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The Global Programme to Eliminate Lymphatic Filariasis (GPELF) provides antifilarial medications to hundreds of millions of people annually to treat filarial infections and prevent elephantiasis. Recent trials have shown that a single-dose, triple-drug treatment (ivermectin with diethylcarbamazine and albendazole [IDA]) is superior to a two-drug combination (diethylcarbamazine plus albendazole [DA]) that is widely used in LF elimination programs. This study was performed to assess the safety of IDA and DA in a variety of endemic settings. Large community studies were conducted in five countries between October 2016 and November 2017. Two studies were performed in areas with no prior mass drug administration (MDA) for filariasis (Papua New Guinea and Indonesia), and three studies were performed in areas with persistent LF despite extensive prior MDA (India, Haiti, and Fiji). Participants were treated with a single oral dose of IDA (ivermectin, 200 μg/kg; diethylcarbamazine, 6 mg/kg; plus albendazole, a fixed dose of 400 mg) or with DA alone. Treatment assignment in each study site was randomized by locality of residence. Treatment was offered to residents who were ≥5 years of age and not pregnant. Adverse events (AEs) were assessed by medical teams with active follow-up for 2 days and passive follow-up for an additional 5 days. A total of 26,836 persons were enrolled (13,535 females and 13,300 males). A total of 12,280 participants were treated with DA, and 14,556 were treated with IDA. On day 1 or 2 after treatment, 97.4% of participants were assessed for AEs. The frequency of all AEs was similar after IDA and DA treatment (12% versus 12.1%, adjusted odds ratio for IDA versus DA 1.15, 95% CI 0.87-1.52, P = 0.316); 10.9% of participants experienced mild (grade 1) AEs, 1% experienced moderate (grade 2) AEs, and 0.1% experienced severe (grade 3) AEs. Rates of serious AEs after DA and IDA treatment were 0.04% (95% CI 0.01%-0.1%) and 0.01% (95% CI 0.00%-0.04%), respectively. Severity of AEs was not significantly different after IDA or DA. Five of six serious AEs reported occurred after DA treatment. The most common AEs reported were headache, dizziness, abdominal pain, fever, nausea, and fatigue. AE frequencies varied by country and were higher in adults and in females. AEs were more common in study participants with microfilaremia (33.4% versus 11.1%, P < 0.001) and more common in microfilaremic participants after IDA than after DA (39.4% versus 25.6%, P < 0.001). However, there was no excess of severe or serious AEs after IDA in this subgroup. The main limitation of the study was that it was open-label. Also, aggregation of AE data from multiple study sites tends to obscure variability among study sites. In this study, we observed that IDA was well tolerated in LF-endemic populations. Posttreatment AE rates and severity did not differ significantly after IDA or DA treatment. Thus, results of this study suggest that IDA should be as safe as DA for use as a MDA regimen for LF elimination in areas that currently receive DA. Clinicaltrials.gov registration number: NCT02899936.

In this trial, rural communities in Niger were randomly assigned to distribute azithromycin or placebo to children (1 to 59 months of age) or infants (1 to 11 months). All-cause mortality was reduced in the child-treated group.

