Antimalarial artesunate–mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial

Emmanuel Bottieau; Moustapha Mbow; Isabel Brosius; Clémentine Roucher; Cheikh Tidiane Gueye; Ousmane Thiam Mbodj; Babacar Thiendella Faye; Annelies De Hondt; Bart Smekens; Diana Arango; Christophe Burm; Achilleas Tsoumanis; Linda Paredis; Yven Van Herrewege; Idzi Potters; Joachim Richter; Anna Rosanas-Urgell; Badara Cissé; Souleymane Mboup; Katja Polman

doi:10.1038/s41591-023-02719-4

Antimalarial artesunate–mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial

Emmanuel Bottieau^*, Moustapha Mbow, Isabel Brosius, Clémentine Roucher, Cheikh Tidiane Gueye, Ousmane Thiam Mbodj, Babacar Thiendella Faye, Annelies De Hondt, Bart Smekens, Diana Arango, Christophe Burm, Achilleas Tsoumanis, Linda Paredis, Yven Van Herrewege, Idzi Potters, Joachim Richter, Anna Rosanas-Urgell, Badara Cissé, Souleymane Mboup, Katja Polman

^*Corresponding author for this work

Research output: Contribution to Journal › Article › Academic › peer-review

Abstract

Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate–mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6–14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg⁻¹ single dose; n = 364) or to artesunate–mefloquine (antimalarial dosage: artesunate 4 mg kg⁻¹ and mefloquine 8 mg kg⁻¹ daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate–mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate–mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate–mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 .

Original language	English
Pages (from-to)	130-137
Number of pages	8
Journal	Nature Medicine
Volume	30
DOIs	https://doi.org/10.1038/s41591-023-02719-4
Publication status	Published - 4 Jan 2024

Bibliographical note

Funding Information:
This study was supported by the Flemish Ministry of Economy, Sciences and Innovation (EWI), which was granted in the framework of the Structural Research Funding of ITM (SOFI), a competitive internal grant of the Institute of Tropical Medicine (grant number DIR/av/2018/90; obtained by E.B. and K.P.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to the Cipla company for providing both study drugs at no cost. The company had no role in study design, data collection, data analysis, data interpretation or writing of the report. We also thank all nurses, community health workers, laboratory technicians, school teachers and directors and community leaders, without whom this trial would not have been possible. We want to especially highlight the tremendous efforts of the field staff, who maintained all follow-up samplings on schedule through door-to-door visits during the COVID-19 pandemic. We are also grateful to the members of the Data Safety Monitoring Board (DSMB) for their critical and regular review of the trial data. The DSMB was composed of (1) D. Van Der Linden, pediatrician specialized in Infectious Diseases, Catholic University of Louvain, Belgium, (2) F. Gobbi, Sacro Cuore don Calabria Hospital, Negrar, Italy, and (3) T. Pistone, University Hospital of Bordeaux, France, both internists specialized in Infectious and Tropical Diseases.

Funding Information:
This study was supported by the Flemish Ministry of Economy, Sciences and Innovation (EWI), which was granted in the framework of the Structural Research Funding of ITM (SOFI), a competitive internal grant of the Institute of Tropical Medicine (grant number DIR/av/2018/90; obtained by E.B. and K.P.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to the Cipla company for providing both study drugs at no cost. The company had no role in study design, data collection, data analysis, data interpretation or writing of the report. We also thank all nurses, community health workers, laboratory technicians, school teachers and directors and community leaders, without whom this trial would not have been possible. We want to especially highlight the tremendous efforts of the field staff, who maintained all follow-up samplings on schedule through door-to-door visits during the COVID-19 pandemic. We are also grateful to the members of the Data Safety Monitoring Board (DSMB) for their critical and regular review of the trial data. The DSMB was composed of (1) D. Van Der Linden, pediatrician specialized in Infectious Diseases, Catholic University of Louvain, Belgium, (2) F. Gobbi, Sacro Cuore don Calabria Hospital, Negrar, Italy, and (3) T. Pistone, University Hospital of Bordeaux, France, both internists specialized in Infectious and Tropical Diseases.

Publisher Copyright:
© 2024, The Author(s).

