Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial
The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed...
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| creator | Kimani, Joshua Phiri, Kamija Kamiza, Steve Duparc, Stephan Ayoub, Ayman Rojo, Ricardo Robbins, Jeffery Orrico, Russell Vandenbroucke, Pol |
| description | The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base) for IPTp relative to IPTp-SP.
A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28-42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, |
| doi_str_mv | 10.1371/journal.pone.0157045 |
| format | Article |
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A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28-42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, <2,500 g], premature birth [<37 weeks], still birth [>28 weeks], abortion [≤28 weeks], lost to follow-up prior to observation of pregnancy outcome, or missing birth weight). The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2%) participants in the AZCQ and 342/1,445 (23.7%) in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR) of 1.11 (95% CI: 0.97, 1.25; p = 0.12). There was no significant difference in the incidence of LBW between treatment groups (57/1138 [5.0%] in the AZCQ group, 68/1188 [5.7%] in the SP group, RR 0.87 [95% CI: 0.62, 1.23]; p = 0.44). IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies, deaths, and serious adverse events were comparable in neonates for both groups. Limitations included the open-label design and early study termination.
IPTp-AZCQ was not superior to IPTp-SP in this study and alternatives for IPTp-SP remain to be identified. The proportions of sub-optimal pregnancy outcomes and LBW were lower than expected, which may be linked to insecticide-treated bednet use throughout the study. Reduced incidences of symptomatic malaria infection and peripheral parasitemia in the AZCQ group relative to SP suggest that AZCQ warrants further investigation as an alternative treatment of uncomplicated malaria.
ClinicalTrials.gov (NCT01103063).</description><identifier>ISSN: 1932-6203</identifier><identifier>EISSN: 1932-6203</identifier><identifier>DOI: 10.1371/journal.pone.0157045</identifier><identifier>PMID: 27326859</identifier><language>eng</language><publisher>United States: Public Library of Science</publisher><subject>Adolescent ; Adult ; Analysis ; Anemia ; Antibiotics ; Antimalarial agents ; Antimalarials ; Azithromycin ; Azithromycin - adverse effects ; Azithromycin - therapeutic use ; Bednets ; Biology and Life Sciences ; Birth weight ; Care and treatment ; Childbirth & labor ; Chloroquine ; Chloroquine - adverse effects ; Chloroquine - therapeutic use ; Clinical trials ; Comparative analysis ; Congenital anomalies ; Congenital defects ; Disease transmission ; Dosage and administration ; Drug Combinations ; Drug dosages ; Erythrocytes ; Ethics ; Female ; HIV ; Human immunodeficiency virus ; Humans ; Infant, Newborn ; Infections ; Insecticide resistance ; Insecticides ; Intention to Treat Analysis ; Low birth weight ; Malaria ; Malaria, Falciparum - drug therapy ; Malaria, Falciparum - prevention & control ; Medical research ; Medicine ; Medicine and Health Sciences ; Mortality ; Neonates ; Newborn babies ; Parasitemia ; Plasmodium falciparum ; Pregnancy ; Pregnancy Outcome ; Pregnant women ; Premature birth ; Prevention ; Preventive medicine ; Pyrimethamine ; Pyrimethamine - adverse effects ; Pyrimethamine - therapeutic use ; Safety ; Sulfadoxine ; Sulfadoxine - adverse effects ; Sulfadoxine - therapeutic use ; Systematic review ; Treatment Outcome ; Vector-borne diseases ; Windows (intervals) ; Womens health ; Young Adult</subject><ispartof>PloS one, 2016-06, Vol.11 (6), p.e0157045-e0157045</ispartof><rights>COPYRIGHT 2016 Public Library of Science</rights><rights>2016 Kimani et al. This is an open access article distributed under the terms of the Creative Commons Attribution License: http://creativecommons.org/licenses/by/4.0/ (the “License”), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2016 Kimani et al 2016 Kimani et al</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c791t-3d06406c2feb359aef403cf846d2699facf9cd1a3598f359676ae5396d3566193</citedby><cites>FETCH-LOGICAL-c791t-3d06406c2feb359aef403cf846d2699facf9cd1a3598f359676ae5396d3566193</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915657/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC4915657/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,315,729,782,786,866,887,2106,2932,23875,27933,27934,53800,53802</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/27326859$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><contributor>Gregson, Aric</contributor><creatorcontrib>Kimani, Joshua</creatorcontrib><creatorcontrib>Phiri, Kamija</creatorcontrib><creatorcontrib>Kamiza, Steve</creatorcontrib><creatorcontrib>Duparc, Stephan</creatorcontrib><creatorcontrib>Ayoub, Ayman</creatorcontrib><creatorcontrib>Rojo, Ricardo</creatorcontrib><creatorcontrib>Robbins, Jeffery</creatorcontrib><creatorcontrib>Orrico, Russell</creatorcontrib><creatorcontrib>Vandenbroucke, Pol</creatorcontrib><title>Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial</title><title>PloS one</title><addtitle>PLoS One</addtitle><description>The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base) for IPTp relative to IPTp-SP.