The emergence and spread of multidrug-resistant Plasmodium falciparum in the Greater Mekong Subregion (GMS) threatens global malaria elimination efforts. Mass drug administration (MDA), the presumptive antimalarial treatment of an entire population to clear the subclinical parasite reservoir, is a strategy to accelerate malaria elimination. We report a cluster randomised trial to assess the effectiveness of dihydroartemisinin-piperaquine (DP) MDA in reducing falciparum malaria incidence and prevalence in 16 remote village populations in Myanmar, Vietnam, Cambodia, and the Lao People's Democratic Republic, where artemisinin resistance is prevalent. After establishing vector control and community-based case management and following intensive community engagement, we used restricted randomisation within village pairs to select 8 villages to receive early DP MDA and 8 villages as controls for 12 months, after which the control villages received deferred DP MDA. The MDA comprised 3 monthly rounds of 3 daily doses of DP and, except in Cambodia, a single low dose of primaquine. We conducted exhaustive cross-sectional surveys of the entire population of each village at quarterly intervals using ultrasensitive quantitative PCR to detect Plasmodium infections. The study was conducted between May 2013 and July 2017. The investigators randomised 16 villages that had a total of 8,445 residents at the start of the study. Of these 8,445 residents, 4,135 (49%) residents living in 8 villages, plus an additional 288 newcomers to the villages, were randomised to receive early MDA; 3,790 out of the 4,423 (86%) participated in at least 1 MDA round, and 2,520 out of the 4,423 (57%) participated in all 3 rounds. The primary outcome, P. falciparum prevalence by month 3 (M3), fell by 92% (from 5.1% [171/3,340] to 0.4% [12/2,828]) in early MDA villages and by 29% (from 7.2% [246/3,405] to 5.1% [155/3,057]) in control villages. Over the following 9 months, the P. falciparum prevalence increased to 3.3% (96/2,881) in early MDA villages and to 6.1% (128/2,101) in control villages (adjusted incidence rate ratio 0.41 [95% CI 0.20 to 0.84]; p = 0.015). Individual protection was proportional to the number of completed MDA rounds. Of 221 participants with subclinical P. falciparum infections who participated in MDA and could be followed up, 207 (94%) cleared their infections, including 9 of 10 with artemisinin- and piperaquine-resistant infections. The DP MDAs were well tolerated; 6 severe adverse events were detected during the follow-up period, but none was attributable to the intervention. Added to community-based basic malaria control measures, 3 monthly rounds of DP MDA reduced the incidence and prevalence of falciparum malaria over a 1-year period in areas affected by artemisinin resistance. P. falciparum infections returned during the follow-up period as the remaining infections spread and malaria was reintroduced from surrounding areas. Limitations of this study include a relatively small sample of villages, heterogeneity between villages, and mobility of villagers that may have limited the impact of the intervention. These results suggest that, if used as part of a comprehensive, well-organised, and well-resourced elimination programme, DP MDA can be a useful additional tool to accelerate malaria elimination. ClinicalTrials.gov NCT01872702.

Childhood mortality remains high in sub-Saharan Africa. In this cluster-randomized, placebo-controlled trial, mortality among children younger than 5 years of age was lower among those who received azithromycin than among those who received placebo.

In this randomized trial, azithromycin or placebo was given to 32,877 infants (5 to 12 weeks of age). No evidence of benefit with respect to mortality before 6 months of age was seen with azithromycin.

Mass administration of azithromycin to children younger than 5 years has been reported to decrease child mortality. In this trial, limited to infants 1 to 11 months of age in Mali, azithromycin did not reduce infant or child mortality.

In low malaria-endemic settings, screening and treatment of individuals in close proximity to index cases, also known as reactive case detection (RACD), is practised for surveillance and response. However, other approaches could be more effective for reducing transmission. We aimed to evaluate the effectiveness of reactive focal mass drug administration (rfMDA) and reactive focal vector control (RAVC) in the low malaria-endemic setting of Zambezi (Namibia). We did a cluster-randomised controlled, open-label trial using a two-by-two factorial design of 56 enumeration area clusters in the low malaria-endemic setting of Zambezi (Namibia). We randomly assigned these clusters using restricted randomisation to four groups: RACD only, rfMDA only, RAVC plus RACD, or rfMDA plus RAVC. RACD involved rapid diagnostic testing and treatment with artemether-lumefantrine and single-dose primaquine, rfMDA involved presumptive treatment with artemether-lumefantrine, and RAVC involved indoor residual spraying with pirimiphos-methyl. Interventions were administered within 500 m of index cases. To evaluate the effectiveness of interventions targeting the parasite reservoir in humans (rfMDA vs RACD), in mosquitoes (RAVC vs no RAVC), and in both humans and mosquitoes (rfMDA plus RAVC vs RACD only), an intention-to-treat analysis was done. For each of the three comparisons, the primary outcome was the cumulative incidence of locally acquired malaria cases. This trial is registered with ClinicalTrials.gov, number NCT02610400. Between Jan 1, 2017, and Dec 31, 2017, 55 enumeration area clusters had 1118 eligible index cases that led to 342 interventions covering 8948 individuals. The cumulative incidence of locally acquired malaria was 30·8 per 1000 person-years (95% CI 12·8–48·7) in the clusters that received rfMDA versus 38·3 per 1000 person-years (23·0–53·6) in the clusters that received RACD; 30·2 per 1000 person-years (15·0–45·5) in the clusters that received RAVC versus 38·9 per 1000 person-years (20·7–57·1) in the clusters that did not receive RAVC; and 25·0 per 1000 person-years (5·2–44·7) in the clusters that received rfMDA plus RAVC versus 41·4 per 1000 person-years (21·5–61·2) in the clusters that received RACD only. After adjusting for imbalances in baseline and implementation factors, the incidence of malaria was lower in clusters receiving rfMDA than in those receiving RACD (adjusted incidence rate ratio 0·52 [95% CI 0·16–0·88], p=0·009), lower in clusters receiving RAVC than in those that did not (0·48 [0·16–0·80], p=0·002), and lower in clusters that received rfMDA plus RAVC than in those receiving RACD only (0·26 [0·10–0·68], p=0·006). No serious adverse events were reported. In a low malaria-endemic setting, rfMDA and RAVC, implemented alone and in combination, reduced malaria transmission and should be considered as alternatives to RACD for elimination of malaria. Novartis Foundation, Bill & Melinda Gates Foundation, and Horchow Family Fund.

