{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,25]],"date-time":"2026-08-25T11:29:42Z","timestamp":1787657382917,"version":"build-2736575974"},"reference-count":44,"publisher":"F1000 Research Ltd","license":[{"start":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T00:00:00Z","timestamp":1651708800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Horizon 2020","award":["RIA2017NCT-1845 \u2013STOP, PSIA2020-3072 STOP-2"],"award-info":[{"award-number":["RIA2017NCT-1845 \u2013STOP, PSIA2020-3072 STOP-2"]}]},{"DOI":"10.13039\/501100014180","name":"Junta of Castile and Le\u00f3n","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100014180","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Social Fund Plus","award":["LE-135-19"],"award-info":[{"award-number":["LE-135-19"]}]}],"content-domain":{"domain":["gatesopenresearch.org"],"crossmark-restriction":false},"short-container-title":["Gates Open Res"],"abstract":"\n Background:<\/ns4:bold>\n Soil-transmitted helminths (STH) are targeted for control through mass drug-administration campaigns to prevent morbidity affecting at-risk groups in endemic regions. Although broadly successful, the use of albendazole and mebendazole achieved variable progress, with deficiencies against\n Trichuris trichiura<\/ns4:italic>\n and a predictable low efficacy against\n Strongyloides stercoralis<\/ns4:italic>\n . Novel drug combinations offer a potential solution, providing they can be delivered safely and maintain efficacy against all STH species. Here we present the protocol of a clinical trial to evaluate a fixed-dose combination (FDC) tablet containing albendazole and ivermectin that will be compared against albendazole against STH\n .<\/ns4:italic>\n <\/ns4:p>\n \n Methods:<\/ns4:bold>\n An\n \n adaptive phase II\/III randomized controlled trial will be undertaken in STH endemic sites in Ethiopia, Kenya and Mozambique to evaluate an oral FDC of 400 mg albendazole and either 9- or 18 mg ivermectin. FDC will be administered as a single dose or single doses over three-consecutive days and assessed against a single dose of 400 mg albendazole. In the phase II trial, 126\n T. trichiura<\/ns4:italic>\n -infected children weighting 15 to 45 kg will be treated in a dose-escalation manner to determine safety objectives. In the phase III trial, 1097 participants aged 5 to 18 years old infected with\n T. trichiura,<\/ns4:italic>\n hookworm and\n S. stercoralis<\/ns4:italic>\n will be recruited to determine safety and efficacy. The trial will be open-label with blinded outcome assessors. Cure rate measured 21-days after-treatment in duplicate Kato-Katz is the primary efficacy outcome. Secondary objectives include efficacy evaluation by quantitative polymerase chain reaction (PCR) as an outcome measurement, description of pharmacokinetic parameters, palatability and acceptability evaluations, and monitoring of anthelmintic resistance.\n <\/ns4:p>\n \n Conclusions:<\/ns4:bold>\n This trial with registrational goals seeks to evaluate an innovative fixed-dose combination of albendazole and ivermectin co-formulated tablets, with the goal of providing an anthelmintic regimen with improved efficacy and spectrum of coverage against STH.\n <\/ns4:p>\n \n ClinicalTrials.gov registration:<\/ns4:bold>\n NCT05124691 (18\/11\/2021).\n <\/ns4:p>","DOI":"10.12688\/gatesopenres.13615.1","type":"journal-article","created":{"date-parts":[[2022,5,5]],"date-time":"2022-05-05T09:55:18Z","timestamp":1651744518000},"page":"62","update-policy":"https:\/\/doi.org\/10.12688\/gatesopenres.crossmark-policy","source":"Crossref","is-referenced-by-count":16,"title":["An adaptive phase II\/III safety and efficacy randomized controlled trial of single day or three-day fixed-dose albendazole-ivermectin co-formulation versus albendazole for the treatment of Trichuris trichiura and other STH infections. ALIVE trial protocol"],"prefix":"10.12688","volume":"6","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9054-1211","authenticated-orcid":false,"given":"Alejandro","family":"Krolewiecki","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wendemagegn","family":"Enbiale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5519-738X","authenticated-orcid":false,"given":"Javier","family":"Gandasegui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8170-1172","authenticated-orcid":false,"given":"Lisette","family":"van Lieshout","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Kepha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1794-2462","authenticated-orcid":false,"given":"Augusto","family":"Messa