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Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial
Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150–200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (
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| Published in: | The Lancet infectious diseases 2018-06, Vol.18 (6), p.615-626 |
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| Main Authors: | , , , , , , , , , , , , , , , , , |
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| cites | cdi_FETCH-LOGICAL-c471t-2d30c7d6663cd937fabc13974e962566e6704558b20a6ad86d571b7ac94d34bc3 |
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| container_title | The Lancet infectious diseases |
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| creator | Smit, Menno R Ochomo, Eric O Aljayyoussi, Ghaith Kwambai, Titus K Abong'o, Bernard O Chen, Tao Bousema, Teun Slater, Hannah C Waterhouse, David Bayoh, Nabie M Gimnig, John E Samuels, Aaron M Desai, Meghna R Phillips-Howard, Penelope A Kariuki, Simon K Wang, Duolao Ward, Steve A ter Kuile, Feiko O |
| description | Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150–200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect ( |
| doi_str_mv | 10.1016/S1473-3099(18)30163-4 |
| format | article |
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We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18–50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs ≥21 kg/m2; women: <23 vs ≥23 kg/m2), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353.
Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 μg/kg per day risk ratio [RR] 2·26, 95% CI 1·93–2·65, p<0·0001; hazard ratio [HR] 6·32, 4·61–8·67, p<0·0001; ivermectin 300 μg/kg per day RR 2·18, 1·86–2·57, p<0·0001; HR 4·21, 3·06–5·79, p<0·0001). Mosquito mortality remained significantly increased 28 days post treatment (ivermectin 600 μg/kg per day RR 1·23, 1·01–1·50, p=0·0374; and ivermectin 300 μg/kg per day 1·21, 1·01–1·44, p=0·0337). Five (11%) of 45 patients receiving ivermectin 600 μg/kg per day, two (4%) of 48 patients receiving ivermectin 300 μg/kg per day, and none of 46 patients receiving placebo had one or more treatment-related adverse events.
Ivermectin at both doses assessed was well tolerated and reduced mosquito survival for at least 28 days after treatment. Ivermectin 300 μg/kg per day for 3 days provided a good balance between efficacy and tolerability, and this drug shows promise as a potential new tool for malaria elimination.
Malaria Eradication Scientific Alliance (MESA) and US Centers for Disease Control and Prevention (CDC).]]></description><identifier>ISSN: 1473-3099</identifier><identifier>EISSN: 1474-4457</identifier><identifier>DOI: 10.1016/S1473-3099(18)30163-4</identifier><identifier>PMID: 29602751</identifier><language>eng</language><publisher>United States: Elsevier Ltd</publisher><subject>Adolescent ; Adult ; Adults ; Albuterol, Ipratropium Drug Combination ; Anemia ; Anopheles ; Anopheles gambiae ; Antimalarials - administration & dosage ; Antimalarials - therapeutic use ; Aquatic insects ; Artemisinins - administration & dosage ; Artemisinins - therapeutic use ; Blood ; Clinical trials ; Culicidae ; Dihydroartemisinin ; Disease control ; Dosage and administration ; Double-Blind Method ; Double-blind studies ; Drug dosages ; Drug Therapy, Combination ; Effectiveness ; Electrocardiography ; FDA approval ; Feeding ; Female ; Filariasis ; Humans ; Infectious diseases ; Insecticides ; Insecticides - administration & dosage ; Insecticides - adverse effects ; Insecticides - therapeutic use ; Ivermectin ; Ivermectin - administration & dosage ; Ivermectin - adverse effects ; Ivermectin - therapeutic use ; Malaria ; Malaria - drug therapy ; Male ; Middle Aged ; Mortality ; Mosquitoes ; Onchocerciasis ; Parasitic diseases ; Patients ; Plasmodium falciparum ; Quinolines - administration & dosage ; Quinolines - pharmacology ; Randomization ; Safety ; Survival ; Tropical diseases ; Tuberculosis ; Vector-borne diseases ; Young Adult</subject><ispartof>The Lancet infectious diseases, 2018-06, Vol.18 (6), p.615-626</ispartof><rights>2018 Elsevier Ltd</rights><rights>Copyright © 2018 Elsevier Ltd. All rights reserved.