Arthropod vectors feeding on the blood of individuals treated with ivermectin have substantially increased mortality. Whether this effect will translate into a useful tool for reducing malaria burden at scale is not clear. Our trial aimed to assess whether using ivermectin as an adjunct to mass drug administration (MDA) with dihydroartemisinin–piperaquine would further reduce malaria prevalence. MATAMAL was a quadruple-blinded, cluster-randomised, placebo-controlled trial, conducted on the Bijagos Archipelago, Guinea-Bissau, an area of seasonal malaria transmission. All residents were invited to participate, with exclusions for drug safety. 24 clusters were randomised in a 1:1 ratio, using restriction randomisation, to either MDA with three daily oral doses of dihydroartemisinin–piperaquine and ivermectin (300 μg/kg per day) in three sequential months during the transmission season in 2021 and 2022, or MDA with dihydroartemisinin–piperaquine and placebo in the same schedule. The primary outcome was quantitative PCR prevalence of Plasmodium falciparum parasitaemia in all age groups, during peak transmission, after the second year of intervention. The primary entomological outcome was anopheline parity rate. The trial is registered with ClinicalTrials.gov (NCT04844905). Participants were recruited between June 7, 2021 and Sept 21, 2022. The baseline population was 25 882 (12 634 [50·6%] were female individuals and 12 317 [49·4%] were male individuals): 13 832 were in the intervention group and 12 050 in the control group. Cluster-level coverage for dihydroartemisinin–piperaquine ranged from 60·4% to 78·7%, and for ivermectin or ivermectin–placebo from 58·1 to 77·1%. Following the intervention, the prevalence of P falciparum infection was 118 (5·05%) of 2300 in the control group and 141 (6·64%) of 2083 in the intervention group. The adjusted risk difference was 1·67% (95% CI –1·44 to 4·78; p=0·28). There were 124 adverse events in the control group (1·0% of participants) and 267 in the intervention group (1·9% of participants). Two serious adverse events were reported, neither related to the intervention, and no treatment-related deaths. The anopheline parity rate was 1679 (67·8%) of 2475 in control clusters and 1740 (72·3%) of 2414 in intervention clusters. The adjusted risk difference was –1·32 (95% CI –14·77 to 12·12; p=0·84). Adding ivermectin to dihydroartemisinin–piperaquine MDA had no additional effect on reducing malaria prevalence or vector parity in this setting. The intervention was well tolerated. To our knowledge, this trial is the first to be designed to assess whether ivermectin has an additive effect on malaria when coadministered with dihydroartemisinin–piperaquine MDA. The National Institute for Health and Care Research, Medical Research Council, Wellcome, and Foreign, Commonwealth & Development Office.

