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Treatments are limited for soil-transmitted helminth infections, especially those due to Trichuris trichiura . In this phase 2a, dose-ranging clinical trial, emodepside showed activity against T. trichiura and hookworm infections.

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.

Infection with the soil-transmitted helminth Trichuris trichiura affects up to 300 million people globally, with children in rural areas in less economically developed countries being most at risk. If untreated, infection compromises physical and cognitive development and leads to long-lasting morbidity. We assessed whether moxidectin co-administered with albendazole is superior to the recommended albendazole monotherapy in treating trichuriasis in school-aged children. This randomised, double-blind, parallel-group, superiority, phase 3 trial took place between May 14 and Aug 5, 2024, in the Piki administrative district primary school in the Wete district, Pemba Island, Tanzania. Children aged between 6 and 11 years were screened for the presence of T trichiura eggs in their stool via quadruplicate Kato–Katz thick smears. Using computer-generated group allocation (block randomisation stratified by infection intensity and age), parasitologically and clinically eligible participants (two or more of four slides positive for eggs) were randomly assigned in a 3:2:1 ratio to receive single oral doses of either moxidectin (4 mg [aged 6–7 years] and 8 mg [aged 8–11 years]) plus 400 mg albendazole, moxidectin placebo plus 400 mg albendazole, or moxidectin placebo plus albendazole placebo. The primary endpoint was cure rate, assessed at 14–21 days post-treatment, using the full analysis set population. Safety was formally assessed at 3 h, 24 h, and 14–21 days post-treatment. This trial is registered at ClinicalTrials.gov (NCT06188715) and is complete. 272 participants were screened, and after 48 participants were excluded for not meeting eligibility criteria, 224 eligible participants were randomly assigned to moxidectin–albendazole (n=114 [51%]), albendazole (n=74 [33%]), or placebo (n=36 [16%]). Of the 224 participants, 129 (58%) were male and 95 (42%) were female, and the mean age was 8·0 years (SD 1·3). For the 213 participants with primary outcome data, we observed a cure rate of 69% (77 of 111) in the moxidectin–albendazole group, which was significantly higher than the cure rate of 16% (11 of 68) in the albendazole group (absolute difference 53·2 percentage points [95% CI 39·6–64·2]). The cure rate in the placebo group was 12% (four of 34). The most common treatment-emergent adverse events were abdominal pain (five [4%] of 114 with moxidectin–albendazole, two [3%] of 74 with albendazole, and one [3%] of 36 with placebo) and headache (two [2%] of 114, none, and one [3%] of 36, respectively), which were all mild and transient. Moxidectin-albendazole combination therapy was superior to albendazole monotherapy in terms of efficacy in the treatment of trichuriasis in school-aged children. Both treatments presented a similar safety profile to placebo. Our study paves the way for a much-needed well tolerated and effective alternative combination treatment for children with trichuriasis. Swiss National Science Foundation (reference 320030_175585).

Ivermectin is an antiparasitic drug that kills mosquitoes feeding on treated persons. In this trial in Kenya, ivermectin given once per month for 3 months led to a 26% lower incidence of malaria than albendazole.

Treatments for soil-transmitted helminthiases face challenges, especially in addressing Trichuris trichiura. Combination regimens, particularly of ivermectin and albendazole, are promising. We aimed to assess the safety, efficacy, and palatability of a combination tablet for the treatment of T trichiura, hookworm, and Strongyloides stercoralis infections among school-aged children in Ethiopia, Kenya, and Mozambique. We conducted an adaptive phase 2/3, randomised, parallel-group, active-controlled, superiority trial in 15 schools in Ethiopia, Kenya, and Mozambique. Eligible participants for both phases were aged 5–18 years, weighed at least 15 kg, and were infected with T trichiura, hookworms, or S stercoralis. Participants were randomly assigned via a computer-generated sequence to either a single dose of a fixed-dose combination (FDC×1) of albendazole (400 mg) plus ivermectin (9 mg or 18 mg), three consecutive daily doses of an FDC (FDC×3) of albendazole (400 mg) plus ivermectin (9 mg or 18 mg), or a single dose of albendazole alone (400 mg) via block randomisation, stratified by soil-transmitted helminth species. Participants and those administering the treatments were not masked to treatment assignment, but those assessing the outcomes were masked. The primary outcome of phase 2 (conducted in Kenya only) was safety during the first 3 h after the intervention and for 7 days, and the primary outcome of phase 3 was efficacy (ie, the proportion of individuals cured at day 21 out of the total number infected at baseline) for T trichiura; both primary outcomes were analysed in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT05124691, and is terminated. Between Jan 20, 2022, and March 24, 2023, 1001 participants were recruited (465 [46%] were female and 536 [54%] were male). 636 (64%) were infected with T trichiura, 360 (36%) with hookworm, and 104 (10%) with S stercoralis; 94 (9%) of 1001 participants had co-infections and were included in the analysis of each infecting species. A total of 243 participants were allocated to the albendazole group, 381 to the FDC×1 group, and 377 to the FDC×3 group. In both phase 2 and 3, gastrointestinal symptoms were the most common mild-to-moderate adverse events in the FDC groups, but resolved within 48 h without intervention. At least one treatment-related adverse event occurred in 34 (14%) of 243 participants in the albendazole group, 75 (20%) of 381 participants in the FDC×1 group, and 88 (23%) of 377 participants in the FDC×3 group. No serious adverse events occurred. For T trichiura, both FDC groups had a higher cure rate (97·2% [95% CI 95·2– 99·3] for FDC×3 and 82·9% [78·2–87·5] for FDC×1) than albendazole (35·9% [27·7–44·1]), with absolute differences of 61·3% (98% CI 50·2–71·2) and 47·0% (34·7–58·1), respectively. For hookworms, FDC×3 had a higher cure rate (95·0% [95% CI 91·1–98·9]) than albendazole (65·1% [56·0–74·2]), with absolute differences of 29·9% (98% CI 17·2–42·4), whereas FDC×1 had a similar cure rate (79·8% [72·8–86·9]) to albendazole. The sample size for efficacy evaluation of S stercoralis was not met. An FDC of albendazole plus ivermectin has a similar safety profile but superior efficacy to albendazole alone against T trichiura infection and hookworms. These findings open opportunities for control of all soil-transmitted helminth species of interest, including potentially S stercoralis. Evaluation of safety in larger populations and implementation scenarios are the next steps for this innovation to promote its incorporation into programmatic activities. European and Developing Countries Clinical Trials Partnership. For the Portuguese translation of the abstract see Supplementary Materials section.