</rights><rights>Copyright Elsevier Limited Jun 2018</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c471t-2d30c7d6663cd937fabc13974e962566e6704558b20a6ad86d571b7ac94d34bc3</citedby><cites>FETCH-LOGICAL-c471t-2d30c7d6663cd937fabc13974e962566e6704558b20a6ad86d571b7ac94d34bc3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,781,785,27926,27927</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/29602751$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Smit, Menno R</creatorcontrib><creatorcontrib>Ochomo, Eric O</creatorcontrib><creatorcontrib>Aljayyoussi, Ghaith</creatorcontrib><creatorcontrib>Kwambai, Titus K</creatorcontrib><creatorcontrib>Abong'o, Bernard O</creatorcontrib><creatorcontrib>Chen, Tao</creatorcontrib><creatorcontrib>Bousema, Teun</creatorcontrib><creatorcontrib>Slater, Hannah C</creatorcontrib><creatorcontrib>Waterhouse, David</creatorcontrib><creatorcontrib>Bayoh, Nabie M</creatorcontrib><creatorcontrib>Gimnig, John E</creatorcontrib><creatorcontrib>Samuels, Aaron M</creatorcontrib><creatorcontrib>Desai, Meghna R</creatorcontrib><creatorcontrib>Phillips-Howard, Penelope A</creatorcontrib><creatorcontrib>Kariuki, Simon K</creatorcontrib><creatorcontrib>Wang, Duolao</creatorcontrib><creatorcontrib>Ward, Steve A</creatorcontrib><creatorcontrib>ter Kuile, Feiko O</creatorcontrib><title>Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial</title><title>The Lancet infectious diseases</title><addtitle>Lancet Infect Dis</addtitle><description><![CDATA[Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150–200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 μg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment.
We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18–50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs ≥21 kg/m2; women: <23 vs ≥23 kg/m2), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353.
Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 μg/kg per day risk ratio [RR] 2·26, 95% CI 1·93–2·65, p<0·0001; hazard ratio [HR] 6·32, 4·61–8·67, p<0·0001; ivermectin 300 μg/kg per day RR 2·18, 1·86–2·57, p<0·0001; HR 4·21, 3·06–5·79, p<0·0001). Mosquito mortality remained significantly increased 28 days post treatment (ivermectin 600 μg/kg per day RR 1·23, 1·01–1·50, p=0·0374; and ivermectin 300 μg/kg per day 1·21, 1·01–1·44, p=0·0337). Five (11%) of 45 patients receiving ivermectin 600 μg/kg per day, two (4%) of 48 patients receiving ivermectin 300 μg/kg per day, and none of 46 patients receiving placebo had one or more treatment-related adverse events.
Ivermectin at both doses assessed was well tolerated and reduced mosquito survival for at least 28 days after treatment. Ivermectin 300 μg/kg per day for 3 days provided a good balance between efficacy and tolerability, and this drug shows promise as a potential new tool for malaria elimination.
Malaria Eradication Scientific Alliance (MESA) and US Centers for Disease Control and Prevention (CDC).]]></description><subject>Adolescent</subject><subject>Adult</subject><subject>Adults</subject><subject>Albuterol, Ipratropium Drug Combination</subject><subject>Anemia</subject><subject>Anopheles</subject><subject>Anopheles gambiae</subject><subject>Antimalarials - administration & dosage</subject><subject>Antimalarials - therapeutic use</subject><subject>Aquatic insects</subject><subject>Artemisinins - administration & dosage</subject><subject>Artemisinins - therapeutic use</subject><subject>Blood</subject><subject>Clinical trials</subject><subject>Culicidae</subject><subject>Dihydroartemisinin</subject><subject>Disease control</subject><subject>Dosage and administration</subject><subject>Double-Blind Method</subject><subject>Double-blind studies</subject><subject>Drug dosages</subject><subject>Drug Therapy, Combination</subject><subject>Effectiveness</subject><subject>Electrocardiography</subject><subject>FDA approval</subject><subject>Feeding</subject><subject>Female</subject><subject>Filariasis</subject><subject>Humans</subject><subject>Infectious diseases</subject><subject>Insecticides</subject><subject>Insecticides - administration & dosage</subject><subject>Insecticides - adverse effects</subject><subject>Insecticides - therapeutic use</subject><subject>Ivermectin</subject><subject>Ivermectin - administration & dosage</subject><subject>Ivermectin - adverse effects</subject><subject>Ivermectin - therapeutic use</subject><subject>Malaria</subject><subject>Malaria - drug therapy</subject><subject>Male</subject><subject>Middle Aged</subject><subject>Mortality</subject><subject>Mosquitoes</subject><subject>Onchocerciasis</subject><subject>Parasitic diseases</subject><subject>Patients</subject><subject>Plasmodium falciparum</subject><subject>Quinolines - administration & dosage</subject><subject>Quinolines - pharmacology</subject><subject>Randomization</subject><subject>Safety</subject><subject>Survival</subject><subject>Tropical diseases</subject><subject>Tuberculosis</subject><subject>Vector-borne diseases</subject><subject>Young Adult</subject><issn>1473-3099</issn><issn>1474-4457</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2018</creationdate><recordtype>article</recordtype><recordid>eNqFkdFu1DAQRSMEoqXwCSBLSKiVCNixE294QauqQMUiJAq8Wo492XXl2KnttORn-Ra8m8IrT7bH594ZzS2K5wS_IZg0b68I47SkuG1PyeqM5hIt2YPiOJdZyVjNHx7uC3JUPInxGmPCCWaPi6OqbXDFa3Jc_L6SPaQZSafR4OPNZJJXRkuLoO-NkmpGvkc7s92V2kdA5hbCACoZh-524JDypdSDcSYmCKDRnUk7pM1u1sHLkGAwMX-6cjQjBJntXfZw6DO4WTok9WRTXESTU34Ybe6Zss8grQxGotPLnxffvqw3Z--QRCFP6bMj6NdI-6mzUHbWuPwarVTQ-VJ5l4K3NjukLLdPi0e9tBGe3Z8nxY8PF9_PP5Wbrx8vz9ebUjFOUllpihXXTdNQpVvKe9kpQlvOoG2qummg4ZjV9aqrsGykXjW65qTjUrVMU9YpelK8XHzH4G8miElc-ym43FJUmFGOSY4kU68WaistCOP208KvtJVTjEKsa4YpZgyTDNYLqIKPMUAvxmAGGWZBsNjHLw7xi322gqzEIX7Bsu7F_RhTN4D-p_qbdwbeLwDkZdwaCCIqA06BNiGnKrQ3_2nxB8dfw2A</recordid><startdate>201806</startdate><enddate>201806</enddate><creator>Smit, Menno R</creator><creator>Ochomo, Eric O</creator><creator>Aljayyoussi, Ghaith</creator><creator>Kwambai, Titus K</creator><creator>Abong'o, Bernard O</creator><creator>Chen, Tao</creator><creator>Bousema, Teun</creator><creator>Slater, Hannah C</creator><creator>Waterhouse, David</creator><creator>Bayoh, Nabie M</creator><creator>Gimnig, John E</creator><creator>Samuels, Aaron M</creator><creator>Desai, Meghna R</creator><creator>Phillips-Howard, Penelope A</creator><creator>Kariuki, Simon K</creator><creator>Wang, Duolao</creator><creator>Ward, Steve A</creator><creator>ter Kuile, Feiko O</creator><general>Elsevier Ltd</general><general>Elsevier B.V</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>0TZ</scope><scope>3V.</scope><scope>7QL</scope><scope>7RV</scope><scope>7U9</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8AO</scope><scope>8C1</scope><scope>8C2</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>BENPR</scope><scope>C1K</scope><scope>CCPQU</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>H94</scope><scope>K9.</scope><scope>KB0</scope><scope>M0S</scope><scope>M1P</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope></search><sort><creationdate>201806</creationdate><title>Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial</title><author>Smit, Menno R ; Ochomo, Eric O ; Aljayyoussi, Ghaith ; Kwambai, Titus K ; Abong'o, Bernard O ; Chen, Tao ; Bousema, Teun ; Slater, Hannah C ; Waterhouse, David ; Bayoh, Nabie M ; Gimnig, John E ; Samuels, Aaron M ; Desai, Meghna R ; Phillips-Howard, Penelope A ; Kariuki, Simon K ; Wang, Duolao ; Ward, Steve A ; ter Kuile, Feiko O</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c471t-2d30c7d6663cd937fabc13974e962566e6704558b20a6ad86d571b7ac94d34bc3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2018</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Adults</topic><topic>Albuterol, Ipratropium Drug Combination</topic><topic>Anemia</topic><topic>Anopheles</topic><topic>Anopheles gambiae</topic><topic>Antimalarials - 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therapeutic use</topic><topic>Malaria</topic><topic>Malaria - drug therapy</topic><topic>Male</topic><topic>Middle Aged</topic><topic>Mortality</topic><topic>Mosquitoes</topic><topic>Onchocerciasis</topic><topic>Parasitic diseases</topic><topic>Patients</topic><topic>Plasmodium