Defining the next generation of severe malaria treatment: a target product profile.

Background: Severe malaria is a life-threatening infection, particularly affecting children under the age of 5 years in Africa. Current treatment with parenteral artemisinin derivatives is highly efficacious. However, artemisinin partial resistance is widespread in Southeast Asia, resulting in delayed parasite clearance after therapy, and has emerged independently in South America, Oceania, and Africa.

Operational effectiveness of tafenoquine and primaquine for the prevention of Plasmodium vivax recurrence in Brazil: a retrospective observational study.

Background: Prevention of Plasmodium vivax malaria recurrence is essential for malaria elimination in Brazil. We evaluated the real-world effectiveness of an updated treatment algorithm for P vivax radical cure in the Brazilian Amazon.

Methods: In this non-interventional observational study, we used retrospective data from the implementation of a P vivax treatment algorithm at 43 health facilities in Manaus and Porto Velho, Brazil.

Safety and efficacy of pyronaridine-artesunate paediatric granules in the treatment of uncomplicated malaria in children: insights from randomized clinical trials and a real-world study.

Background: Children are particularly at risk of malaria. This analysis consolidates the clinical data for pyronaridine-artesunate (PA) paediatric granules in children from three randomized clinical trials and a real-world study (CANTAM).

Methods: An integrated safety analysis of individual patient data from three randomized clinical trials included patients with microscopically-confirmed Plasmodium falciparum, body weight ≥ 5 kg to < 20 kg, who received at least one dose of study drug (paediatric safety population).

Operational feasibility of Plasmodium vivax radical cure with tafenoquine or primaquine following point-of-care, quantitative glucose-6-phosphate dehydrogenase testing in the Brazilian Amazon: a real-life retrospective analysis.

Background: To achieve malaria elimination, Brazil must implement Plasmodium vivax radical cure. We aimed to investigate the operational feasibility of point-of-care, quantitative, glucose-6-phosphate dehydrogenase (G6PD) testing followed by chloroquine plus tafenoquine or primaquine.

Methods: This non-interventional, observational study was done at 43 health facilities in Manaus (Amazonas State) and Porto Velho (Rondônia State), Brazil, implementing a new P vivax treatment algorithm incorporating point-of-care quantitative G6PD testing to identify G6PD status and single-dose tafenoquine (G6PD normal, aged ≥16 years, and not pregnant or breastfeeding) or primaquine (intermediate or normal G6PD, aged ≥6 months, not pregnant, or breastfeeding >1 month).

Community health workers in clinical research at the example of a phase IIIb/ IV antimalarial drug trial conducted in five African countries.

Global health, particularly in underserved settings can benefit immensely from well-trained community health workers (CHWs) supporting primary healthcare interventions. They can reduce morbidity and mortality of infectious diseases like malaria. Disease control programs can particularly benefit from a tight link between CHWs and communities and several studies have shown the benefit of the participation of non-facility-based CHWs in malaria control program activities for reducing malaria-related mortality in children.

Randomized, open-label, phase 2a study to evaluate the contribution of artefenomel to the clinical and parasiticidal activity of artefenomel plus ferroquine in African patients with uncomplicated Plasmodium falciparum malaria.

Background: The contribution of artefenomel to the clinical and parasiticidal activity of ferroquine and artefenomel in combination in uncomplicated Plasmodium falciparum malaria was investigated.

Methods: This Phase 2a, randomized, open-label, parallel-group study was conducted from 11th September 2018 to 6th November 2019 across seven centres in Benin, Burkina Faso, Gabon, Kenya, and Uganda. Patients aged ≥ 14-69 years with microscopically confirmed infection (≥ 3000 to ≤ 50,000 parasites/µL blood) were randomized 1:1:1:1 to 400 mg ferroquine, or 400 mg ferroquine plus artefenomel 300, 600, or 1000 mg, administered as a single oral dose.

