Efficacy, Safety and Tolerability of Pyronaridine-artesunate in Asymptomatic Malaria-infected Individuals: a Randomized Controlled Trial.
asymptomatic
malaria
pediatric
pyronaridine-artesunate
randomized controlled clinical trial
Journal
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America
ISSN: 1537-6591
Titre abrégé: Clin Infect Dis
Pays: United States
ID NLM: 9203213
Informations de publication
Date de publication:
29 01 2022
29 01 2022
Historique:
received:
18
01
2021
pubmed:
14
5
2021
medline:
15
3
2022
entrez:
13
5
2021
Statut:
ppublish
Résumé
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. This phase II, multi-center, open label, randomized clinical trial was conducted in The Gambia and Zambia. Participants with microscopically confirmed asymptomatic P. falciparum infection were randomly assigned (1:1:1) to receive a 3-day, 2-day, or 1-day treatment regimen of PA (180:60 mg), dosed according to bodyweight. The primary efficacy outcome was polymerase chain reaction (PCR)-adjusted adequate parasitological response (APR) at day 28 in the per-protocol population. A total of 303 participants were randomized. Day 28 PCR-adjusted APR was 100% for both the 3-day (98/98) and 2-day regimens (96/96), and 96.8% (89/94) for the 1-day regimen. Efficacy was maintained at 100% until day 63 for the 3-day and 2-day regimens but declined to 94.4% (84/89) with the 1-day regimen. Adverse event frequency was similar between the 3-day (51.5% [52/101]), 2-day (52.5% [52/99]), and 1-day (54.4% [56/103]) regimens; the majority of adverse events were of grade 1 or 2 severity (85% [136/160]). Asymptomatic, transient increases (>3 times the upper limit of normal) in alanine aminotransferase/aspartate aminotransferase were observed for 6/301 (2.0%) participants. PA had high efficacy and good tolerability in asymptomatic P. falciparum-infected individuals, with similar efficacy for the full 3-day and incomplete 2-day regimens. Although good adherence to the 3-day regimen should be encouraged, these results support the further investigation of PA for mass drug administration campaigns. NCT03814616.
Sections du résumé
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. Participants with microscopically confirmed asymptomatic P. falciparum infection were randomly assigned (1:1:1) to receive a 3-day, 2-day, or 1-day treatment regimen of PA (180:60 mg), dosed according to bodyweight. The primary efficacy outcome was polymerase chain reaction (PCR)-adjusted adequate parasitological response (APR) at day 28 in the per-protocol population.
RESULTS
A total of 303 participants were randomized. Day 28 PCR-adjusted APR was 100% for both the 3-day (98/98) and 2-day regimens (96/96), and 96.8% (89/94) for the 1-day regimen. Efficacy was maintained at 100% until day 63 for the 3-day and 2-day regimens but declined to 94.4% (84/89) with the 1-day regimen. Adverse event frequency was similar between the 3-day (51.5% [52/101]), 2-day (52.5% [52/99]), and 1-day (54.4% [56/103]) regimens; the majority of adverse events were of grade 1 or 2 severity (85% [136/160]). Asymptomatic, transient increases (>3 times the upper limit of normal) in alanine aminotransferase/aspartate aminotransferase were observed for 6/301 (2.0%) participants.
CONCLUSIONS
PA had high efficacy and good tolerability in asymptomatic P. falciparum-infected individuals, with similar efficacy for the full 3-day and incomplete 2-day regimens. Although good adherence to the 3-day regimen should be encouraged, these results support the further investigation of PA for mass drug administration campaigns.
CLINICAL TRIALS REGISTRATION
NCT03814616.
Identifiants
pubmed: 33983371
pii: 6275208
doi: 10.1093/cid/ciab425
pmc: PMC8800175
doi:
Substances chimiques
Antimalarials
0
Drug Combinations
0
Naphthyridines
0
pyronaridine tetraphosphate, artesunate drug combination
0
Artesunate
60W3249T9M
Banques de données
ClinicalTrials.gov
['NCT03814616']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
180-188Subventions
Organisme : Medical Research Council
ID : MC_UU_00026/1
Pays : United Kingdom
Organisme : Shin Poong Pharmaceutical and Medicines for Malaria Venture
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.
