Background

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.

Methods

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).

Findings

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).

Interpretation

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.

Funding

The National Institute for Health and Care Research, Medical Research Council, Wellcome, and Foreign, Commonwealth & Development Office.

中文翻译：

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在几内亚比绍比热戈斯群岛 （MATAMAL） 上辅助伊维菌素大规模药物管理以控制疟疾：一项四盲、整群随机、安慰剂对照试验

 背景

以伊维菌素治疗个体血液为食的节肢动物媒介大大增加了死亡率。目前尚不清楚这种效果是否会转化为大规模减轻疟疾负担的有用工具。我们的试验旨在评估使用伊维菌素作为双氢青蒿素-哌喹大规模给药 （MDA） 的辅助手段是否会进一步降低疟疾患病率。

 方法

MATAMAL 是一项四盲、整群随机、安慰剂对照试验，在几内亚比绍的比热戈斯群岛进行，这是一个季节性疟疾传播的地区。所有居民都被邀请参加，但出于药物安全考虑，除外。使用限制性随机化，以 1：1 的比例将 24 组随机分配到 2021 年和 2022 年传播季节连续三个月口服三次双氢青蒿素-哌喹和伊维菌素（每天 300 μg/kg）的 MDA，或在同一时间表中使用双氢青蒿素-哌喹和安慰剂的 MDA。主要结局是干预第二年后，在传播高峰期，所有年龄组恶性疟原虫寄生虫血症的定量 PCR 患病率。主要昆虫学结局是按蚊胎次率。试用版已在 ClinicalTrials.gov （NCT04844905） 注册。

 发现

参与者是在 2021 年 6 月 7 日至 2022 年 9 月 21 日期间招募的。基线人群为 25 882 人 （12 634 [50·6%] 为女性个体，12 317 [49·4%] 为男性个体）：干预组 13 832 人，对照组 12 050 人。双氢青蒿素-哌喹的聚集性覆盖率从 60·4% 到 78·7% 不等，伊维菌素或伊维菌素-安慰剂的聚集性覆盖率从 58·1 到 77·1%。干预后，恶性疟原虫感染的患病率为对照组 2300 例中的 118 例 （5·05%），干预组 2083 例中的 141 例 （6·64%）。调整后的风险差为 1·67%（95% CI -1·44 至 4·78;p=0·28）。对照组 （1·0% 的参与者） 有 124 例不良事件，干预组有 267 例 （1·9% 的参与者）。报告了 2 例严重不良事件，均与干预无关，也没有与治疗相关的死亡。按蚊胎次率在对照集群中为 2475 例中的 1679 例 （67·8%），在干预集群中为 2414 例中的 1740 例 （72·3%）。调整后的风险差为 -1·32（95% CI -14·77 至 12·12;p=0·84）。

 解释

在这种情况下，在双氢青蒿素-哌喹 MDA 中添加伊维菌素对降低疟疾流行率或病媒胎次没有额外影响。干预耐受性良好。据我们所知，该试验是第一个旨在评估伊维菌素与双氢青蒿素-哌喹 MDA 联合给药时是否对疟疾具有累加作用的试验。

 资金

国家健康与护理研究所，医学研究委员会，惠康，以及外交，联邦与发展办公室。