Efficacy, Safety, Tolerability, and Pharmacokinetics of MMV390048 in Acute Uncomplicated Malaria.

An open label, phase IIa study conducted in Ethiopia evaluated the efficacy, safety, tolerability, and pharmacokinetics of a single 120-mg dose of the phosphatidylinositol 4-kinase inhibitor MMV390048 in Plasmodium vivax malaria. The study was not completed for operational reasons and emerging teratotoxicity data. For the eight adult male patients enrolled, adequate clinical and parasitological response at day 14 (primary endpoint) was 100% (8/8).

Plasmodium vivax in Children: Hidden Burden and Conspicuous Challenges, a Narrative Review.

There has been progress towards decreasing malaria prevalence globally; however, Plasmodium vivax has been less responsive to elimination efforts compared with Plasmodium falciparum. P. vivax malaria remains a serious public health concern in regions where it is the dominant species (South and South-East Asia, the Eastern Mediterranean region, and South America) and is increasingly recognized for its contribution to overall morbidity and mortality worldwide.

Safety and efficacy of four drug regimens versus standard-of-care for the treatment of symptomatic outpatients with COVID-19: A randomised, open-label, multi-arm, phase 2 clinical trial.

Background: This exploratory study investigated four repurposed anti-infective drug regimens in outpatients with COVID-19.

Methods: This phase 2, single centre, randomised, open-label, clinical trial was conducted in South Africa between 3rd September 2020 and 23rd August 2021. Symptomatic outpatients aged 18-65 years, with RT-PCR confirmed SARS-CoV-2 infection were computer randomised (1:1:1:1:1) to standard-of-care (SOC) with paracetamol, or SOC plus artesunate-amodiaquine (ASAQ), pyronaridine-artesunate (PA), favipiravir plus nitazoxanide (FPV + NTZ), or sofosbuvir-daclatasvir (SOF-DCV).

A pharmacometrics approach to assess the feasibility of capillary microsampling to replace venous sampling in clinical studies: Tafenoquine case study.

Aim: Microsampling has the advantage of smaller blood sampling volume and suitability in vulnerable populations compared to venous sampling in clinical pharmacokinetics studies. Current regulatory guidance requires correlative studies to enable microsampling as a technique. A post hoc population pharmacokinetic (POPPK) approach was utilized to investigate blood capillary microsampling as an alternative to venous sampling.

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

Background: High-quality evidence for the therapeutic efficacy and effectiveness of antimalarials for infections caused by Plasmodium malariae, Plasmodium ovale spp, and mixed-Plasmodium infections is scarce. In this study, we aimed to analyse the efficacy of pyronaridine-artesunate for the treatment of non-falciparum and mixed-species Plasmodium infections from a large phase 3b/4 clinical trial in central Africa.

Methods: This post-hoc analysis was done in a random subset of samples from two sites (in the Democratic Republic of the Congo and in Gabon) of the CANTAM-Pyramax trial assessing pyronaridine-artesunate therapy.

Impact of the malaria comprehensive case management programme in Odisha, India.

Background: The Comprehensive Case Management Project (CCMP), was a collaborative implementation research initiative to strengthen malaria early detection and complete treatment in Odisha State, India.

Methods: A two-arm quasi-experimental design was deployed across four districts in Odisha, representing a range of malaria endemicity: Bolangir (low), Dhenkanal (moderate), Angul (high), and Kandhamal (hyper). In each district, a control block received routine malaria control measures, whereas a CCMP block received a range of interventions to intensify surveillance, diagnosis, and case management.

Active Pharmacovigilance for Primaquine Radical Cure of Plasmodium vivax Malaria in Odisha, India.

Plasmodium vivax malaria elimination requires radical cure with chloroquine/primaquine. However, primaquine causes hemolysis in glucose-6-phosphate dehydrogenase-deficient (G6PDd) individuals. Between February 2016 and July 2017 in Odisha State, India, a prospective, observational, active pharmacovigilance study assessed the hematologic safety of directly observed 25 mg/kg chloroquine over 3 days plus primaquine 0.