falciparum</topic><topic>Quinolines - administration & dosage</topic><topic>Quinolines - pharmacology</topic><topic>Randomization</topic><topic>Safety</topic><topic>Survival</topic><topic>Tropical diseases</topic><topic>Tuberculosis</topic><topic>Vector-borne diseases</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Smit, Menno R</creatorcontrib><creatorcontrib>Ochomo, Eric O</creatorcontrib><creatorcontrib>Aljayyoussi, Ghaith</creatorcontrib><creatorcontrib>Kwambai, Titus K</creatorcontrib><creatorcontrib>Abong'o, Bernard O</creatorcontrib><creatorcontrib>Chen, Tao</creatorcontrib><creatorcontrib>Bousema, Teun</creatorcontrib><creatorcontrib>Slater, Hannah C</creatorcontrib><creatorcontrib>Waterhouse, David</creatorcontrib><creatorcontrib>Bayoh, Nabie M</creatorcontrib><creatorcontrib>Gimnig, John E</creatorcontrib><creatorcontrib>Samuels, Aaron M</creatorcontrib><creatorcontrib>Desai, Meghna R</creatorcontrib><creatorcontrib>Phillips-Howard, Penelope A</creatorcontrib><creatorcontrib>Kariuki, Simon K</creatorcontrib><creatorcontrib>Wang, Duolao</creatorcontrib><creatorcontrib>Ward, Steve A</creatorcontrib><creatorcontrib>ter Kuile, Feiko O</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Pharma and Biotech Premium PRO</collection><collection>ProQuest Central (Corporate)</collection><collection>Bacteriology Abstracts (Microbiology B)</collection><collection>Nursing & Allied Health Database</collection><collection>Virology and AIDS Abstracts</collection><collection>ProQuest Health and Medical</collection><collection>ProQuest Central (purchase pre-March 2016)</collection><collection>Medical Database (Alumni Edition)</collection><collection>ProQuest Pharma Collection</collection><collection>Public Health Database</collection><collection>Lancet Titles</collection><collection>Hospital Premium Collection</collection><collection>Hospital Premium Collection (Alumni Edition)</collection><collection>ProQuest Central (Alumni) (purchase pre-March 2016)</collection><collection>ProQuest Central (Alumni)</collection><collection>ProQuest Central</collection><collection>ProQuest Central</collection><collection>Environmental Sciences and Pollution Management</collection><collection>ProQuest One Community College</collection><collection>Health Research Premium Collection</collection><collection>Health Research Premium Collection (Alumni)</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Database (Alumni Edition)</collection><collection>Health & Medical Collection (Alumni Edition)</collection><collection>PML(ProQuest Medical Library)</collection><collection>Algology Mycology and Protozoology Abstracts (Microbiology C)</collection><collection>Nursing & Allied Health Premium</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><jtitle>The Lancet infectious diseases</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Smit, Menno R</au><au>Ochomo, Eric O</au><au>Aljayyoussi, Ghaith</au><au>Kwambai, Titus K</au><au>Abong'o, Bernard O</au><au>Chen, Tao</au><au>Bousema, Teun</au><au>Slater, Hannah C</au><au>Waterhouse, David</au><au>Bayoh, Nabie M</au><au>Gimnig, John E</au><au>Samuels, Aaron M</au><au>Desai, Meghna R</au><au>Phillips-Howard, Penelope A</au><au>Kariuki, Simon K</au><au>Wang, Duolao</au><au>Ward, Steve A</au><au>ter Kuile, Feiko O</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial</atitle><jtitle>The Lancet infectious diseases</jtitle><addtitle>Lancet Infect Dis</addtitle><date>2018-06</date><risdate>2018</risdate><volume>18</volume><issue>6</issue><spage>615</spage><epage>626</epage><pages>615-626</pages><issn>1473-3099</issn><eissn>1474-4457</eissn><abstract><![CDATA[Ivermectin is being considered for mass drug administration for malaria due to its ability to kill mosquitoes feeding on recently treated individuals. However, standard, single doses of 150–200 μg/kg used for onchocerciasis and lymphatic filariasis have a short-lived mosquitocidal effect (<7 days). Because ivermectin is well tolerated up to 2000 μg/kg, we aimed to establish the safety, tolerability, and mosquitocidal efficacy of 3 day courses of high-dose ivermectin, co-administered with a standard malaria treatment.
