Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in EthiopiaResearch in context
Summary: Background: Neglected Tropical Disease (NTD) programs require separate and distinct drug regimens for treatment. This has required countries to undertake multiple independent mass drug administration (MDA) programmes, each targeting one or more diseases. The possibility of safely combining...
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| Format: | Article |
| Language: | English |
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Elsevier
2023-05-01
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| Series: | EClinicalMedicine |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S258953702300161X |
| _version_ | 1797837716658847744 |
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| author | Scott McPherson Getinet Tafese Temesgen Tafese Sinknesh Wolde Behaksra Hiwot Solomon Birhanu Oljira Hirpa Miecha Kaleab A. Debebe Biruck Kebede Teshome Gebre Fikreab Kebede Fikre Seife Fentahun Tadesse Belete Mammo Abraham Aseffa Anthony W. Solomon David C.W. Mabey Michael Marks Endalamaw Gadisa |
| author_facet | Scott McPherson Getinet Tafese Temesgen Tafese Sinknesh Wolde Behaksra Hiwot Solomon Birhanu Oljira Hirpa Miecha Kaleab A. Debebe Biruck Kebede Teshome Gebre Fikreab Kebede Fikre Seife Fentahun Tadesse Belete Mammo Abraham Aseffa Anthony W. Solomon David C.W. Mabey Michael Marks Endalamaw Gadisa |
| author_sort | Scott McPherson |
| collection | DOAJ |
| description | Summary: Background: Neglected Tropical Disease (NTD) programs require separate and distinct drug regimens for treatment. This has required countries to undertake multiple independent mass drug administration (MDA) programmes, each targeting one or more diseases. The possibility of safely combining different drug regimens together in one MDA may offer several advantages to national programs. We conducted a study to assess the safety of combining ivermectin, albendazole and azithromycin in one integrated MDA. Methods: We conducted an open-label, non-inferiority cluster-randomised trial comparing the frequency of adverse events in communities receiving co-administered ivermectin, albendazole and azithromycin to that in communities given albendazole and ivermectin MDA followed by azithromycin MDA after a two-week interval. The study took place in 58 gares (small administrative units) across two kebeles (sub-districts) in Kofele woreda (district) in the Oromia region of Ethiopia. We randomly assigned 29 gares to the combined treatment arm and 29 gares to the control arm. The study team revisited all individuals within 48 h and actively collected data on the occurrence of adverse events using a dedicated questionnaire and a pre-specified list of adverse events. The study team followed the same process in the control arm for the azithromycin distribution and again after the ivermectin plus albendazole distribution. Following this initial active surveillance, passive surveillance was undertaken for one week after the first visit. The primary outcome was the frequency of adverse events occurring following MDA. The study team determined that the safety of the combined MDA would be non-inferior to that of separate MDAs if the upper limit of the two-sided CI for the difference in rates was equal to or lower than 5%. The trial was registered with ClinicalTrials.gov, NCT03570814. Findings: The study took place from December 2021 to January 2022. The combined MDA arm consisted of 7292 individuals who were eligible to participate, of whom 7068 received all three medications. The separate MDA arm consisted of 6219 eligible individuals of whom 6211 received ivermectin and albendazole and 4611 received azithromycin two weeks later. Overall, adverse events were reported by 197 (1.2%) of individuals. The most commonly reported adverse events included headache, gastrointestinal disturbance and dizziness. There were no serious adverse events in either arm. The cluster-level mean frequency of reported adverse events varied markedly between clusters, ranging from 0.1 to 10.4%. The cluster-level mean frequency of adverse events was 1.4% in the combined MDA arm and 1.2% following ivermectin and albendazole MDA (absolute difference 0.2%, 95% confidence interval [CI] −0.6% to +1.1%). This met the pre-defined 1.5% non-inferiority margin. For the combined MDA comparison to the stand-alone azithromycin MDA the absolute difference was −0.4% (1.4 versus 1.8%, 95% CI −0.8 to +1.5) which