Tafenoquine exposure assessment, safety, and relapse prevention efficacy in children with Plasmodium vivax malaria: open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 trial.

Background: Single-dose tafenoquine 300 mg is approved for Plasmodium vivax malaria relapse prevention in patients at least 16 years old. We aimed to determine appropriate oral tafenoquine paediatric dosing regimens, including a dispersible formulation, and evaluated tafenoquine efficacy and safety in children infected with P vivax.

Methods: This open-label, single-arm, non-comparative, multicentre, pharmacokinetic bridging, phase 2 study enrolled children (2-15 years) who weighed 5 kg or more, with glucose-6-phosphate dehydrogenase activity more than 70% of the local population median, and P vivax malaria infection, from three community health centres in Vietnam and one in Colombia.

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

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.

Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial.

Background: Pyronaridine-artesunate (PA) is a registered artemisinin-based combination therapy, potentially useful for mass drug administration campaigns. However, further data are needed to evaluate its efficacy, safety and tolerability as full or incomplete treatment in asymptomatic Plasmodium falciparum-infected individuals.

Methods: This phase II, multi-center, open label, randomized clinical trial was conducted in The Gambia and Zambia.

Longitudinal study based on a safety registry for malaria patients treated with artenimol-piperaquine in six European countries.

Background: European travellers to endemic countries are at risk of malaria and may be affected by a different range of co-morbidities than natives of endemic regions. The safety profile, especially cardiac issues, of artenimol (previously dihydroartemisinin)-piperaquine (APQ) Eurartesim during treatment of uncomplicated imported falciparum malaria is not adequately described due to the lack of longitudinal studies in this population. The present study was conducted to partially fill this gap.

Efficacy and Safety of Pyronaridine-Artesunate for the Treatment of Uncomplicated and Malaria in Myanmar.

Four single-arm, prospective, clinical studies of pyronaridine-artesunate efficacy in uncomplicated or malaria were conducted in Myanmar between 2017 and 2019. Eligible subjects were aged at least 6 years, with microscopically confirmed ( = 196) or mono-infection ( = 206). Patients received pyronaridine-artesunate once daily for 3 days with follow-up until day 42 for or day 28 for .

Pharmacogenetic assessment of tafenoquine efficacy in patients with Plasmodium vivax malaria.

Plasmodium vivax has the largest geographic range of human malaria species and is challenging to manage and eradicate due to its ability to establish a dormant liver stage, the hypnozoite, which can reactivate leading to relapse. Until recently, the only treatment approved to kill hypnozoites was the 8-aminoquinoline, primaquine, requiring daily treatment for 14 days. Tafenoquine, an 8-aminoquinoline single-dose treatment with activity against P.

Neurological and psychiatric safety of tafenoquine in Plasmodium vivax relapse prevention: a review.

Background: Tafenoquine is an 8-aminoquinoline anti-malarial drug recently approved as a single-dose (300 mg) therapy for Plasmodium vivax relapse prevention, when co-administered with 3-days of chloroquine or other blood schizonticide. Tafenoquine 200 mg weekly after a loading dose is also approved as travellers' prophylaxis. The development of tafenoquine has been conducted over many years, using various dosing regimens in diverse populations.

Factors affecting the electrocardiographic QT interval in malaria: A systematic review and meta-analysis of individual patient data.

Background: Electrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria.

Safety, Tolerability, Pharmacokinetics, and Antimalarial Activity of the Novel Phosphatidylinositol 4-Kinase Inhibitor MMV390048 in Healthy Volunteers.

MMV390048 is a novel antimalarial compound that inhibits phosphatidylinositol-4-kinase. The safety, tolerability, pharmacokinetic profile, and antimalarial activity of MMV390048 were determined in healthy volunteers in three separate studies. A first-in-human, double-blind, randomized, placebo-controlled, single-ascending-dose study was performed.