, alanine aminotransferase; AST, aspartate aminotransferase; LFT, liver function test; ULN, upper limit of normal.

Fig 2. Frequency of adverse events of any cause subgroup analysis in the safety population.

Data are shown for the number of patients. Patients may have been categorized differently for different malaria episodes. Categorical data were not available for all patients. ALT, alanine aminotransferase; AST, aspartate aminotransferase; CI, confidence interval; LFT, liver function test.

Fig 3. Day 28 PCR-adjusted treatment effectiveness in the per-protocol population subgroup analysis.

Data are shown for the number of malaria episodes. CI, confidence interval; PCR, polymerase chain reaction.