Funding

This study was supported by the Flemish Ministry of Economy, Sciences and Innovation (EWI), which was granted in the framework of the Structural Research Funding of ITM (SOFI), a competitive internal grant of the Institute of Tropical Medicine (grant number DIR/av/2018/90; obtained by E.B. and K.P.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to the Cipla company for providing both study drugs at no cost. The company had no role in study design, data collection, data analysis, data interpretation or writing of the report. We also thank all nurses, community health workers, laboratory technicians, school teachers and directors and community leaders, without whom this trial would not have been possible. We want to especially highlight the tremendous efforts of the field staff, who maintained all follow-up samplings on schedule through door-to-door visits during the COVID-19 pandemic. We are also grateful to the members of the Data Safety Monitoring Board (DSMB) for their critical and regular review of the trial data. The DSMB was composed of (1) D. Van Der Linden, pediatrician specialized in Infectious Diseases, Catholic University of Louvain, Belgium, (2) F. Gobbi, Sacro Cuore don Calabria Hospital, Negrar, Italy, and (3) T. Pistone, University Hospital of Bordeaux, France, both internists specialized in Infectious and Tropical Diseases. This study was supported by the Flemish Ministry of Economy, Sciences and Innovation (EWI), which was granted in the framework of the Structural Research Funding of ITM (SOFI), a competitive internal grant of the Institute of Tropical Medicine (grant number DIR/av/2018/90; obtained by E.B. and K.P.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to the Cipla company for providing both study drugs at no cost. The company had no role in study design, data collection, data analysis, data interpretation or writing of the report. We also thank all nurses, community health workers, laboratory technicians, school teachers and directors and community leaders, without whom this trial would not have been possible. We want to especially highlight the tremendous efforts of the field staff, who maintained all follow-up samplings on schedule through door-to-door visits during the COVID-19 pandemic. We are also grateful to the members of the Data Safety Monitoring Board (DSMB) for their critical and regular review of the trial data. The DSMB was composed of (1) D. Van Der Linden, pediatrician specialized in Infectious Diseases, Catholic University of Louvain, Belgium, (2) F. Gobbi, Sacro Cuore don Calabria Hospital, Negrar, Italy, and (3) T. Pistone, University Hospital of Bordeaux, France, both internists specialized in Infectious and Tropical Diseases.

Funders	Funder number
Flemish Ministry of Economy, Sciences and Innovation
Instituut voor Tropische Geneeskunde	DIR/av/2018/90
Instituut voor Tropische Geneeskunde
ITM University-Gwalior
Université Catholique de Louvain
Departement Economie, Wetenschap en Innovatie

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10.1038/s41591-023-02719-4

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Bottieau, E., Mbow, M., Brosius, I., Roucher, C., Gueye, C. T., Mbodj, O. T., Faye, B. T., De Hondt, A., Smekens, B., Arango, D., Burm, C., Tsoumanis, A., Paredis, L., Van Herrewege, Y., Potters, I., Richter, J., Rosanas-Urgell, A., Cissé, B., Mboup, S., & Polman, K. (2024). Antimalarial artesunate–mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial. Nature Medicine, 30, 130-137. https://doi.org/10.1038/s41591-023-02719-4

@article{c3d18fc5db754b209ef7182248b0c710,

title = "Antimalarial artesunate–mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial",

abstract = "Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate–mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6–14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg−1 single dose; n = 364) or to artesunate–mefloquine (antimalarial dosage: artesunate 4 mg kg−1 and mefloquine 8 mg kg−1 daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate–mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate–mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate–mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 .",

author = "Emmanuel Bottieau and Moustapha Mbow and Isabel Brosius and Cl{\'e}mentine Roucher and Gueye, {Cheikh Tidiane} and Mbodj, {Ousmane Thiam} and Faye, {Babacar Thiendella} and {De Hondt}, Annelies and Bart Smekens and Diana Arango and Christophe Burm and Achilleas Tsoumanis and Linda Paredis and {Van Herrewege}, Yven and Idzi Potters and Joachim Richter and Anna Rosanas-Urgell and Badara Ciss{\'e} and Souleymane Mboup and Katja Polman",

