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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).

Multiple medications in common use have been considered for the treatment of Covid-19. In this double-blind, randomized, placebo-controlled trial, ivermectin that was administered within 7 days after Covid-19 symptom onset was shown not to be of any clinical benefit.

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.

Background. Available treatments for lymphatic filariasis (LF) are limited in their longterm clearance of microfilaria from the blood. The safety and efficacy of a single-dose triple-drug therapy of the antifilarial drugs diethylcarbamazine (DEC), ivermectin (IVM), and albendazole (ALB) for LF are unknown. Methods. We performed a pilot study to test the efficacy, safety, and pharmacokinetics of single-dose DEC, IVM, and ALB in Wuchereria bancrofti-infected Papua New Guineans. Adults were randomized into 2 treatment arms, DEC 6 mg/kg + ALB 400 mg (N = 12) or DEC 6 mg/kg + ALB 400 mg + IVM 200 μg/kg (N = 12), and monitored for microfilaria, parasite antigenemia, adverse events (AEs), and serum drug levels. Results. Triple-drug therapy induced >2-log reductions in microfilaria levels at 36 and 168 hours after treatment compared with approximately 1-log reduction with 2 drugs. All 12 individuals who received 3 drugs were microfilaria negative 1 year after treatment, whereas 11 of 12 individuals in the 2-drug regimen were microfilaria positive. In 6 participants followed 2 years after treatment, those who received 3 drugs remained microfilaria negative. AEs, particularly fever, myalgias, pruritus, and proteinuria/hematuria, occurred in 83% vs 50% of those receiving triple-drug compared to 2-drug treatment respectively (P = .021); all resolved within 7 days after treatment. No serious AEs were observed in either group. There was no significant effect of IVM on DEC or ALB drug levels. Conclusions. Triple-drug therapy is safe and more effective than DEC + ALB for Bancroftian filariasis and has the potential to accelerate elimination of lymphatic filariasis. Clinical Trials Registration. NCT01975441.

Ivermectin is an FDA-approved broad-spectrum anti-parasitic agent that has been shown to inhibit SARS-CoV-2 replication . We aimed to assess the therapeutic efficacy of ivermectin mucoadhesive nanosuspension intranasal spray in treatment of patients with mild COVID-19. This clinical trial included 114 patients diagnosed as mild COVID-19. Patients were divided randomly into two age and sex-matched groups; group A comprising 57 patients received ivermectin nanosuspension nasal spray twice daily plus the Egyptian protocol of treatment for mild COVID-19 and group B comprising 57 patients received the Egyptian protocol for mild COVID-19 only. Evaluation of the patients was performed depending on improvement of presenting manifestations, negativity of two consecutive pharyngeal swabs for the COVID-19 nucleic acid via rRT-PCR and assessments of hematological and biochemical parameters in the form of complete blood counts, C-reactive protein, serum ferritin and d-dimer which were performed at presentation and 7 days later. Of the included patients confirmed with mild COVID-19, 82 were males (71.9%) and 32 females (28.1%) with mean age 45.1 ± 18.9. In group A, 54 patients (94.7%) achieved 2 consecutive negative PCR nasopharyngeal swabs in comparison to 43 patients (75.4%) in group B with P = 0.004. The durations of fever, cough, dyspnea and anosmia were significantly shorter in group A than group B, without significant difference regarding the duration of gastrointestinal symptoms. Duration taken for nasopharyngeal swab to be negative was significantly shorter in group A than in group B (8.3± 2.8 days versus 12.9 ± 4.3 days; P = 0.0001). Local use of ivermectin mucoadhesive nanosuspension nasal spray is safe and effective in treatment of patients with mild COVID-19 with rapid viral clearance and shortening the anosmia duration. NCT04716569; https://clinicaltrials.gov/ct2/show/NCT04716569.