In Africa, the scale-up of malaria-control interventions has reduced malaria burden, but progress towards elimination has stalled. Mass drug administration (MDA) is promising as a transmission-reducing strategy, but evidence from low-to-moderate transmission settings is needed. We aimed to assess the safety, coverage, and effect of three cycles of MDA with dihydroartemisinin–piperaquine plus single, low-dose primaquine on Plasmodium falciparum incidence and prevalence in southeast Senegal. We conducted a two-arm, open-label, cluster-randomised controlled trial in villages in the Tambacounda health district of southeast Senegal. Eligible villages had a population size of 200–800, were within a health-post catchment area with an annual malaria incidence of 60–160 cases per 1000 people, and had an established or planned Prise en Charge à Domicile Plus model. We randomly assigned villages (1:1) using a stratified, constrained randomisation approach to receive either three cycles of MDA with oral dihydroartemisinin–piperaquine plus single, low-dose primaquine administered at 6-week intervals (intervention) or to standard of care, which included three cycles of seasonal malaria chemoprevention (SMC) with oral sulfadoxine–pyrimethamine plus amodiaquine administered at 4-week intervals (control). Participants, the field team, and all investigators, including those who assessed outcomes and analysed data, were unmasked to allocation assignment. Laboratory technicians were masked to intervention assignment. The primary outcome was village-level, P falciparum-confirmed malaria incidence in the post-intervention year (ie, July to December, 2022). Secondary outcomes included malaria incidence during the intervention year (ie, July to December, 2021), coverage and safety of MDA, and adverse events. We conducted analyses using an intention-to-treat approach. The trial is registered with ClinicalTrials.gov (NCT04864444) and is completed. Between Sept 1 and Oct 25, 2020, 523 villages were geolocated and screened for eligibility; 111 met the inclusion criteria. Of these, 60 villages were randomly selected and assigned to the intervention arm or control arm. Distribution coverage of all three doses of dihydroartemisinin–piperaquine was 6057 (73·6%) of 8229 participants in the first cycle, 6836 (78·8%) of 8673 participants in the second cycle, and 7065 (81·3%) of 8690 participants in the third cycle. Distribution coverage of single, low-dose primaquine was 6286 (78·6%) of 7999 participants in the first cycle, 6949 (82·1%) of 8462 participants in the second cycle, and 7199 (84·0%) of 8575 participants in the third cycle. Distribution coverage of all three doses of SMC was 3187 (92·2%) of 3457 children aged 3–120 months in the first cycle, 3158 (91·8%) of 3442 children aged 3–120 months in the second cycle, and 3139 (91·4%) of 3434 children aged 3–120 months in the third cycle. In the intervention year (ie, July to December, 2021), the adjusted effect of MDA was 55% (95% CI 28 to 71). In the post-intervention year (ie, July to December 2022), the adjusted MDA effect was 26% (–17 to 53). Malaria incidence during the transmission season of the post-intervention year was 126 cases per 1000 population in the intervention arm and 146 cases per 1000 population in the control arm. No serious adverse events were reported. In southeast Senegal, a low-to-moderate transmission setting where malaria-control measures have been scaled up, three cycles of MDA with dihydroartemisinin–piperaquine plus single, low-dose primaquine was safe and reduced malaria burden during the intervention year. However, its sustained effect was weak and continuation of MDA or another transmission-reducing strategy could be required. US President's Malaria Initiative.