note = "Funding Information: This study was supported by the Flemish Ministry of Economy, Sciences and Innovation (EWI), which was granted in the framework of the Structural Research Funding of ITM (SOFI), a competitive internal grant of the Institute of Tropical Medicine (grant number DIR/av/2018/90; obtained by E.B. and K.P.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to the Cipla company for providing both study drugs at no cost. The company had no role in study design, data collection, data analysis, data interpretation or writing of the report. We also thank all nurses, community health workers, laboratory technicians, school teachers and directors and community leaders, without whom this trial would not have been possible. We want to especially highlight the tremendous efforts of the field staff, who maintained all follow-up samplings on schedule through door-to-door visits during the COVID-19 pandemic. We are also grateful to the members of the Data Safety Monitoring Board (DSMB) for their critical and regular review of the trial data. The DSMB was composed of (1) D. Van Der Linden, pediatrician specialized in Infectious Diseases, Catholic University of Louvain, Belgium, (2) F. Gobbi, Sacro Cuore don Calabria Hospital, Negrar, Italy, and (3) T. Pistone, University Hospital of Bordeaux, France, both internists specialized in Infectious and Tropical Diseases. Funding Information: This study was supported by the Flemish Ministry of Economy, Sciences and Innovation (EWI), which was granted in the framework of the Structural Research Funding of ITM (SOFI), a competitive internal grant of the Institute of Tropical Medicine (grant number DIR/av/2018/90; obtained by E.B. and K.P.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to the Cipla company for providing both study drugs at no cost. The company had no role in study design, data collection, data analysis, data interpretation or writing of the report. We also thank all nurses, community health workers, laboratory technicians, school teachers and directors and community leaders, without whom this trial would not have been possible. We want to especially highlight the tremendous efforts of the field staff, who maintained all follow-up samplings on schedule through door-to-door visits during the COVID-19 pandemic. We are also grateful to the members of the Data Safety Monitoring Board (DSMB) for their critical and regular review of the trial data. The DSMB was composed of (1) D. Van Der Linden, pediatrician specialized in Infectious Diseases, Catholic University of Louvain, Belgium, (2) F. Gobbi, Sacro Cuore don Calabria Hospital, Negrar, Italy, and (3) T. Pistone, University Hospital of Bordeaux, France, both internists specialized in Infectious and Tropical Diseases. Publisher Copyright: {\textcopyright} 2024, The Author(s).",

year = "2024",

month = jan,

day = "4",

doi = "10.1038/s41591-023-02719-4",

language = "English",

volume = "30",

pages = "130--137",

journal = "Nature Medicine",

issn = "1078-8956",

publisher = "Nature Research",

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Bottieau, E, Mbow, M, Brosius, I, Roucher, C, Gueye, CT, Mbodj, OT, Faye, BT, De Hondt, A, Smekens, B, Arango, D, Burm, C, Tsoumanis, A, Paredis, L, Van Herrewege, Y, Potters, I, Richter, J, Rosanas-Urgell, A, Cissé, B, Mboup, S & Polman, K 2024, 'Antimalarial artesunate–mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial', Nature Medicine, vol. 30, pp. 130-137. https://doi.org/10.1038/s41591-023-02719-4

TY - JOUR

T1 - Antimalarial artesunate–mefloquine versus praziquantel in African children with schistosomiasis