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 .

Lymphatic filariasis caused by Wuchereria bancrofti causes hydroceles and lymphedema in millions of individuals worldwide. Annual mass drug administration of ivermectin plus albendazole (IA) temporarily clears microfilariae from the blood of infected individuals and is used in Africa to reduce W bancrofti transmission. This study aimed to investigate whether moxidectin combination therapies are superior to ivermectin combination therapies for clearance of W bancrofti microfilaremia. In this open-label, parallel assignment, masked-observer, randomised, superiority clinical trial in Côte d'Ivoire, we used gender-stratified, block randomisation to sequentially assign adults with bancroftian filariasis (1:1:1:1) to receive annual ivermectin plus albendazole (IA; standard of care) or one of three single-dose regimens: moxidectin plus albendazole (MoxA), ivermectin plus diethylcarbamazine (DEC) plus albendazole (IDA), or moxidectin plus DEC plus albendazole (MoxDA). This trial was conducted at the Filariasis Research Center in Agboville, located at the Centre Hôspitalier Regional, d'Agboville, Côte d'Ivoire. Men and non-pregnant, non-breastfeeding women aged 18–70 years in good general health and with screening microfilaria loads of at least 40 per mL (≥3 microfilariae on 60μL nocturnal thick blood smear) were eligible for enrolment; those found to have at least 40 microfilariae per mL by 1 mL blood filtration at enrolment were eligible for inclusion in the primary, modified intention-to-treat, efficacy analysis. Medicines were administered by an unmasked pharmacist; all other team members were masked to treatment assignment. Primary outcomes were complete microfilaria clearance at 12 months (MoxA vs IA) or 24 months (MoxDA vs IDA) post-treatment. This trial is registered at ClinicalTrials.gov (NCT04410406) and is complete. Enrolment occurred from Aug 20, 2020 to July 31, 2021. 190 individuals were predicted to have nocturnal blood microfilariae counts of at least 40 microfilariae per mL, of whom 26 were excluded and 164 were randomly assigned to an intervention (41 to the IA group, 40 to the MoxA group, 41 to the IDA group, and 42 to the MoxDA group). 113 participants met the pre-specified efficacy analysis criteria and completed follow-up. The proportion of participants who were amicrofilaraemic at 12 months was eight of 25 (32% [95% CI 15–54]) among IA recipients versus 18 of 19 (95% [95% CI 74–100]) among MoxA recipients (adjusted risk ratio [RR] 2·79 [95% CI 1·59–4·90]; p=0·0004). The proportion of amicrofilaraemic participants at 24 months was 20 of 22 (91% [95% CI 71–99]) for IDA versus 21 of 23 (91% [72–99]) for MoxDA (adjusted RR 0·98 [95% CI 0·83–1·15]; p=0·78). Most MoxA recipients (14 of 16 [88%; 95% CI 62–98]) remained amicrofilaraemic at 24 months. In this study, single-dose MoxA was superior to IA for W bancrofti microfilaria clearance at 12 months and provided prolonged microfilaria clearance for most participants. These results suggest that MoxA could be a powerful tool to accelerate the elimination of lymphatic filariasis in Africa. The Bill & Melinda Gates Foundation. For the French translation of the abstract see Supplementary Materials section.