also met the pre-specified non-inferiority margin. Interpretation: This study is the largest of its kind to date and demonstrates that the safety of combined MDA of azithromycin, ivermectin and albendazole is non-inferior to the safety of ivermectin-plus-albendazole MDA then azithromycin MDA conducted separately although we may not have been powered to detect very small differences between arms. Co-administration of these three medicines is safe and feasible in this setting and allows national programs to develop new strategies for integrated MDA programs. Funding: Ivermectin (Mectizan) was donated by the Mectizan Donation Program, albendazole was donated by GlaxoSmithKline, and azithromycin (Zithromax®) was donated by Pfizer via the International Trachoma Initiative (ITI). The trial was funded by ITI using operational research funds from the Bill and Melinda Gates Foundation. |
| first_indexed | 2024-04-09T15:30:17Z |
| format | Article |
| id | doaj.art-89df27b0222c443989a13fdc46eb38f9 |
| institution | Directory Open Access Journal |
| issn | 2589-5370 |
| language | English |
| last_indexed | 2024-04-09T15:30:17Z |
| publishDate | 2023-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | EClinicalMedicine |
| spelling | doaj.art-89df27b0222c443989a13fdc46eb38f92023-04-28T08:56:16ZengElsevierEClinicalMedicine2589-53702023-05-0159101984Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in EthiopiaResearch in contextScott McPherson0Getinet Tafese1Temesgen Tafese2Sinknesh Wolde Behaksra3Hiwot Solomon4Birhanu Oljira5Hirpa Miecha6Kaleab A. Debebe7Biruck Kebede8Teshome Gebre9Fikreab Kebede10Fikre Seife11Fentahun Tadesse12Belete Mammo13Abraham Aseffa14Anthony W. Solomon15David C.W. Mabey16Michael Marks17Endalamaw Gadisa18Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK; RTI International, Research Triangle Park, NC, USAArmauer Hansen Research Institute, Addis Ababa, EthiopiaArmauer Hansen Research Institute, Addis Ababa, EthiopiaArmauer Hansen Research Institute, Addis Ababa, EthiopiaDisease Prevention and Control Directorate, Ministry of Health, Addis Ababa, EthiopiaOromia Regional Health Bureau, Addis Ababa, EthiopiaOromia Regional Health Bureau, Addis Ababa, EthiopiaArmauer Hansen Research Institute, Addis Ababa, EthiopiaRTI International, Research Triangle Park, NC, USAInternational Trachoma Initiative, Decatur, GA, USADisease Prevention and Control Directorate, Ministry of Health, Addis Ababa, EthiopiaDisease Prevention and Control Directorate, Ministry of Health, Addis Ababa, EthiopiaDisease Prevention and Control Directorate, Ministry of Health, Addis Ababa, EthiopiaRTI International, Research Triangle Park, NC, USAArmauer Hansen Research Institute, Addis Ababa, EthiopiaClinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK; Department of Control of Neglected Tropical Diseases, World Health Organization, Geneva, SwitzerlandClinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UKClinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK; Hospital for Tropical Diseases, University College London Hospital, London, UK; Division of Infection and Immunity, University College London, London, UK; Corresponding author. Clinical Research Department, Faculty of Infectious and Tropical Diseases, London School of Hygiene & Tropical Medicine, London, UK.Armauer Hansen Research Institute, Addis Ababa, EthiopiaSummary: Background: Neglected Tropical Disease (NTD) programs require separate and distinct drug regimens for treatment. This has required countries to undertake multiple independent mass drug administration (MDA) programmes, each targeting one or more diseases. The possibility of safely combining different drug regimens together in one MDA may offer several advantages to national programs. We conducted a study to assess the safety of combining ivermectin, albendazole and azithromycin in one integrated MDA. Methods: We conducted an open-label, non-inferiority cluster-randomised trial comparing the frequency of adverse events in communities receiving co-administered ivermectin, albendazole and azithromycin to that in communities given albendazole and ivermectin MDA followed by azithromycin MDA after a two-week interval. The study took place in 58 gares (small administrative units) across two kebeles (sub-districts) in Kofele woreda (district) in the Oromia region of Ethiopia. We randomly assigned 29 gares to the combined treatment arm and 29 gares to the control arm. The study team revisited all individuals within 