T2 - an open-label, randomized controlled trial

AU - Bottieau, Emmanuel

AU - Mbow, Moustapha

AU - Brosius, Isabel

AU - Roucher, Clémentine

AU - Gueye, Cheikh Tidiane

AU - Mbodj, Ousmane Thiam

AU - Faye, Babacar Thiendella

AU - De Hondt, Annelies

AU - Smekens, Bart

AU - Arango, Diana

AU - Burm, Christophe

AU - Tsoumanis, Achilleas

AU - Paredis, Linda

AU - Van Herrewege, Yven

AU - Potters, Idzi

AU - Richter, Joachim

AU - Rosanas-Urgell, Anna

AU - Cissé, Badara

AU - Mboup, Souleymane

AU - Polman, Katja

N1 - Funding Information: This study was supported by the Flemish Ministry of Economy, Sciences and Innovation (EWI), which was granted in the framework of the Structural Research Funding of ITM (SOFI), a competitive internal grant of the Institute of Tropical Medicine (grant number DIR/av/2018/90; obtained by E.B. and K.P.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to the Cipla company for providing both study drugs at no cost. The company had no role in study design, data collection, data analysis, data interpretation or writing of the report. We also thank all nurses, community health workers, laboratory technicians, school teachers and directors and community leaders, without whom this trial would not have been possible. We want to especially highlight the tremendous efforts of the field staff, who maintained all follow-up samplings on schedule through door-to-door visits during the COVID-19 pandemic. We are also grateful to the members of the Data Safety Monitoring Board (DSMB) for their critical and regular review of the trial data. The DSMB was composed of (1) D. Van Der Linden, pediatrician specialized in Infectious Diseases, Catholic University of Louvain, Belgium, (2) F. Gobbi, Sacro Cuore don Calabria Hospital, Negrar, Italy, and (3) T. Pistone, University Hospital of Bordeaux, France, both internists specialized in Infectious and Tropical Diseases. Funding Information: This study was supported by the Flemish Ministry of Economy, Sciences and Innovation (EWI), which was granted in the framework of the Structural Research Funding of ITM (SOFI), a competitive internal grant of the Institute of Tropical Medicine (grant number DIR/av/2018/90; obtained by E.B. and K.P.). The funder of the study had no role in study design, data collection, data analysis, data interpretation or writing of the report. We are grateful to the Cipla company for providing both study drugs at no cost. The company had no role in study design, data collection, data analysis, data interpretation or writing of the report. We also thank all nurses, community health workers, laboratory technicians, school teachers and directors and community leaders, without whom this trial would not have been possible. We want to especially highlight the tremendous efforts of the field staff, who maintained all follow-up samplings on schedule through door-to-door visits during the COVID-19 pandemic. We are also grateful to the members of the Data Safety Monitoring Board (DSMB) for their critical and regular review of the trial data. The DSMB was composed of (1) D. Van Der Linden, pediatrician specialized in Infectious Diseases, Catholic University of Louvain, Belgium, (2) F. Gobbi, Sacro Cuore don Calabria Hospital, Negrar, Italy, and (3) T. Pistone, University Hospital of Bordeaux, France, both internists specialized in Infectious and Tropical Diseases. Publisher Copyright: © 2024, The Author(s).

PY - 2024/1/4

Y1 - 2024/1/4

N2 - Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate–mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6–14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg−1 single dose; n = 364) or to artesunate–mefloquine (antimalarial dosage: artesunate 4 mg kg−1 and mefloquine 8 mg kg−1 daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate–mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate–mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate–mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 .

AB - Schistosomiasis treatment entirely relies on a single drug, praziquantel, prompting research into alternative therapeutics. Here we evaluated the efficacy and safety of the antimalarial combination artesunate–mefloquine for the treatment of schistosomiasis in a proof-of-concept, pragmatic, open-label, randomized controlled trial in primary schools of six villages endemic for schistosomiasis in northern Senegal. Children (6–14 years) were eligible if Schistosoma eggs were detected by microscopy in urine and/or stool. In total, 726 children were randomized 1:1 to praziquantel (standard care: 40 mg kg−1 single dose; n = 364) or to artesunate–mefloquine (antimalarial dosage: artesunate 4 mg kg−1 and mefloquine 8 mg kg−1 daily for three consecutive days; n = 362). Eight children not meeting the inclusion criteria were excluded from efficacy analysis. Median age of the remaining 718 participants was 9 years; 399 (55.6%) were male, and 319 (44.4%) female; 99.3% were infected with Schistosoma haematobium and 15.2% with S. mansoni. Primary outcomes were cure rate, assessed by microscopy, and frequency of drug-related adverse effects of artesunate–mefloquine versus praziquantel at 4 weeks after treatment. Cure rate was 59.6% (208/349) in the artesunate–mefloquine arm versus 62.1% (211/340) in the praziquantel arm. The difference of −2.5% (95% confidence interval (CI) −9.8 to 4.8) met the predefined criteria of noninferiority (margin set at 10%). All drug-related adverse events were mild or moderate, and reported in 28/361 children receiving artesunate–mefloquine (7.8%; 95% CI 5.4 to 11.0) versus 8/363 (2.2%; 95% CI 1.1 to 4.3) receiving praziquantel (P < 0.001). Artesunate–mefloquine at antimalarial dosage was moderately safe and noninferior to standard-care praziquantel for the treatment of schistosomiasis, predominantly due to S. haematobium. Multicentric trials in different populations and epidemiological settings are needed to confirm these findings. ClinicalTrials.gov identifier: NCT03893097 .

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Antimalarial artesunate–mefloquine versus praziquantel in African children with schistosomiasis: an open-label, randomized controlled trial

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