A randomized, double‑blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single‑dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria
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Date
2021
Journal Title
Journal ISSN
Volume Title
Publisher
Malaria journal
Abstract
For uncomplicated Plasmodium falciparum malaria, highly efficacious single-dose treatments
are expected to increase compliance and improve treatment outcomes, and thereby may slow the development
of resistance. The efficacy and safety of a single-dose combination of artefenomel (800 mg) plus ferroquine
(400/600/900/1200 mg doses) for the treatment of uncomplicated P. falciparum malaria were evaluated in Africa
(focusing on children ≤ 5 years) and Asia.
Methods: The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged > 6 months
to < 70 years, from six African countries and Vietnam. Patients were followed up for 63 days to assess treatment efficacy,
safety and pharmacokinetics. The primary efficacy endpoint was the polymerase chain reaction (PCR)-adjusted
adequate clinical and parasitological response (ACPR) at Day 28 in the Per-Protocol [PP] Set comprising only African
patients ≤ 5 years. The exposure–response relationship for PCR-adjusted ACPR at Day 28 and prevalence of kelch-13
mutations were explored.
Results: A total of 373 patients were treated: 289 African patients ≤ 5 years (77.5%), 64 African patients > 5 years
and 20 Asian patients. None of the treatment arms met the target efficacy criterion for PCR-adjusted ACPR at Day 28 (lower limit of 95% confidence interval [CI] > 90%). PCR-adjusted ACPR at Day 28 [95% CI] in the PP Set ranged
from 78.4% [64.7; 88.7%] to 91.7% [81.6; 97.2%] for the 400 mg to 1200 mg ferroquine dose. Efficacy rates were low in
Vietnamese patients, ranging from 20 to 40%. A clear relationship was found between drug exposure (artefenomel
and ferroquine concentrations at Day 7) and efficacy (primary endpoint), with higher concentrations of both drugs
resulting in higher efficacy. Six distinct kelch-13 mutations were detected in parasite isolates from 10/272 African
patients (with 2 mutations known to be associated with artemisinin resistance) and 18/20 Asian patients (all C580Y
mutation). Vomiting within 6 h of initial artefenomel administration was common (24.6%) and associated with lower
drug exposures.
Conclusion: The efficacy of artefenomel/ferroquine combination was suboptimal in African children aged ≤ 5 years,
the population of interest, and vomiting most likely had a negative impact on efficacy.
Trial registration ClinicalTrials.gov, NCT02497612. Registered 14 Jul 2015, https:// clini caltr ials. gov/ ct2/ show/ NCT02
497612? term= NCT02 49761 2& draw= 2& rank=1
Description
Keywords
Ferroquine, Combination treatment, Pharmacokinetics/pharmacodynamics, Exposure–response, C580Y
Citation
Adoke, Y., Zoleko-Manego, R., Ouoba, S., Tiono, A. B., Kaguthi, G., Bonzela, J. E., ... & Tinto, H. (2021). A randomized, double-blind, phase 2b study to investigate the efficacy, safety, tolerability and pharmacokinetics of a single-dose regimen of ferroquine with artefenomel in adults and children with uncomplicated Plasmodium falciparum malaria. Malaria journal, 20(1), 1-25. https://doi.org/10.1186/s12936-021-03749-4