The success of crucial vector control efforts in Africa (eg, long-lasting insecticide-treated nets [ITNs] and indoor residual spraying) are threatened by widespread insecticide resistance and insufficient effect on outdoor mosquito biting. Studies have shown that ivermectin, used for the treatment of parasitic diseases, can kill malaria vectors that feed on the blood of treated people and thus might be an effective complementary vector control tool if administered widely to communities in malaria endemic regions. We aimed to test the safety of repeated, high-dose ivermectin mass drug administration (MDA) and its efficacy for reducing malaria incidence among children when integrated with seasonal malaria chemoprevention (SMC) delivery. We conducted a phase 3, double-blind, placebo-controlled, cluster-randomised, parallel-group trial in southwest Burkina Faso over two consecutive rainy seasons (2019–20). 14 villages or village sectors (clusters) were randomly assigned (1:1) to ivermectin or placebo MDA by random draw, and study-eligible participants (those who regularly lived in the cluster and provided written informed consent) from all households were enrolled in July, 2019 and July, 2020. Participants were eligible for MDA if they were 90 cm in height or taller and not excluded for other safety reasons (eg, pregnancy or taking SMC drugs). There were no age restrictions for participants. Each rainy season (July to October), eligible participants from the intervention group clusters received monthly high-dose oral ivermectin MDA (three daily doses, approximately 300 μg/kg dosed by height bands) and those from the control group received monthly oral placebo MDA for up to eight treatment rounds. MDA was performed by study staff alongside community health worker administration of monthly SMC to children aged 3–59 months in both groups. All participants and study personnel, apart from the pharmacist, were masked to group assignment. The primary outcome was weekly malaria incidence in children aged 10 years and younger, as assessed by weekly active case detection until week 16 of year 2, by intention to treat. Adverse events were monitored in all MDA participants through active and passive surveillance. Blood was sampled for secondary parasitological outcomes, including analysis of parasite species distribution among malaria cases. Mosquitoes were sampled from pre-selected households in three clusters per group for secondary entomological outcomes, including analysis of blood-fed mosquito survivorship, mosquito biting rates, and entomological inoculation rates. Changes in haemoglobin pre-intervention and post-intervention in children aged 10 years and younger were assessed in 2020. The trial is registered with ClinicalTrials.gov (NCT03967054) and the Pan African Clinical Trials Registry (PACT201907479787308) and is completed. The study took place from July 13, 2019, to Nov 8, 2020, with seven villages assigned to the control group and seven to the intervention group. Participants were enrolled from households in both groups in July, 2019, and July, 2020. In the intervention group, 1928 participants in 2019 and 2163 participants in 2020 were followed up, and 703 children in 2019 and 686 children in 2020 were analysed. In the control group, 1604 participants in 2019 and 1921 participants in 2020 were followed up, and 605 children in 2019 and 641 children in 2020 were analysed. MDA coverage (receiving ≥1 dose) in the enrolled population (including those who were ineligible) varied over the intervention period (68–74%), with 86–95% of participants who were eligible receiving ivermectin or placebo over the study period. 288 (47·2%) of 610 children in the control group and 312 (44·2%) of 706 children in the ivermectin group received SMC, and all clusters received new dual-chemistry Interceptor G2 ITNs containing chlorfenapyr and α-cypermethrin by government authorities in October, 2019. The average estimated weekly malaria incidence rate per 100 person-weeks among children in the intervention group was 1·78 (95% CI 1·24–2·53) and 1·84 (1·29–2·64) in the control group, and the incidence rate ratio was 0·96 (95% CI 0·58–1·59; p=0·8723). The risk of adverse events among eligible participants in the intervention group was lower than in the control group (risk ratio 0·63, 95% CI 0·46–0·87; p=0·0049). The distribution of Plasmodium spp detected in children with clinical malaria was unexpectedly diverse with non-Plasmodium falciparum species detected in 56 (11%) of 505 symptomatic children; however, species distribution did not differ between groups (p=0·15). Blood-fed Anopheles gambiae species complex mosquitoes captured in intervention group clusters the week after MDA in 2019 had decreased survival relative to those captured from control group clusters (p<0·0001), but this effect was not seen in mosquitoes captured 3 weeks after MDA. Overall entomological inoculation rates (EIRs; infectious bites per person per night) did not differ between groups (intervention EIR 0·010; control EIR 0·011; between-group ratio 0·91, 95% CI 0·56–1·30; p=0·45). In 2020, children aged 10 years and younger in the intervention group had a significantly higher increase in haemoglobin pre-intervention versus post-intervention than children in the control group (p=0·007). Repeated high-dose ivermectin MDA integrated with SMC distributions at the study site did not reduce malaria incidence among children relative to placebo MDA, despite evidence that, compared with the control group, mosquito survivorship in the first year was reduced in the intervention group the week following MDA and overall improvements in haemoglobin were greater in children in the intervention group. Confounding factors, including unexpectedly low malaria incidence over the trial period, possibly due to government distribution of dual-chemistry ITNs to all trial clusters in the middle of the intervention period, overdispersion of the primary incidence outcome between clusters, and high parasite and mosquito species diversity, might have influenced the primary outcome. National Institute of Allergy and Infectious Diseases.