A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28-42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, <2,500 g], premature birth [<37 weeks], still birth [>28 weeks], abortion [≤28 weeks], lost to follow-up prior to observation of pregnancy outcome, or missing birth weight). The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2%) participants in the AZCQ and 342/1,445 (23.7%) in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR) of 1.11 (95% CI: 0.97, 1.25; p = 0.12). There was no significant difference in the incidence of LBW between treatment groups (57/1138 [5.0%] in the AZCQ group, 68/1188 [5.7%] in the SP group, RR 0.87 [95% CI: 0.62, 1.23]; p = 0.44). IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies, deaths, and serious adverse events were comparable in neonates for both groups. Limitations included the open-label design and early study termination.
IPTp-AZCQ was not superior to IPTp-SP in this study and alternatives for IPTp-SP remain to be identified. The proportions of sub-optimal pregnancy outcomes and LBW were lower than expected, which may be linked to insecticide-treated bednet use throughout the study. Reduced incidences of symptomatic malaria infection and peripheral parasitemia in the AZCQ group relative to SP suggest that AZCQ warrants further investigation as an alternative treatment of uncomplicated malaria.
ClinicalTrials.gov (NCT01103063).</description><subject>Adolescent</subject><subject>Adult</subject><subject>Analysis</subject><subject>Anemia</subject><subject>Antibiotics</subject><subject>Antimalarial agents</subject><subject>Antimalarials</subject><subject>Azithromycin</subject><subject>Azithromycin - adverse effects</subject><subject>Azithromycin - therapeutic use</subject><subject>Bednets</subject><subject>Biology and Life Sciences</subject><subject>Birth weight</subject><subject>Care and treatment</subject><subject>Childbirth & labor</subject><subject>Chloroquine</subject><subject>Chloroquine - adverse effects</subject><subject>Chloroquine - therapeutic use</subject><subject>Clinical trials</subject><subject>Comparative analysis</subject><subject>Congenital anomalies</subject><subject>Congenital defects</subject><subject>Disease transmission</subject><subject>Dosage and administration</subject><subject>Drug Combinations</subject><subject>Drug dosages</subject><subject>Erythrocytes</subject><subject>Ethics</subject><subject>Female</subject><subject>HIV</subject><subject>Human immunodeficiency virus</subject><subject>Humans</subject><subject>Infant, Newborn</subject><subject>Infections</subject><subject>Insecticide resistance</subject><subject>Insecticides</subject><subject>Intention to Treat Analysis</subject><subject>Low birth weight</subject><subject>Malaria</subject><subject>Malaria, Falciparum - drug therapy</subject><subject>Malaria, Falciparum - prevention & control</subject><subject>Medical research</subject><subject>Medicine</subject><subject>Medicine and Health Sciences</subject><subject>Mortality</subject><subject>Neonates</subject><subject>Newborn babies</subject><subject>Parasitemia</subject><subject>Plasmodium falciparum</subject><subject>Pregnancy</subject><subject>Pregnancy Outcome</subject><subject>Pregnant women</subject><subject>Premature birth</subject><subject>Prevention</subject><subject>Preventive medicine</subject><subject>Pyrimethamine</subject><subject>Pyrimethamine - adverse effects</subject><subject>Pyrimethamine - therapeutic