Junior","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michel","family":"Bengtson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8128-1048","authenticated-orcid":false,"given":"Woyneshet","family":"Gelaye","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9424-7503","authenticated-orcid":false,"given":"Valdemiro","family":"Escola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"Martinez-Valladares","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8898-992X","authenticated-orcid":false,"given":"Mar\u00eda","family":"Cambra-Pellej\u00e0","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jaime","family":"Algorta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helena","family":"Mart\u00ed-Soler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Fleitas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0472-9558","authenticated-orcid":false,"given":"Maria Rosa","family":"Ballester","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9167-7532","authenticated-orcid":false,"given":"Stephen R.","family":"Doyle","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nana Aba","family":"Williams","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5088-6872","authenticated-orcid":false,"given":"Almudena","family":"Legarda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1078-2187","authenticated-orcid":false,"given":"Inacio","family":"Mandomando","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles","family":"Mwandawiro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Mu\u00f1oz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"2560","published-online":{"date-parts":[[2022,5,5]]},"reference":[{"key":"ref-1","article-title":"Accelerating Work to Overcome the Global Impact of Neglected Tropical Diseases: 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Research"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/gatesopenresearch.org\/articles\/6-62\/v1\/xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/6-62\/v1\/pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/gatesopenresearch.org\/articles\/6-62\/v1\/iparadigms","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,8,17]],"date-time":"2022-08-17T12:05:14Z","timestamp":1660737914000},"score":1,"resource":{"primary":{"URL":"https:\/\/gatesopenresearch.org\/articles\/6-62\/v1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,5]]},"references-count":44,"URL":"https:\/\/doi.org\/10.12688\/gatesopenres.13615.1","relation":{"has-review":[{"id-type":"doi","id":"10.21956\/gatesopenres.14889.r32202","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/gatesopenres.14889.r32064","asserted-by":"subject"},{"id-type":"doi","id":"10.21956\/gatesopenres.14889.r32064","asserted-by":"object"},{"id-type":"doi","id":"10.21956\/gatesopenres.14889.r32202","asserted-by":"object"}]},"ISSN":["2572-4754"],"issn-type":[{"value":"2572-4754","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,5]]},"assertion":[{"value":"Indexed","URL":"https:\/\/gatesopenresearch.org\/articles\/6-62\/v1#article-reports","order":0,"name":"referee-status","label":"Referee status","group":{"name":"current-referee-status","label":"Current Referee Status"}},{"value":"10.21956\/gatesopenres.14889.r32064, Antonio Montresor, Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, Switzerland, 16 May 2022, version 1, indexed","URL":"https:\/\/gatesopenresearch.org\/articles\/6-62\/v1#referee-response-32064","order":0,"name":"referee-response-32064","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"ALEJANDRO JAVIER KROLEWIECKI<\/b>; \nPosted: 26 May 2022<\/i>; Response to Dr. Montresor. We appreciate the comments and insightful opinions from Dr. Antonio Montresor on our protocol and would like to highlight that we fully agree that a regimen with improved efficacy against \nT. trichiura<\/i> than what is achieved with albendazole is feasible through its combination with available medications, as is the case for ivermectin. Besides the available data on its efficacy, safety is also encouraging even at high doses of ivermectin, as demonstrated in preliminary trials performed by our groups in healthy adult volunteers and infected children (1,2). With the same ultimate implementation goals in mind as those expressed in the review, our Phase II\/III adaptive trial is relevant and necessary. The ALIVE trial contains innovations in the strategy (a fixed-dose approach to the use of ivermectin along with albendazole) and in the product (the fixed-dose combinations (FDC)); as such, this is a registrational trial with primary safety and efficacy objectives. For that, the protocol has been developed with the scientific advice from the European Medicines Agency (EMA). The selection of albendazole as the control arm is based on the rationale of using the current standard of care as the proper comparator. The ALIVE trial is a key step in the development and registration of the FDC, which includes prior developments and trials as the acquisition of capacities for the industrial fermentation of ivermectin and the WHO prequalification of a generic ivermectin by Liconsa Labs, producer of the FDC and member of the STOP Consortium (https:\/\/extranet.who.int\/pqweb\/news\/lab-liconsa%E2%80%99s-ivermectin-prequalified), as