The World Health Organization has recently included a drug called artesunate-pyronaridine as a recommended artemisinin-based combination therapy (ACT) option for the treatment of uncomplicated malaria in adults and children weighing >5 kg in all malaria-endemic areas (1).Combining data from many individual trials will generate evidence to inform safety of artesunate-pyronaridine compared to other recommended antimalarial drugs, particularly the related artesunate-amodiaquine combination.

To date, we have completed a systematic review of publications and clinical trial registries to identify eligible clinical trials investigating safety and tolerability of artesunate-pyronaridine as well as the currently more widely used artesunate-amodiaquine. We are contacting data contributors of over 150 eligible studies and collating relevant safety and tolerability data to enable a safety comparison of the two recommended ACTs.

Artesunate-pyronaridine is an artemisinin-based combination therapy indicated for the treatment of both blood-stage Plasmodium falciparum and Plasmodium vivax (1). Although highly effective and recently added to the ACT options recommended by the World Health Organisation, there has been limited adoption of artesunate-pyronaridine by policy makers outside areas of multi-drug resistant malaria in the Greater Mekong Subregion.   There have been some concerns that the pyronaridine component may be associated with a higher risk of transient increases in transaminases and vomiting, especially in young children and those with hepatic risk factors (2,3). However, recent observational data has been more reassuring (4–6). A comparison of the safety and tolerability profiles of artesunate-pyronaridine and that other recommended ACTs, particularly the related ACT, artesunate-amodiaquine, would be considered helpful to understand artesunate-pyronaridine safety and tolerability including in key target populations such as young children and those with prevalent co-morbidities (including HIV, TB and malnutrition).

To describe and compare the safety and tolerability of artesunate-pyronaridine and artesunate-amodiaquine for the treatment of uncomplicated or asymptomatic malaria infections, how this relates to the daily dose and whether this differs for key target populations such as young children and those with prevalent co-morbidities (including HIV, TB and malnutrition).

Studies will be deemed eligible for the purpose of these analyses if they provide Individual Patient Data (IPD) from a clinical trial or prospective cohort study published or registered on a clinical trial registry within the past 15 years (2008 – 2022 inclusive) and evaluating treatments including artesunate-pyronaridine and / or artesunate-amodiaquine for any asymptomatic or uncomplicated Plasmodium infection. We will not include mass drug administration or healthy volunteer studies.

Minimum data required

• Malaria species
• Information on artesunate-pyronaridine and / or artesunate-amodiaquine / and or other ACT use, indication and mg/kg dosage regimen administered (at least as per protocol);
• Baseline data on patient/participant demographics (including age, sex);
• Safety and tolerability data on at least one of the following:
  • Liver function tests (LFTs): At least one of the following on day 0 and any follow up day until day 28: alanine aminotransferase (ALT) and aspartate aminotransferase (AST), Bilirubin (total);
  • Gastrointestinal tolerability: At least one of the following from day 2 to 14: Nausea; vomiting; abdominal pain; diarrhoea; anorexia / loss of appetite;
  • Haematological safety: At least one of the following: Haemoglobin on day 0 and any follow up day until day 28;
  • Serious Adverse Events (SAEs) and Adverse Events (AEs): Raw term / description; (S)AE dates / days relative to start of ACT dosing.

https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=396463

Study group participants are generally encouraged to share all available data, to ensure a comprehensive understanding of ACT safety and tolerability in relation to dose, malaria status, comorbidities and concomitant medication.

 Desirable methodological data include:

• Methods used for eliciting participant reported AEs
• Normal ranges for laboratory values

Desirable baseline characteristics include:

• Actual total or mg/kg ACT dose
• Documentation on the supervision of drug administration
• Nutritional status as gauged by weight and age +/- height (BMI) and/or middle upper arm circumference (MUAC)
• Baseline parasitaemia
• Malaria status (e.g. asymptomatic / uncomplicated / severe)
• Treatment response (ACPR / ETF / Recrudescence / Reinfection / PCR indeterminant / day of treatment failure);
• Comorbidities (e.g. HIV & CD4 count, tuberculosis);
• Concomitant medication (specify antiretrovirals, TB treatment, other);
• Pregnancy status

Desirable safety and tolerability data include:

• Time of Vomiting (whether or not within 1 hour of dosing);
• SAEs and AEs: severity; causality assessments by study site / PI (with any narrative / comments); whether these resulted in study discontinuation;
• Hb or haematocrit levels at visits after day 14
• Data on blood transfusions (if not included as part of above)
• Haemoglobinuria (including reports of dark urine by any method) assessed at baseline and during follow up
• White blood cell and neutrophil count on day 0 and follow up
• Data on any gastro-intestinal disturbance detected within 28 days of dose (if not included as part of above)

Alkaline Phosphatase and any additional liver function tests on day 0 and any follow up day/s

The data sets uploaded to the WWARN repository will be standardised using the WWARN Data Management and Statistical Analysis Plans for clinical data and pooled into a single database of quality-assured individual patient data. Analysis will be performed based on statistical analysis plan designed together with the study group specifically for these analyses.

The Study Group is led by Prof Karen Barnes coordinated by Joanna Czekajska, Project Coordinator at WWARN. The Study Group comprises participating investigators who contribute relevant data sets to the pooled analysis. Data sets will remain the property of the principal investigator / sponsor. The Study Group collectively makes decisions with respect to including additional studies, data analysis and plans for publication, in line with the WWARN Publication Policy of April 2019. The Study Group will identify one or two people to coordinate activities including data analysis, and drafting of publications and reports for group review. The WWARN statistician(s) will be responsible for statistical analyses.

For further information, please email: karen.barnes@wwarn.org, Daniel.yilma@wwarn.org or wwarn@wwarn.org

1.            WHO Guidelines for malaria [Internet]. [cited 2023 Apr 3]. Available from: https://www.who.int/publications-detail-redirect/guidelines-for-malaria

2.            Shibeshi W, Alemkere G, Mulu A, Engidawork E. Efficacy and safety of artemisinin-based combination therapies for the treatment of uncomplicated malaria in pediatrics: a systematic review and meta-analysis. BMC Infect Dis. 2021 Apr 7;21(1):326.

3.            Duparc S, Borghini-Fuhrer I, Craft CJ, Arbe-Barnes S, Miller RM, Shin CS, et al. Safety and efficacy of pyronaridine-artesunate in uncomplicated acute malaria: an integrated analysis of individual patient data from six randomized clinical trials. Malar J. 2013 Feb 21;12:70.

4.            Tona Lutete G, Mombo-Ngoma G, Assi SB, Bigoga JD, Koukouikila-Koussounda F, Ntamabyaliro NY, et al. Pyronaridine-artesunate real-world safety, tolerability, and effectiveness in malaria patients in 5 African countries: A single-arm, open-label, cohort event monitoring study. PLoS Med. 2021 Jun;18(6):e1003669.

5.            Rouamba T, Sondo P, Yerbanga IW, Compaore A, Traore-Coulibaly M, Hien FS, et al. Prospective observational study to evaluate the clinical and biological safety profile of pyronaridine-artesunate in a rural health district in Burkina Faso. Pharmacol Res Perspect. 2022 Aug;10(4):e00987.

6.            West African Network for Clinical Trials of Antimalarial Drugs (WANECAM). 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. Lancet Lond Engl. 2018 Apr 7;391(10128):1378–90.