FRINK Linked Data Fragments server

Matches in SemOpenAlex for { <https://semopenalex.org/work/W4382933189> ?p ?o ?g. }

• W4382933189 endingPage "1174" @default.
• W4382933189 startingPage "1164" @default.
• W4382933189 abstract "Background Cabamiquine is a novel antimalarial that inhibits Plasmodium falciparum translation elongation factor 2. We investigated the causal chemoprophylactic activity and dose–exposure–response relationship of single oral doses of cabamiquine following the direct venous inoculation (DVI) of P falciparum sporozoites in malaria-naive, healthy volunteers. Methods This was a phase 1b, randomised, double-blind, placebo-controlled, adaptive, dose-finding, single-centre study performed in Leiden, Netherlands. Malaria-naive, healthy adults aged 18–45 years were divided into five cohorts and randomly assigned (3:1) to receive cabamiquine or placebo. Randomisation was done by an independent statistician using codes in a permuted block schedule with a block size of four. Participants, investigators, and study personnel were masked to treatment allocation. A single, oral dose regimen of cabamiquine (200, 100, 80, 60, or 30 mg) or matching placebo was administered either at 2 h (early liver-stage) or 96 h (late liver-stage) after DVI. The primary endpoints based on a per-protocol analysis set were the number of participants who developed parasitaemia within 28 days of DVI, time to parasitaemia, number of participants with documented parasite blood-stage growth, clinical symptoms of malaria, and exposure–efficacy modelling. The impact of cabamiquine on liver stages was evaluated indirectly by the appearance of parasitaemia in the blood. The Clopper–Pearson CI (nominal 95%) was used to express the protection rate. The secondary outcomes were safety and tolerability, assessed in those who had received DVI and were administered one dose of the study intervention. The trial was prospectively registered on ClinicalTrials.gov (NCT04250363). Findings Between Feb 17, 2020 and April 29, 2021, 39 healthy participants were enrolled (early liver-stage: 30 mg [n=3], 60 mg [n=6], 80 mg [n=6], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=6]; late liver-stage: 60 mg [n=3], 100 mg [n=3], 200 mg [n=3], pooled placebo [n=3]). A dose-dependent causal chemoprophylactic effect was observed, with four (67%) of six participants in the 60 mg, five (83%) of six participants in the 80 mg, and all three participants in the 100 and 200 mg cabamiquine dose groups protected from parasitaemia up to study day 28, whereas all participants in the pooled placebo and 30 mg cabamiquine dose group developed parasitaemia. A single, oral dose of 100 mg cabamiquine or higher provided 100% protection against parasitaemia when administered during early or late liver-stage malaria. The median time to parasitaemia in those with early liver-stage malaria was prolonged to 15, 22, and 24 days for the 30, 60, and 80 mg dose of cabamiquine, respectively, compared with 10 days for the pooled placebo. All participants with positive parasitaemia showed documented blood-stage parasite growth, apart from one participant in the pooled placebo group and one participant in the 30 mg cabamiquine group. Most participants did not exhibit any malaria symptoms in both the early and late liver-stage groups, and those reported were mild in severity. A positive dose–exposure–efficacy relationship was established across exposure metrics. The median maximum concentration time was 1–6 h, with a secondary peak observed between 6 h and 12 h in all cabamiquine dose groups (early liver-stage). All cabamiquine doses were safe and well tolerated. Overall, 26 (96%) of 27 participants in the early liver-stage group and ten (83·3%) of 12 participants in the late liver-stage group reported at least one treatment-emergent adverse event (TEAE) with cabamiquine or placebo. Most TEAEs were of mild severity, transient, and resolved without sequelae. The most frequently reported cabamiquine-related TEAE was headache. No dose-related trends were observed in the incidence, severity, or causality of TEAEs. Interpretation The results from this study show that cabamiquine has a dose-dependent causal chemoprophylactic activity. Together with previously demonstrated activity against the blood stages combined with a half-life of more than 150 h, these results indicate that cabamiquine could be developed as a single-dose monthly regimen for malaria prevention. Funding The healthcare business of Merck KGaA, Darmstadt, Germany." @default.
• W4382933189 created "2023-07-04" @default.
• W4382933189 creator A5000004024 @default.
• W4382933189 creator A5008310854 @default.
• W4382933189 creator A5011316789 @default.
• W4382933189 creator A5013884136 @default.