well as trials showing the pharmacokinetic behavior of high dose ivermectin and the bioavailability of each component of the FDC in comparison to the reference products (manuscript under review); the later being the standard approach to assess the comparability of a drug combination to each of its components administered separately (1). As described in the manuscript, that bioavailability trial provided data supporting the design of the ALIVE trial. In full agreement with the opinion of Dr Montresor regarding the logistic advantages foreseen for the FDC, the STOP project includes further studies assessing the acceptability and implementation strategy for these innovations. References Muñoz J, Ballester MR, Antonijoan RM, Gich I, Rodríguez M, Colli E, et al. Safety and pharmacokinetic profile of fixed-dose ivermectin with an innovative 18mg tablet in healthy adult volunteers. Prichard RK, editor. PLoS Negl Trop Dis. PLoS Negl Trop Dis; 2018;12:e0006020. Matamoros G, Sánchez A, Gabrie JA, Juárez M, Ceballos L, Escalada A, et al. Efficacy and Safety of Albendazole and High-Dose Ivermectin Coadministration in School-Aged Children Infected With Trichuris trichiura in Honduras: A Randomized Controlled Trial. Clin Infect Dis; 2021;73:1203\u201310.Response to Dr. Montresor.","URL":"https:\/\/gatesopenresearch.org\/articles\/6-62\/v1#referee-comment-3542","order":1,"name":"referee-comment-3542","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"10.21956\/gatesopenres.14889.r32202, Kevin Kobylinski, Department of Entomology, Armed Forces Research Institute of Medical Sciences, Bangkok, Thailand, 05 Jul 2022, version 1, indexed","URL":"https:\/\/gatesopenresearch.org\/articles\/6-62\/v1#referee-response-32202","order":2,"name":"referee-response-32202","label":"Referee Report","group":{"name":"article-reports","label":"Article Reports"}},{"value":"ALEJANDRO JAVIER KROLEWIECKI<\/b>; \nPosted: 11 Aug 2022<\/i>; We thank Kevin Kobilinsky for his review and comments on our protocol, and take the opportunity to further clarify the following concepts: Dose escalation: among the study candidates of the Phase II trial, which recruits children between 15 and 45 Kg of body weight, the design is to start with the subgroup between 23 and 30 Kg, receiving doses of IVM between 300 and 391 µg\/Kg and only upon DSMB clearance, to recruit the cohort including participants receiving a higher dose of IVM of 400 to 600 µg\/Kg (children weighting 30 to 45Kg), followed by, after DSMB approval, the lighter group of children (15 to 23Kg), who received 391 to 600µ\/Kg. The rationale for this study design is to progress to higher doses and younger\/lighter participants progressively upon confirmation of adequate safety in each subgroup. Sample size in Phase II: in this trial, the 1:2:2 randomization between the 3 study arms is applied in the 3 sequential weight sub-groups; therefore within each sub-group the number of participants per study arms would be distributed approximately in a 1:2:2 manner. Weight distribution in Phase III: for this trial participants receive FDC 400\/9mg if the weight is below 45Kg and 400\/18 in those 45Kg and up, without any dose escalation included. PK: there is a scarcity of data on the pharmacokinetics of IVM in pediatric populations further worsened by an almost complete absence of evidence of PK\/PD parameters related to antihelmintic drugs against STH. The effect of age on these parameters is another variable of consideration given variations in the expression of cytochrome P450s at different pediatric ages (1) \nReferences<\/b> 1.         Upreti VV, Wahlstrom JL. Meta-analysis of hepatic cytochrome P450 ontogeny to underwrite the prediction of pediatric pharmacokinetics using physiologically based pharmacokinetic modeling. J Clin Pharmacol. 2016 Mar;56(3):266\u201383.","URL":"https:\/\/gatesopenresearch.org\/articles\/6-62\/v1#referee-comment-3562","order":3,"name":"referee-comment-3562","label":"Referee Comment","group":{"name":"article-reports","label":"Article Reports"}},{"value":"This project is funded by the EDCTP2 program supported by the European Union (grant number RIA2017NCT-1845 \u2013STOP and PSIA2020-3072 STOP-2; www.stoptheworm.org) Horizon 2020 European Union Funding for Research and Innovation. For the purpose of Open Access, the author has applied a CC BY public copyright license to any Author Accepted Manuscript version arising from this submission. MC-P is funded by Junta de Castilla y Le\u00f3n and Fondo Social Europeo (grant number LE-135-19). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":4,"name":"grant-information","label":"Grant Information"},{"value":"This is an open access article distributed under the terms of the Creative Commons Attribution Licence, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.","order":0,"name":"copyright-info","label":"Copyright"}]}}