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 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

Perceptions and acceptability of co-administered albendazole, ivermectin and azithromycin mass drug administration, among the health workforce and recipient communities in Ethiopia.

Several neglected tropical diseases (NTDs) employ mass drug administration (MDA) as part of their control or elimination strategies. This has historically required multiple distinct campaigns, each targeting one or more NTDs, representing a strain on both the recipient communities and the local health workforce implementing the distribution. We explored perceptions and attitudes surrounding combined MDA among these two groups of stakeholders. Our qualitative study was nested within a cluster randomized non-inferiority safety trial of combined ivermectin, albendazole and azithromycin MDA. Using semi-structured question guides, we conducted 16 key informant interviews with selected individuals involved in implementing MDA within the participating district. To better understand the perceptions of recipient communities, we also conducted four focus group discussions with key community groups. Individuals were selected from both the trial arm (integrated MDA) and the control arm (standard MDA) to provide a means of comparison and discussion. All interviews and focus group discussions were led by fluent Afaan oromo speakers. Interviewers transcribed and later translated all discussions into English. The study team synthesized and analyzed the results via a coding framework and software. Most respondents appreciated the time and effort saved via the co-administered MDA strategy but there were some misgivings amongst community beneficiaries surrounding pill burden. Both the implementing health work force members and beneficiaries reported refusals stemming from lack of understanding around the need for the new drug regimen as well as some mistrust of government officials among the youth. The house-to-house distribution method, adopted as a COVID-19 prevention strategy, was by far preferred by all beneficiaries over central-point MDA, and may have led to greater acceptability of co-administration. Our data demonstrate that a co-administration strategy for NTDs is acceptable to both communities and health staff