Loa loa infection is endemic in central African countries and particularly in Gabon. Treatment typically involves the use of ivermectin and albendazole, with albendazole often administered to reduce microfilaremia in individuals with high microfilaremia before taking ivermectin. This study aims to evaluate the efficacy and safety of albendazole in patients with low microfilaremia. The study was conducted from November 2021 to April, 2022 in the Woleu-Ntem province of northern Gabon. Following a questionnaire, direct examination of 10 µL of blood and leukoconcentration technique were perfomed for Loa loa detection. Of 406 identified microfilaremic cases, 48 volunteers were randomized, 21 women and 27 men, their mean age was 51 ± 13 years. Overall, 24 received, daily 400 mg albendazole for30 days and 24 others were treated with a single course of 200 μg/kg ivermectin. Microfilaremia and adverse events were monitored from D0 to D30. In the per-protocol analysis, the mean microfilaremia decreased significantly by 82.3% and 90.4% in the albendazole and ivermectin groups, respectively (p< 0.001). The risk difference between both treatments was 8.1% [95% CI: 16.8; -0.6%]. In the intention-to-treat analysis, the mean microfilaremia decreased significantly by 82.4% and 90.8% in the ALB and IVM groups, respectively (p< 0.001), with a risk difference of 8.4% [95% CI: 16.2; 0.6%]. Eosinophil levels decreased by day 30, although they were not significantly different following albendazole and ivermectin treatments. Albendazole demonstrated microfilaricidal activity in individuals with low Loa loa microfilaremia following a 30-day treatment. The monitoring of parasite density 3-10 months post-treatment is needed to complete the present findings.

Soil-transmitted helminths are targeted for elimination as a public health problem. This study assessed whether, with high coverage, community-wide mass drug administration (MDA) could lead to transmission interruption. DeWorm3 is an open-label, community cluster-randomised controlled trial in Benin, India, and Malawi. In each country, a single governmental administrative unit (population ≥80 000 individuals) with soil-transmitted helminth endemicity and participation in at least five rounds of community-wide MDA for lymphatic filariasis, was divided into 40 clusters (population ≥1650 individuals), which were randomly assigned (1:1) to community-wide MDA versus school-based deworming. Laboratory personnel were masked to exposure status and all investigators were masked to post-baseline outcome data until unmasking. In all clusters, preschool-aged and school-aged children received school-based deworming as per national guidelines for 3 years. In intervention clusters, door-to-door community-wide MDA (a single oral dose of 400 mg albendazole) was delivered to all eligible individuals biannually by community drug distributors for 3 years. All individuals aged 12 months and older in India and Benin and aged 24 months and older in Malawi were eligible for treatment, except women in the first trimester of pregnancy, those with adverse reactions to benzimidazoles, those who were acutely ill or intoxicated, or those reporting treatment within the previous 2 weeks. The co-primary outcomes were individual-level prevalence and cluster-level transmission interruption (ie, weighted prevalence of predominant species of ≤2%) of the predominant soil-transmitted helminth species, assessed by quantitative PCR (qPCR) 24 months after the last round of MDA. The analysis set contained a subset of randomly selected participants per cluster who enrolled in the endline assessment, provided a stool sample, and had a qPCR result. All individuals who received treatment were eligible for inclusion in the safety population. This trial is registered with ClinicalTrials.gov (NCT03014167), and is active but not recruiting. Between Oct 10, 2017, and Feb 17, 2023, 120 clusters (40 clusters per country, comprising 357 716 individuals) were randomly assigned, 60 to community-wide MDA and 60 to school-based deworming. 184 030 (51·4%) individuals in the clusters at baseline were female, 173 663 (48·5%) were male, and 23 (<0·1%) were other. The analysis set consisted of 58 827 individuals in the control group and 58 554 in the intervention group 24 months after the cessation of all deworming, Necator americanus prevalence (the predominant species at all sites) in the community-wide MDA group was lower than the school-based deworming group in Benin (adjusted prevalence ratio [aPR] 0·44 [95% CI 0·34–0·58]), India (0·41 [0·32–0·52]), and Malawi (0·40 [0·34–0·46]). Transmission interruption was achieved for N americanus in 11 (55%) of 20 intervention clusters versus six (30%) of 20 control clusters in Benin (p=0·20), in one (5%) intervention cluster versus no control clusters in India (p=1·00), and in no clusters in either group in Malawi (p=1·00). 984 adverse events were reported among 487 participants over the study, of which 32 among 13 participants resulted in hospitalisation and were classified as serious adverse events (three of which were related to study procedures). Soil-transmitted helminth transmission interruption might be possible in focal geographies but does not appear to be programmatically feasible within the evaluated timeframe. Community-wide MDA should be considered as an alternative strategy to school-based deworming programmes to improve equity and outcomes in helminth-endemic areas. The Gates Foundation.

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.