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The efficacy and safety of a single-dose combination of artefenomel (800\u00a0mg) plus ferroquine (400\/600\/900\/1200\u00a0mg doses) for the treatment of uncomplicated <jats:italic>P. falciparum<\/jats:italic> malaria were evaluated in Africa (focusing on children\u2009\u2264\u20095\u00a0years) and Asia.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>The study was a randomized, double-blind, single-dose, multi-arm clinical trial in patients aged\u2009&gt;\u20096\u00a0months to\u2009&lt;\u200970\u00a0years, from six African countries and Vietnam. Patients were followed up for 63\u00a0days 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\u00a028 in the Per-Protocol [PP] Set comprising only African patients\u2009\u2264\u20095\u00a0years. The exposure\u2013response relationship for PCR-adjusted ACPR at Day 28 and prevalence of <jats:italic>kelch-13<\/jats:italic> mutations were explored.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>A total of 373 patients were treated: 289 African patients\u2009\u2264\u20095\u00a0years (77.5%), 64\u00a0African patients\u2009&gt;\u20095\u00a0years 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]\u2009&gt;\u200990%). 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\u00a0mg to 1200\u00a0mg 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 <jats:italic>kelch-13<\/jats:italic> mutations were detected in parasite isolates from 10\/272\u00a0African patients (with 2 mutations known to be associated with artemisinin resistance) and 18\/20\u00a0Asian patients (all C580Y mutation). Vomiting within 6\u00a0h of initial artefenomel administration was common (24.6%) and associated with lower drug exposures.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusion<\/jats:title>\n                <jats:p>The efficacy of artefenomel\/ferroquine combination was suboptimal in African children aged\u2009\u2264\u20095\u00a0years, the population of interest, and vomiting most likely had a negative impact on efficacy.<\/jats:p>\n                <jats:p><jats:italic>Trial registration<\/jats:italic> ClinicalTrials.gov, NCT02497612. Registered 14\u00a0Jul\u00a02015, <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"uri\" xlink:href=\"https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02497612?term=NCT02497612&amp;draw=2&amp;rank=1\">https:\/\/clinicaltrials.gov\/ct2\/show\/NCT02497612?term=NCT02497612&amp;draw=2&amp;rank=1<\/jats:ext-link><\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s12936-021-03749-4","type":"journal-article","created":{"date-parts":[[2021,5,19]],"date-time":"2021-05-19T13:09:40Z","timestamp":1621429780000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":51,"title":["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"],"prefix":"10.1186","volume":"20","clinical-trial-number":[{"clinical-trial-number":"nct02497612","registry":"10.18810\/clinical-trials-gov"}],"author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2899-1470","authenticated-orcid":false,"given":"Yeka","family":"Adoke","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rella","family":"Zoleko-Manego","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Serge","family":"Ouoba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alfred B.","family":"Tiono","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Grace","family":"Kaguthi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juv\u00eancio Eduardo","family":"Bonzela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran Thanh","family":"Duong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alain","family":"Nahum","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marielle","family":"Bouyou-Akotet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bernhards","family":"Ogutu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alphonse","family":"Ouedraogo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Macintyre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Jessel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bart","family":"Laurijssens","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed H.","family":"Cherkaoui-Rbati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Cantalloube","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne Claire","family":"Marrast","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rapha\u00ebl","family":"Bejuit","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"White","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Timothy N. 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The study was conducted at 10 sites across 6 African countries, Benin (Zinvi\u00e9), Burkina Faso (Nanoro, Banfora and Niangoloko), Gabon (Libreville, Lambar\u00e9n\u00e9), Kenya (Siaya, Kisumu), Mozambique (Chokwe), and Uganda (Tororo), and 4 sites in Vietnam (Binh Phuoc, Gia Lai, Khanh Hoa, Quang tri, although the last 2 sites did not randomize any patient). Participants provided written informed consent prior to inclusion. The local and national IECs that approved the study are the following: Comit\u00e9 National d\u2019Ethique pour la Recherche en Sant\u00e9, Cotonou, Benin (national IEC). Centre National de la Recherche Scientifique et Technologique (CNRST)\u2014Comit\u00e9 d'Ethique Institutionnel, Bobo-Dioulasso, Burkina Faso (local IEC), Comit\u00e9 d\u2019Ethique pour la Recherche en Sant\u00e9, Ouagadougou, Burkina Faso (national IEC), Comit\u00e9 Institutionnel de Bio\u00e9thique, Centre National de Recherche et de Formation sur le Paludisme (CNRFP), Ouagadougou, Burkina Faso (local IEC), Comit\u00e9 National d\u2019Ethique pour la Recherche (CNER), Libreville, Gabon (national IEC), Kenya Medical Research Institute (KEMRI)\u2014Scientific and Ethics Review Unit (SERU), Nairobi, Kenya (local IEC), Ao Comit\u00ea Nacional Bio\u00e9tica para a Sa\u00fade (CNBS), Maputo, Mozambique (national IEC), Makerere University, College of Health Sciences, School of Biomedical Sciences, Higher Degrees Research and Ethics Committee, Kampala, Uganda (local IEC), Ethics Committee of National Institute of Malariology, Parasitology and Entomology (NIMPE), Ha Noi, Vietnam (local IEC), National Ethics committee in Biomedical Research, Ministry of Health, Vietnam (national IEC).","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval and consent to participate"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for publication"}},{"value":"FM, MHCR, ACM, TW, FW, and DL are employed by MMV. BL is a consultant for MMV and was paid for his work on the FALCI Study. AJ, CC and RB are employed by Sanofi. AJ holds shares in the company. The other authors declare that they have no competing interests.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"222"}}