use</subject><subject>Safety</subject><subject>Sulfadoxine</subject><subject>Sulfadoxine - adverse effects</subject><subject>Sulfadoxine - therapeutic use</subject><subject>Systematic review</subject><subject>Treatment Outcome</subject><subject>Vector-borne diseases</subject><subject>Windows (intervals)</subject><subject>Womens health</subject><subject>Young 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and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial</title><author>Kimani, Joshua ; Phiri, Kamija ; Kamiza, Steve ; Duparc, Stephan ; Ayoub, Ayman ; Rojo, Ricardo ; Robbins, Jeffery ; Orrico, Russell ; Vandenbroucke, Pol</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c791t-3d06406c2feb359aef403cf846d2699facf9cd1a3598f359676ae5396d3566193</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2016</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Analysis</topic><topic>Anemia</topic><topic>Antibiotics</topic><topic>Antimalarial agents</topic><topic>Antimalarials</topic><topic>Azithromycin</topic><topic>Azithromycin - adverse effects</topic><topic>Azithromycin - therapeutic use</topic><topic>Bednets</topic><topic>Biology and Life 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Premium</collection><collection>Advanced Technologies & Aerospace Database</collection><collection>ProQuest Advanced Technologies & Aerospace Collection</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Environmental Science Database</collection><collection>Materials Science Collection</collection><collection>Publicly Available Content Database</collection><collection>ProQuest One Academic Eastern Edition (DO NOT USE)</collection><collection>ProQuest One Academic</collection><collection>ProQuest One Academic UKI Edition</collection><collection>ProQuest Central China</collection><collection>Engineering Collection</collection><collection>Environmental Science Collection</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>ASFA: Aquatic Sciences and Fisheries Abstracts</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 1: Biological Sciences & Living Resources</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) 3: Aquatic Pollution & Environmental Quality</collection><collection>Aquatic Science & Fisheries Abstracts (ASFA) Professional</collection><collection>PubMed Central (Full Participant titles)</collection><collection>DOAJ Directory of Open Access Journals</collection><jtitle>PloS one</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Kimani, Joshua</au><au>Phiri, Kamija</au><au>Kamiza, Steve</au><au>Duparc, Stephan</au><au>Ayoub, Ayman</au><au>Rojo, Ricardo</au><au>Robbins, Jeffery</au><au>Orrico, Russell</au><au>Vandenbroucke, Pol</au><au>Gregson, Aric</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial</atitle><jtitle>PloS one</jtitle><addtitle>PLoS One</addtitle><date>2016-06-21</date><risdate>2016</risdate><volume>11</volume><issue>6</issue><spage>e0157045</spage><epage>e0157045</epage><pages>e0157045-e0157045</pages><issn>1932-6203</issn><eissn>1932-6203</eissn><abstract>The World Health Organization recommends intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine-pyrimethamine (SP) in African regions with moderate to high malaria transmission. However, growing resistance to SP threatens the effectiveness of IPTp-SP, and alternative drugs are needed. This study tested the efficacy, tolerability, and safety of a fixed-dose combination azithromycin-chloroquine (AZCQ; 250 mg AZ/155 mg CQ base) for IPTp relative to IPTp-SP.