Strongyloidiasis is a pernicious, sometimes fatal, infectious disease caused by the parasitic nematode Strongyloides stercoralis and infects millions of people worldwide. Ivermectin is the only recommended single-dose treatment option available, but concerns of drug resistance are rightly founded, therefore driving the demand for efficacious alternatives. Emodepside, an anthelmintic recently repurposed from the veterinary field, is currently under clinical development for the treatment of onchocerciasis and soil-transmitted helminthiasis. We aimed to identify the most efficacious and safe dose of emodepside against S stercoralis infections. We conducted a phase 2a, dose-ranging, randomised, parallel-group, placebo-controlled, single-blind clinical trial. Recruitment took place in 17 endemic villages in the Champhone district of Laos. Adults aged 18–60 years who provided three stool samples with a mean number of S stercoralis larvae per g of at least 0·75, as assessed by sextuplicate Baermann assays, were invited to participate. Clinically eligible participants were randomly assigned (1:1:1:1:1:1:1:1) to receive a single oral dose of placebo, ivermectin (200 μg/kg), or emodepside at doses 5 mg, 10 mg, 15 mg, 20 mg, 25 mg, or 30 mg. The participants, laboratory technicians, study nurses, and physicians were masked to the treatment assignments; study investigators were not masked. Participants providing at least one sample during follow-up were included in the primary outcome analysis, whereby efficacy was estimated by cure rate (defined as the proportion of participants who became S stercoralis negative 14–21 days after treatment). Treated patients were assessed for adverse events at 3-h, 24-h, 72-h, and 14 days post-treatment. This trial is registered at ClinicalTrials.gov (NCT06373835) and is completed. Between May 20, 2024, and Aug 14, 2024, 820 individuals were screened for S stercoralis infection and, of these, 202 individuals (108 male and 94 female) were randomly allocated to treatment groups and treated. 25 participants were treated with ivermectin, 25 with placebo, 25 participants with emodepside at 5 mg, 15 mg, 25 mg, or 30 mg dose, and 26 participants with emodepside at 10 mg or 20 mg dose. 5 mg emodepside had a predicted cure rate of 78·3% (95% CI 59·4–89·9), which was higher than the observed cure rate in the placebo treatment group (0%; 0·0–13·7; 0 of 25 participants). The dose–response curve plateaued at 15 mg, with a predicted cure rate of 89·1% (81·6–93·7). The observed cure rate in the ivermectin treatment group was 88·0% (68·8–97·5; 22 of 25 participants). The most common adverse event in all treatment groups was somnolence at 3-h post-treatment (ranging from nine [36%] of 25 participants in the emodepside 15 mg group to 17 [68%] of 25 in the 30 mg group). Other common adverse events included vision blur (two [8%] of 25 participants in the ivermectin group to 11 [44%] of 25 in the emodepside 30 mg group at 3-h post-treatment), vision impairment (three [4%] of 26 in the 10 mg group to eight [32%] of 25 in the emodepside 30 mg group), and dizziness (two [8%] of 25 participants in the emodepside 5 mg group to seven [28%] of 25 in the emodepside 30 mg group) at 3-h post-treatment. Adverse events were predominantly mild in nature and no serious adverse events occurred. At all doses tested, emodepside was efficacious and well tolerated in individuals infected with S stercoralis. The broad-spectrum weight-independent dose and robust safety profile positions emodepside as a promising new candidate for strongyloidiasis treatment. European Research Council and the Uniscientia Foundation.

Background Evidence on ivermectin as a treatment for Covid-19 is controversial. A Cochrane review concluded that the efficacy and safety of ivermectin is uncertain (evidence up to April 2022) and WHO recommended its use only in the setting of clinical trials. This study aimed to assess the efficacy and safety of oral ivermectin in hospitalized patients with mild to moderate Covid-19. Trial design and methods A double-blind, randomized placebo-controlled clinical trial was conducted among RT-PCR-confirmed, adults, hospitalised within the first four days of symptoms. Patients received oral ivermectin 24 mg or placebo daily for five days. RT-PCR was repeated on days five and ten. Clinical progression was monitored using the World Health Organization Clinical Progression Scale. Serum ivermectin levels were measured on days three, five, and seven. The primary outcome was the difference in the viral load between day zero and ten in the two groups. Results Out of 1699 patients screened, 249 underwent randomization and 127 received ivermectin, and 122 placebo. D10 median viral load for E gene (IQR) was 2,000 copies/mL (100 − 20,500) with ivermectin ( n  = 80) and 4,100 copies/mL (1,000–65,600) with placebo ( n  = 81, p  = 0.028), per protocol analysis. The difference in Log viral load between day zero and ten between ivermectin and placebo was 3.72 and 2.97 respectively ( p  = 0.022). There was no significant difference in the WHO clinical progression scale or the adverse effects. Ivermectin blood levels taken before or with meals were not significantly different. Only 7 and 17 patients achieved blood levels above 160ng/ML and 100ng/ML respectively and they did not achieve a significantly lower viral load. Conclusion Although ivermectin resulted in statistically significant lower viral load in patients with mild to moderate Covid-19, it had no significant effect on clinical symptoms. Trial registration number SLCTR/2021/020, Sri Lanka Clinical Trials Registry. 19/07/2021.