• W4382933189 creator A5014435515 @default.
• W4382933189 creator A5039713932 @default.
• W4382933189 creator A5041818067 @default.
• W4382933189 creator A5044912577 @default.
• W4382933189 creator A5056672925 @default.
• W4382933189 creator A5059510888 @default.
• W4382933189 creator A5059973952 @default.
• W4382933189 creator A5065510234 @default.
• W4382933189 creator A5067346478 @default.
• W4382933189 creator A5068032162 @default.
• W4382933189 creator A5071314941 @default.
• W4382933189 creator A5072848549 @default.
• W4382933189 creator A5073240441 @default.
• W4382933189 creator A5073272812 @default.
• W4382933189 creator A5074589981 @default.
• W4382933189 creator A5075402055 @default.
• W4382933189 creator A5082309326 @default.
• W4382933189 creator A5083837708 @default.
• W4382933189 creator A5084273651 @default.
• W4382933189 creator A5089035181 @default.
• W4382933189 creator A5089742839 @default.
• W4382933189 date "2023-10-01" @default.
• W4382933189 modified "2023-10-13" @default.
• W4382933189 title "Causal chemoprophylactic activity of cabamiquine against Plasmodium falciparum in a controlled human malaria infection: a randomised, double-blind, placebo-controlled study in the Netherlands" @default.
• W4382933189 cites W1935711444 @default.
• W4382933189 cites W2122409545 @default.
• W4382933189 cites W2138840836 @default.
• W4382933189 cites W2171102256 @default.
• W4382933189 cites W2603629512 @default.
• W4382933189 cites W2773291920 @default.
• W4382933189 cites W2892391706 @default.
• W4382933189 cites W2922072591 @default.
• W4382933189 cites W2971723454 @default.
• W4382933189 cites W3004689665 @default.
• W4382933189 cites W3015560669 @default.
• W4382933189 cites W3041820413 @default.
• W4382933189 cites W3046809066 @default.
• W4382933189 cites W3092849554 @default.
• W4382933189 cites W3108025284 @default.
• W4382933189 cites W3127084640 @default.
• W4382933189 cites W3154986366 @default.
• W4382933189 cites W3200040377 @default.
• W4382933189 cites W3209076871 @default.
• W4382933189 cites W4220736588 @default.
• W4382933189 cites W4220860960 @default.
• W4382933189 cites W4221037950 @default.
• W4382933189 cites W4280627276 @default.
• W4382933189 doi "https://doi.org/10.1016/s1473-3099(23)00212-8" @default.
• W4382933189 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37414066" @default.
• W4382933189 hasPublicationYear "2023" @default.
• W4382933189 type Work @default.
• W4382933189 citedByCount "1" @default.
• W4382933189 countsByYear W43829331892023 @default.
• W4382933189 crossrefType "journal-article" @default.
• W4382933189 hasAuthorship W4382933189A5000004024 @default.
• W4382933189 hasAuthorship W4382933189A5008310854 @default.
• W4382933189 hasAuthorship W4382933189A5011316789 @default.
• W4382933189 hasAuthorship W4382933189A5013884136 @default.
• W4382933189 hasAuthorship W4382933189A5014435515 @default.
• W4382933189 hasAuthorship W4382933189A5039713932 @default.
• W4382933189 hasAuthorship W4382933189A5041818067 @default.
• W4382933189 hasAuthorship W4382933189A5044912577 @default.
• W4382933189 hasAuthorship W4382933189A5056672925 @default.
• W4382933189 hasAuthorship W4382933189A5059510888 @default.
• W4382933189 hasAuthorship W4382933189A5059973952 @default.
• W4382933189 hasAuthorship W4382933189A5065510234 @default.
• W4382933189 hasAuthorship W4382933189A5067346478 @default.
• W4382933189 hasAuthorship W4382933189A5068032162 @default.
• W4382933189 hasAuthorship W4382933189A5071314941 @default.
• W4382933189 hasAuthorship W4382933189A5072848549 @default.
• W4382933189 hasAuthorship W4382933189A5073240441 @default.
• W4382933189 hasAuthorship W4382933189A5073272812 @default.
• W4382933189 hasAuthorship W4382933189A5074589981 @default.
• W4382933189 hasAuthorship W4382933189A5075402055 @default.
• W4382933189 hasAuthorship W4382933189A5082309326 @default.
• W4382933189 hasAuthorship W4382933189A5083837708 @default.
• W4382933189 hasAuthorship W4382933189A5084273651 @default.
• W4382933189 hasAuthorship W4382933189A5089035181 @default.
• W4382933189 hasAuthorship W4382933189A5089742839 @default.
• W4382933189 hasConcept C126322002 @default.
• W4382933189 hasConcept C141071460 @default.
• W4382933189 hasConcept C142724271 @default.
• W4382933189 hasConcept C197934379 @default.
• W4382933189 hasConcept C203014093 @default.
• W4382933189 hasConcept C204787440 @default.
• W4382933189 hasConcept C27081682 @default.
• W4382933189 hasConcept C2778048844 @default.
• W4382933189 hasConcept C2778371730 @default.
• W4382933189 hasConcept C2778375690 @default.
• W4382933189 hasConcept C2781413609 @default.
• W4382933189 hasConcept C535046627 @default.
• W4382933189 hasConcept C71924100 @default.

• next