A randomized, Phase 3, open-label, multi-center study was conducted in sub-Saharan Africa (Benin, Kenya, Malawi, Tanzania, and Uganda) between October 2010 and November 2013. Pregnant women received 3 IPTp courses with AZCQ (each course: 1,000/620 mg AZCQ QD for 3 days) or SP (each course 1,500/75 mg SP QD for 1 day) at 4- to 8-week intervals during the second and third trimester. Long-lasting insecticide-treated bednets were also provided at enrollment. Study participants were followed up until day 28 post delivery (time window: day 28-42). The primary endpoint was the proportion of participants with sub-optimal pregnancy outcomes (a composite endpoint comprising live-borne neonates with low birth weight [LBW, <2,500 g], premature birth [<37 weeks], still birth [>28 weeks], abortion [≤28 weeks], lost to follow-up prior to observation of pregnancy outcome, or missing birth weight). The study was terminated early after recruitment of 2,891 of the planned 5,044 participants, due to futility observed in a pre-specified 35% interim analysis. In the final intent-to-treat dataset, 378/1,445 (26.2%) participants in the AZCQ and 342/1,445 (23.7%) in the SP group had sub-optimal pregnancy outcomes, with an estimated risk ratio (RR) of 1.11 (95% CI: 0.97, 1.25; p = 0.12). There was no significant difference in the incidence of LBW between treatment groups (57/1138 [5.0%] in the AZCQ group, 68/1188 [5.7%] in the SP group, RR 0.87 [95% CI: 0.62, 1.23]; p = 0.44). IPTp-AZCQ was less well-tolerated in mothers than IPTp-SP. Occurrences of congenital anomalies, deaths, and serious adverse events were comparable in neonates for both groups. Limitations included the open-label design and early study termination.
IPTp-AZCQ was not superior to IPTp-SP in this study and alternatives for IPTp-SP remain to be identified. The proportions of sub-optimal pregnancy outcomes and LBW were lower than expected, which may be linked to insecticide-treated bednet use throughout the study. Reduced incidences of symptomatic malaria infection and peripheral parasitemia in the AZCQ group relative to SP suggest that AZCQ warrants further investigation as an alternative treatment of uncomplicated malaria.
ClinicalTrials.gov (NCT01103063).</abstract><cop>United States</cop><pub>Public Library of Science</pub><pmid>27326859</pmid><doi>10.1371/journal.pone.0157045</doi><oa>free_for_read</oa></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 1932-6203 |
| ispartof | PloS one, 2016-06, Vol.11 (6), p.e0157045-e0157045 |
| issn | 1932-6203 1932-6203 |
| language | eng |
| recordid | cdi_plos_journals_1798776950 |
| source | Public Library of Science (PLoS) Journals Open Access; MEDLINE; DOAJ Directory of Open Access Journals; EZB-FREE-00999 freely available EZB journals; PubMed Central; Free Full-Text Journals in Chemistry |
| subjects | Adolescent Adult Analysis Anemia Antibiotics Antimalarial agents Antimalarials Azithromycin Azithromycin - adverse effects Azithromycin - therapeutic use Bednets Biology and Life Sciences Birth weight Care and treatment Childbirth & labor Chloroquine Chloroquine - adverse effects Chloroquine - therapeutic use Clinical trials Comparative analysis Congenital anomalies Congenital defects Disease transmission Dosage and administration Drug Combinations Drug dosages Erythrocytes Ethics Female HIV Human immunodeficiency virus Humans Infant, Newborn Infections Insecticide resistance Insecticides Intention to Treat Analysis Low birth weight Malaria Malaria, Falciparum - drug therapy Malaria, Falciparum - prevention & control Medical research Medicine Medicine and Health Sciences Mortality Neonates Newborn babies Parasitemia Plasmodium falciparum Pregnancy Pregnancy Outcome Pregnant women Premature birth Prevention Preventive medicine Pyrimethamine Pyrimethamine - adverse effects Pyrimethamine - therapeutic use Safety Sulfadoxine Sulfadoxine - adverse effects Sulfadoxine - therapeutic use Systematic review Treatment Outcome Vector-borne diseases Windows (intervals) Womens health Young Adult |
| title | Efficacy and Safety of Azithromycin-Chloroquine versus Sulfadoxine-Pyrimethamine for Intermittent Preventive Treatment of Plasmodium falciparum Malaria Infection in Pregnant Women in Africa: An Open-Label, Randomized Trial |
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