Références
Cochrane Database Syst Rev. 2019 Jan 08;1:CD006404
pubmed: 30620055
Expert Rev Anti Infect Ther. 2013 Jun;11(6):623-39
pubmed: 23750733
J Infect Dis. 2016 Dec 15;214(12):1831-1839
pubmed: 27923947
Antimicrob Agents Chemother. 2016 Jun 20;60(7):3884-90
pubmed: 26926629
Malar J. 2018 May 15;17(1):199
pubmed: 29764419
Antimicrob Agents Chemother. 2018 Aug 27;62(9):
pubmed: 29967019
PLoS One. 2012;7(4):e35019
pubmed: 22514702
Am J Trop Med Hyg. 2020 Aug;103(2_Suppl):7-18
pubmed: 32618247
Malar J. 2009 Feb 20;8:31
pubmed: 19228438
Parasitol Int. 2000 Feb;48(4):275-80
pubmed: 10725690
J Infect. 2015 Nov;71(5):587-96
pubmed: 26304688
Malar J. 2015 Aug 14;14:314
pubmed: 26268225
BMC Infect Dis. 2015 Mar 22;15:144
pubmed: 25887935
Antimicrob Agents Chemother. 2019 Sep 23;63(10):
pubmed: 31358594
Antimicrob Agents Chemother. 2019 Feb 26;63(3):
pubmed: 30602520
J Infect Dis. 2020 Jul 21;:
pubmed: 32691047
Lancet. 2018 Apr 7;391(10128):1378-1390
pubmed: 29606364
Lancet Glob Health. 2017 Jul;5(7):e680-e687
pubmed: 28566213
N Engl J Med. 2012 Apr 5;366(14):1298-309
pubmed: 22475593
Am J Trop Med Hyg. 2020 Aug;103(2_Suppl):54-65
pubmed: 32618245
Clin Infect Dis. 2020 May 6;70(10):2187-2195
pubmed: 31251812
Cochrane Database Syst Rev. 2009 Jul 08;(3):CD007483
pubmed: 19588433
Am J Trop Med Hyg. 2020 Aug;103(2_Suppl):3-6
pubmed: 32618265
Malar J. 2009 Dec 02;8:274
pubmed: 19954532
Antimicrob Agents Chemother. 2013 Jul;57(7):3268-74
pubmed: 23629698
Am J Trop Med Hyg. 2020 Aug;103(2_Suppl):19-27
pubmed: 32618251
Sci Rep. 2020 Oct 30;10(1):18740
pubmed: 33127922
Lancet Infect Dis. 2016 Feb;16(2):189-98
pubmed: 26601738
PLoS One. 2012;7(9):e45542
pubmed: 23029082
PLoS One. 2014 Oct 22;9(10):e110926
pubmed: 25338083
Am J Trop Med Hyg. 2018 Oct;99(4):970-977
pubmed: 30105967
BMC Med. 2016 Mar 08;14:40
pubmed: 26952094
Am J Trop Med Hyg. 2020 Sep;103(3):1088-1093
pubmed: 32524960
Malar J. 2011 Sep 13;10:263
pubmed: 21914160
BMC Med. 2016 May 24;14:79
pubmed: 27221542
Clin Infect Dis. 2020 May 6;70(10):2196-2198
pubmed: 31251323
Malar J. 2008 Jul 09;7:125
pubmed: 18613962
Lancet. 2010 Apr 24;375(9724):1457-67
pubmed: 20417857
Malar J. 2018 Jun 4;17(1):223
pubmed: 29866116
Malar J. 2019 Aug 22;18(1):281
pubmed: 31438950
J Infect Dis. 2008 Sep 15;198(6):911-9
pubmed: 18694333
Proc Natl Acad Sci U S A. 2011 Nov 22;108(47):E1214-23
pubmed: 22042867
Am J Trop Med Hyg. 2020 Aug;103(2_Suppl):37-45
pubmed: 32618267
EBioMedicine. 2016 Nov;13:348-355
pubmed: 27825738
Malar J. 2013 Feb 21;12:70
pubmed: 23433102
Malar J. 2012 Oct 31;11:364
pubmed: 23113947