Background and Objective Trichuriasis caused by the human whipworm Trichuris trichiura poses a significant public health concern. Albendazole-ivermectin co-medication is currently the most effective treatment. Studies conducted in Tanzania and Côte d’Ivoire unveiled differences in efficacy for albendazole-ivermectin combination therapy in both countries. A pharmacometrics approach was used to assess co-medication and study population effects on the pharmacokinetics of the two main metabolites of albendazole. An exploratory exposure-efficacy analysis was also carried out to investigate relationships between exposure measures and the egg reduction rate. Methods Pharmacokinetic data from studies in Tanzania and Côte d’Ivoire in adolescents (aged 12–19 years) were included in the pharmacometric analysis. Participants received a single dose of either albendazole 400 mg alone or in combination with ivermectin 200 µg/kg. A pharmacometric analysis was performed to investigate the potential effects of the study population and co-administered ivermectin on the apparent clearance of the metabolites of albendazole. Non-linear mixed-effects modeling was conducted with MonolixSuite 2023R1. The pharmacokinetic exposure measures derived from simulations with individual model parameters were used in the exploratory-exposure response analysis. Results Pharmacokinetic profiles were best described by a two-compartment model for albendazole sulfoxide and a one-compartment model for albendazole sulfone, with a transit compartment and linear elimination. While no co-medication effect was found, apparent clearance of albendazole sulfoxide (albendazole sulfone) in the Tanzanian study population was 75% (46%) higher than that in the Côte d'Ivoire study population. Exposure-efficacy response analyses indicated that peak concentration and the time-above-exposure threshold were associated with the egg reduction rate. Conclusions Study population but not co-administered ivermectin showed an effect on apparent clearance of albendazole sulfoxide and albendazole sulfone. Polymorphisms in drug-metabolizing enzymes and host-parasite interaction may explain this result. Difference in drug exposure did not explain the disparate efficacy responses in Tanzania and Côte d‘Ivoire. Peak concentration and time-above-threshold were exposure measures associated with the egg reduction rate. Further studies evaluating genetic and resistance patterns in various regions in Africa are warranted.

The increased incidence of dengue poses a substantially global public health challenge. There are no approved antiviral drugs to treat dengue infections. Ivermectin, an old anti‐parasitic drug, had no effect on dengue viremia, but reduced the dengue non‐structural protein 1 (NS1) in a clinical trial. This is potentially important, as NS1 may play a causal role in the pathogenesis of severe dengue. This study established an in‐host model to characterize the plasma kinetics of dengue virus and NS1 with host immunity and evaluated the effects of ivermectin, using a population pharmacokinetic–pharmacodynamic (PK–PD) modeling approach, based on two studies in acute dengue fever: a placebo‐controlled ivermectin study in 250 adult patients and an ivermectin PK–PD study in 24 pediatric patients. The proposed model described adequately the observed ivermectin pharmacokinetics, viral load, and NS1 data. Bodyweight was a significant covariate on ivermectin pharmacokinetics. We found that ivermectin reduced NS1 with an EC50 of 67.5 μg/mL. In silico simulations suggested that ivermectin should be dosed within 48 h after fever onset, and that a daily dosage of 800 μg/kg could achieve substantial NS1 reduction. The in‐host dengue model is useful to assess the drug effect in antiviral drug development for dengue fever.

Trichuris trichiura , a soil-transmitted helminth (STH), often persists after a single dose of anthelminthic treatment. To overcome limited efficacy against T . trichiura of benzimidazoles (albendazole or mebendazole), the primary drugs used in mass drug administration (MDA) campaigns, the World Health Organization endorses the use of a combination of ivermectin and albendazole as a more effective treatment to be used for preventive chemotherapy. Given observed considerable differences in efficacy of the combination therapy over albendazole monotherapy between different settings, it is necessary to evaluate the performance of the combination before introducing it on a larger scale. This open-label, randomized controlled superiority trial in two Ugandan primary schools enrolled eligible 6- to 12-year-olds positive for T . trichiura . Participants were randomized 1:1 to receive either a single dose of albendazole alone or co-administered albendazole and ivermectin. Adverse events were monitored at three and 24h post-treatment. Follow-up samples were collected 14 to 21 days post-treatment for efficacy assessment. The combination of albendazole with ivermectin showed superior efficacy against T . trichiura compared to albendazole alone, both in terms of cure rates (31.3% versus 12.3%, difference 18.9%-points, 95% CI 6.2–31.2, p < 0.004) and in terms of egg reduction rates (ERRs; 91.4% versus 52.7%). A higher cure rate against co-infecting Ascaris lumbricoides was observed in the combination compared to the albendazole monotherapy arm (100% versus 83.9%). Both therapies showed an excellent safety profile with few and only mild and transient treatment emergent adverse events observed in the albendazole monotherapy and albendazole plus ivermectin arm (total of 22 and 19 events, respectively). In conclusion, the efficacy of the combination therapy against T . trichiura in Uganda is superior to that of albendazole alone. Given the high ERRs observed, albendazole-ivermectin might aid in eliminating morbidity, an important target of STH control programs. Trial registration (clinicaltrials.gov): NCT06037876 .