Background

Preventive chemotherapy with albendazole or mebendazole remains one of the cornerstones of soil-transmitted helminth control. However, these drugs are less effective against Trichuris trichiura. Combined ivermectin–albendazole is a promising treatment alternative, yet robust evidence is lacking. We aimed to demonstrate superiority of co-administered ivermectin–albendazole over albendazole monotherapy in three distinct epidemiological settings.

Methods

We conducted a double-blind, parallel-group, phase 3, randomised controlled trial in community members aged 6–60 years infected with T trichiura in Côte d'Ivoire, Laos, and Pemba Island, Tanzania, between Sept 26, 2018, and June 29, 2020. Participants with at least 100 T trichiura eggs per g of stool at baseline were randomly assigned (1:1) using computer-generated randomisation sequences in varying blocks of four, six, and eight, stratified by baseline T trichiura infection intensity, to orally receive either a single dose of ivermectin (200 μg/kg) plus albendazole (400 mg) or albendazole (400 mg) plus placebo. Patients, field staff, and outcome assessors were masked to treatment assignment. The primary outcome was cure rate against T trichiura, defined as the proportion of participants with no eggs in their faeces 14–21 days after treatment, assessed by Kato-Katz thick smears, and analysed in the available-case population according to intention-to-treat principles. Safety was a secondary outcome and was assessed 3 h and 24 h after drug administration. The trial is registered at ClinicalTrials.gov, NCT03527732.

Findings

Between Sept 13 and Dec 18, 2019, Jan 12 and April 5, 2019, and Sept 26 and Nov 5, 2018, 3737, 3694, and 1435 community members were screened for trial eligibility in Côte d'Ivoire, Laos, and Pemba Island, respectively. In Côte d'Ivoire, Laos, and Pemba Island, 256, 274, and 305 participants, respectively, were randomly assigned to the albendazole group, and 255, 275, and 308, respectively, to the ivermectin–albendazole group. Primary outcome data were available for 722 participants treated with albendazole and 733 treated with ivermectin–albendazole. Ivermectin–albendazole showed significantly higher cure rates against T trichiura than albendazole in Laos (66% [140 of 213]vs 8% [16 of 194]; difference 58 percentage points, 95% CI 50 to 65, p<0·0001) and Pemba Island (49% [140 of 288]vs 6% [18 of 293], 43 percentage points, 36 to 49, p<0·0001) but had similar efficacy in Côte d'Ivoire (14% [32 of 232]vs 10% [24 of 235], 4 percentage points, −2 to 10, p=0·24). No serious adverse events were reported; observed events were mostly classified as mild (95% [266 of 279] in the albendazole group and 91% [288 of 317] in the ivermectin–albendazole group), and all were transient in nature.

Interpretation

Treatment with ivermectin–albendazole resulted in higher efficacy against trichuriasis than albendazole alone in Laos and Pemba Island but not in Côte d'Ivoire. We recommend implementation of this combination therapy for soil-transmitted helminth control in countries with high T trichiura prevalence and proven enhanced efficacy of this treatment, particularly where ivermectin is beneficial against other endemic helminthiases.

Funding

Bill & Melinda Gates Foundation.

中文翻译：

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在科特迪瓦、老挝和坦桑尼亚奔巴岛感染毛鞭虫的学龄儿童和成人中，伊维菌素和阿苯达唑联合给药的疗效和安全性：一项双盲、平行组、3 期、随机对照试验

背景

阿苯达唑或甲苯咪唑的预防性化疗仍然是土壤传播的蠕虫控制的基石之一。然而，这些药物对毛鞭毛虫的效果较差。伊维菌素-阿苯达唑联合用药是一种很有前景的治疗选择，但缺乏有力的证据。我们旨在证明在三种不同的流行病学背景下，伊维菌素-阿苯达唑联合给药优于阿苯达唑单药治疗。

方法

我们于 2018 年 9 月 26 日在老挝科特迪瓦和坦桑尼亚奔巴岛的6-60 岁感染T 毛虫的社区成员中进行了一项双盲、平行组、3 期随机对照试验，以及2020 年 6 月 29 日。 基线时每克粪便至少含有 100 个T 毛虫卵的参与者被随机分配 (1:1)，使用计算机生成的随机序列在不同的4、6和 8 块中随机分配，按基线T 毛虫感染分层强度，口服接受单剂量伊维菌素 (200 μg/kg) 加阿苯达唑 (400 mg) 或阿苯达唑 (400 mg) 加安慰剂。患者、现场工作人员和结果评估员对治疗分配不知情。主要结果是对毛滴虫的治愈率，定义为治疗后 14-21 天粪便中无卵的参与者比例，通过 Kato-Katz 厚涂片评估，并根据意向治疗原则在可用病例人群中进行分析。安全性是次要结果，在给药后 3 小时和 24 小时进行评估。该试验已在 ClinicalTrials.gov 注册，NCT03527732。

发现

在2019年9月13日至12月18日、2019年1月12日至4月5日以及2018年9月26日至11月5日期间，对科特迪瓦、老挝和奔巴岛的3737、3694和1435名社区成员进行了试验资格筛选， 分别。在科特迪瓦、老挝和奔巴岛，分别有 256、274 和 305 名参与者被随机分配到阿苯达唑组，分别有 255、275 和 308 名参与者被随机分配到伊维菌素-阿苯达唑组。722 名接受阿苯达唑治疗的参与者和 733 名接受伊维菌素-阿苯达唑治疗的参与者可获得主要结果数据。在老挝，伊维菌素-阿苯达唑对毛滴虫的治愈率显着高于阿苯达唑（66% [140 of 213] vs 8% [16 of 194]；差异 58 个百分点，95% CI 50 至 65，p<vs 6% [18 of 293]，43 个百分点，36 到 49，p<0·0001）但在科特迪瓦有相似的疗效（14% [32 of 232] vs 10% [24 of 235], 4个百分点，-2 到 10，p=0·24）。没有报告严重的不良事件；观察到的事件大多被归类为轻度（阿苯达唑组 95% [279 次中的 266 次]，伊维菌素-阿苯达唑组中 91% [317 次中的 288 次]），并且所有事件本质上都是短暂的。

解释

在老挝和奔巴岛，使用伊维菌素-阿苯达唑治疗鞭虫病的疗效高于单独使用阿苯达唑，但在科特迪瓦则不然。我们建议在旋毛虫流行率高且证明这种治疗效果增强的国家实施这种联合疗法来控制土壤传播的蠕虫病，特别是在伊维菌素对其他地方性蠕虫病有益的地方。

资金

比尔和梅琳达盖茨基金会。