We did a randomised, double-blind, placebo-controlled, superiority trial at the Jaramogi Oginga Odinga Teaching and Referral Hospital (Kisumu, Kenya). Adults (aged 18–50 years) were eligible if they had confirmed symptomatic uncomplicated Plasmodium falciparum malaria and agreed to the follow-up schedule. Participants were randomly assigned (1:1:1) using sealed envelopes, stratified by sex and body-mass index (men: <21 vs ≥21 kg/m2; women: <23 vs ≥23 kg/m2), with permuted blocks of three, to receive 3 days of ivermectin 300 μg/kg per day, ivermectin 600 μg/kg per day, or placebo, all co-administered with 3 days of dihydroartemisinin-piperaquine. Blood of patients taken on post-treatment days 0, 2 + 4 h, 7, 10, 14, 21, and 28 was fed to laboratory-reared Anopheles gambiae sensu stricto mosquitoes, and mosquito survival was assessed daily for 28 days after feeding. The primary outcome was 14-day cumulative mortality of mosquitoes fed 7 days after ivermectin treatment (from participants who received at least one dose of study medication). The study is registered with ClinicalTrials.gov, number NCT02511353.
Between July 20, 2015, and May 7, 2016, 741 adults with malaria were assessed for eligibility, of whom 141 were randomly assigned to receive ivermectin 600 μg/kg per day (n=47), ivermectin 300 μg/kg per day (n=48), or placebo (n=46). 128 patients (91%) attended the primary outcome visit 7 days post treatment. Compared with placebo, ivermectin was associated with higher 14 day post-feeding mosquito mortality when fed on blood taken 7 days post treatment (ivermectin 600 μg/kg per day risk ratio [RR] 2·26, 95% CI 1·93–2·65, p<0·0001; hazard ratio [HR] 6·32, 4·61–8·67, p<0·0001; ivermectin 300 μg/kg per day RR 2·18, 1·86–2·57, p<0·0001; HR 4·21, 3·06–5·79, p<0·0001). Mosquito mortality remained significantly increased 28 days post treatment (ivermectin 600 μg/kg per day RR 1·23, 1·01–1·50, p=0·0374; and ivermectin 300 μg/kg per day 1·21, 1·01–1·44, p=0·0337). Five (11%) of 45 patients receiving ivermectin 600 μg/kg per day, two (4%) of 48 patients receiving ivermectin 300 μg/kg per day, and none of 46 patients receiving placebo had one or more treatment-related adverse events.
Ivermectin at both doses assessed was well tolerated and reduced mosquito survival for at least 28 days after treatment. Ivermectin 300 μg/kg per day for 3 days provided a good balance between efficacy and tolerability, and this drug shows promise as a potential new tool for malaria elimination.
Malaria Eradication Scientific Alliance (MESA) and US Centers for Disease Control and Prevention (CDC).]]></abstract><cop>United States</cop><pub>Elsevier Ltd</pub><pmid>29602751</pmid><doi>10.1016/S1473-3099(18)30163-4</doi><tpages>12</tpages><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1473-3099 |
| ispartof | The Lancet infectious diseases, 2018-06, Vol.18 (6), p.615-626 |
| issn | 1473-3099 1474-4457 |
| language | eng |
| recordid | cdi_proquest_journals_2043701445 |
| source | ScienceDirect Freedom Collection 2022-2024 |
| subjects | Adolescent Adult Adults Albuterol, Ipratropium Drug Combination Anemia Anopheles Anopheles gambiae Antimalarials - administration & dosage Antimalarials - therapeutic use Aquatic insects Artemisinins - administration & dosage Artemisinins - therapeutic use Blood Clinical trials Culicidae Dihydroartemisinin Disease control Dosage and administration Double-Blind Method Double-blind studies Drug dosages Drug Therapy, Combination Effectiveness Electrocardiography FDA approval Feeding Female Filariasis Humans Infectious diseases Insecticides Insecticides - administration & dosage Insecticides - adverse effects Insecticides - therapeutic use Ivermectin Ivermectin - administration & dosage Ivermectin - adverse effects Ivermectin - therapeutic use Malaria Malaria - drug therapy Male Middle Aged Mortality Mosquitoes Onchocerciasis Parasitic diseases Patients Plasmodium falciparum Quinolines - administration & dosage Quinolines - pharmacology Randomization Safety Survival Tropical diseases Tuberculosis Vector-borne diseases Young Adult |
| title | Safety and mosquitocidal efficacy of high-dose ivermectin when co-administered with dihydroartemisinin-piperaquine in Kenyan adults with uncomplicated malaria (IVERMAL): a randomised, double-blind, placebo-controlled trial |
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