48 h and actively collected data on the occurrence of adverse events using a dedicated questionnaire and a pre-specified list of adverse events. The study team followed the same process in the control arm for the azithromycin distribution and again after the ivermectin plus albendazole distribution. Following this initial active surveillance, passive surveillance was undertaken for one week after the first visit. The primary outcome was the frequency of adverse events occurring following MDA. The study team determined that the safety of the combined MDA would be non-inferior to that of separate MDAs if the upper limit of the two-sided CI for the difference in rates was equal to or lower than 5%. The trial was registered with ClinicalTrials.gov, NCT03570814. Findings: The study took place from December 2021 to January 2022. The combined MDA arm consisted of 7292 individuals who were eligible to participate, of whom 7068 received all three medications. The separate MDA arm consisted of 6219 eligible individuals of whom 6211 received ivermectin and albendazole and 4611 received azithromycin two weeks later. Overall, adverse events were reported by 197 (1.2%) of individuals. The most commonly reported adverse events included headache, gastrointestinal disturbance and dizziness. There were no serious adverse events in either arm. The cluster-level mean frequency of reported adverse events varied markedly between clusters, ranging from 0.1 to 10.4%. The cluster-level mean frequency of adverse events was 1.4% in the combined MDA arm and 1.2% following ivermectin and albendazole MDA (absolute difference 0.2%, 95% confidence interval [CI] −0.6% to +1.1%). This met the pre-defined 1.5% non-inferiority margin. For the combined MDA comparison to the stand-alone azithromycin MDA the absolute difference was −0.4% (1.4 versus 1.8%, 95% CI −0.8 to +1.5) which also met the pre-specified non-inferiority margin. Interpretation: This study is the largest of its kind to date and demonstrates that the safety of combined MDA of azithromycin, ivermectin and albendazole is non-inferior to the safety of ivermectin-plus-albendazole MDA then azithromycin MDA conducted separately although we may not have been powered to detect very small differences between arms. Co-administration of these three medicines is safe and feasible in this setting and allows national programs to develop new strategies for integrated MDA programs. Funding: Ivermectin (Mectizan) was donated by the Mectizan Donation Program, albendazole was donated by GlaxoSmithKline, and azithromycin (Zithromax®) was donated by Pfizer via the International Trachoma Initiative (ITI). The trial was funded by ITI using operational research funds from the Bill and Melinda Gates Foundation.http://www.sciencedirect.com/science/article/pii/S258953702300161XCo-administrationIntegrationLymphatic filariasisTrachomaOnchocerciasisSoil transmitted helminths |
| spellingShingle | Scott McPherson Getinet Tafese Temesgen Tafese Sinknesh Wolde Behaksra Hiwot Solomon Birhanu Oljira Hirpa Miecha Kaleab A. Debebe Biruck Kebede Teshome Gebre Fikreab Kebede Fikre Seife Fentahun Tadesse Belete Mammo Abraham Aseffa Anthony W. Solomon David C.W. Mabey Michael Marks Endalamaw Gadisa Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in EthiopiaResearch in context EClinicalMedicine Co-administration Integration Lymphatic filariasis Trachoma Onchocerciasis Soil transmitted helminths |
| title | Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in EthiopiaResearch in context |
| title_full | Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in EthiopiaResearch in context |
| title_fullStr | Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in EthiopiaResearch in context |
| title_full_unstemmed | Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in EthiopiaResearch in context |
| title_short | Safety of integrated mass drug administration of azithromycin, albendazole and ivermectin versus standard treatment regimens: a cluster-randomised trial in EthiopiaResearch in context |
| title_sort | safety of integrated mass drug administration of azithromycin albendazole and ivermectin versus standard treatment regimens a cluster randomised trial in ethiopiaresearch in context |
| topic | Co-administration Integration Lymphatic filariasis Trachoma Onchocerciasis Soil transmitted helminths |
| url | http://www.sciencedirect.com/science/article/pii/S258953702300161X |
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