Efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole coadministration in adolescents infected with Trichuris trichiura in Tanzania: an open-label, non-inferiority, randomised, controlled, phase 2/3 trial - The...

Introduction

Trichuris trichiura is an intestinal parasite belonging to the soil-transmitted helminths. Trichuriasis is a neglected tropical disease that mostly affects populations in tropical and subtropical climates and is closely linked to poverty.

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WHO
Ending the neglect to attain the Sustainable Development Goals: a road map for neglected tropical diseases 2021–2030.

An estimated 1·5 billion people are infected with soil-transmitted helminths worldwide and infections have resulted in 2 million disability adjusted life-years in 2017.

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WHO
Soil-transmitted helminth infections.

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³

• Kyu HH
• Abate D
• Abate KH
• et al.

Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990–2017: a systematic analysis for the Global Burden of Disease Study 2017.

Soil-transmitted helminth infections cause numerous symptoms and morbidity has been linked to infection intensity, chronic infection, and coinfection with several parasites, such as Plasmodium spp and Schistosoma spp.

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• Jourdan PM
• Lamberton PHL
• Fenwick A
• Addiss DG

Soil-transmitted helminth infections.

Infections can lead to nutrient deficiency, anaemia, and impaired growth, thus children and adolescents are especially clinically vulnerable to these detrimental effects.

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• Bethony J
• Brooker S
• Albonico M
• et al.

Soil-transmitted helminth infections: ascariasis, trichuriasis, and hookworm.

Therefore, control programmes often focus on children of preschool (2–4 years) and school age (5–14 years).

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WHO
2030 targets for soil-transmitted helminthiases control programmes.

Research in context

Evidence before this study

We searched PubMed and Google Scholar for articles published without language restrictions from database inception to May 6, 2022, using different combinations of the following search terms: "moxidectin", "albendazole", "T trichiura", "hookworm", "soil-transmitted helminths", and "trial". Our search identified two clinical trials on the combination of moxidectin and albendazole for the treatment of Trichuris trichiura in humans. A dose-finding study that was preceded by a non-inferiority trial found a combination of 8 mg moxidectin and 400 mg albendazole more efficacious than moxidectin alone. However, none of these studies directly compared moxidectin and albendazole with the new recommended combination of ivermectin and albendazole.

Added value of this study

We conducted a randomised controlled trial to assess the efficacy of moxidectin and albendazole versus ivermectin and albendazole against T trichiura infections in adolescents on Pemba Island, Tanzania. Our study showed superior ERRs and cure rates with a combination of ivermectin and albendazole compared with moxidectin and albendazole. The trial results confirmed that combination chemotherapy has higher efficacy against T trichiura than monotherapy and the treatments are well tolerated.

Implications of all the available evidence

Ivermectin and albendazole is currently recommended for T trichiura and concomitant soil-transmitted helminth infections. Due to an easy administration of moxidectin as a single, weight-independent dose and its benefits over albendazole monotherapy, moxidectin-albendazole combination could serve as a backup in preventive chemotherapy and other control programmes.

The main strategy to eliminate soil-transmitted helminth infections as a public health problem is preventive chemotherapy in the form of mass drug administration programmes that heavily rely on safe, cost-effective, and easily administered drugs.

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WHO
2030 targets for soil-transmitted helminthiases control programmes.

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• Savioli L
• Albonico M
• Daumerie D
• et al.

Review of the 2017 WHO Guideline: Preventive chemotherapy to control soil-transmitted helminth infections in at-risk population groups. An opportunity lost in translation.

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• Albonico M
• Allen H
• Chitsulo L
• Engels D
• Gabrielli AF
• Savioli L

Controlling soil-transmitted helminthiasis in pre-school-age children through preventive chemotherapy.

The drugs of choice are two benzimidazoles—ie, albendazole and mebendazole—that have shown excellent efficacy against Ascaris lumbricoides, but moderate efficacies against hookworm and unsatisfactory results against T trichiura infection.

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• Moser W
• Schindler C
• Keiser J

Efficacy of recommended drugs against soil transmitted helminths: systematic review and network meta-analysis.

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• Montresor A
• Crompton DW
• Gyorkos TW
• Savioli L

Helminth control in school-age children: a guide for managers of control programmes.

Combination chemotherapies gained increasing attention in the past 5 years as a control strategy for soil-transmitted helminth infections to enhance efficacy and slow down drug-resistance development. WHO mentioned the combination of ivermectin and albendazole as a recommended treatment against soil-transmitted helminths in 2017.

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WHO
The selection and use of essential medicines: report of the WHO Expert Committee, 2017 (including the 20th WHO model list of essential medicines and the 6th model list of essential medicines for children).

A recent multicountry, randomised controlled trial

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• Hürlimann E
• Keller L
• Patel C
• et al.

Efficacy and safety of co-administered ivermectin and albendazole in school-aged children and adults infected with Trichuris trichiura in Côte d'Ivoire, Laos, and Pemba Island, Tanzania: a double-blind, parallel-group, phase 3, randomised controlled trial.

of ivermectin and albendazole showed superior cure rates compared with albendazole monotherapy in two of three study settings (66% [Laos] and 49% [Pemba Island] for ivermectin and albendazole vs 8% [Laos] and 6% [Pemba Island] for albendazole) and a good safety profile with only few minor adverse events reported. Additionally, the combination also improved infection status and intensity 12 months after treatment with intermediate retreatment after 6 months.

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• Keller L
• Welsche S
• Patel C
• et al.

Long-term outcomes of ivermectin-albendazole versus albendazole alone against soil-transmitted helminths: results from randomized controlled trials in Lao PDR and Pemba Island, Tanzania.

Ivermectin is widely used for veterinary deworming and against human lymphatic filariasis and onchocerciasis in control programmes.

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• Vercruysse J
• Rew RS

Macrocyclic lactones in antiparasitic therapy.

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• Laing R
• Gillan V
• Devaney E

Ivermectin–old drug, new tricks?.

Since usage across various fields and infections is often associated with an increased risk for the development of resistance, concerns have been voiced on the possible emergence of ivermectin resistance.

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Prospects for the control of neglected tropical diseases by mass drug administration.

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¹⁷

• Vercruysse J
• Levecke B
• Prichard R

Human soil-transmitted helminths: implications of mass drug administration.

The ubiquitous use of anthelmintics for livestock and humans increases selection pressure on these parasites. Accordingly, resistance to all major classes of anthelmintics was reported in the veterinary field and remains a threat to human health.

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• Tinkler SH

Preventive chemotherapy and anthelmintic resistance of soil-transmitted helminths—can we learn nothing from veterinary medicine?.

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• Geerts S
• Gryseels B

Drug resistance in human helminths: current situation and lessons from livestock.

Moxidectin, similarly to ivermectin, is a macrocyclic lactone used as an antiparasitic, and was approved by the US Food and Drug Administration in 2018 for the treatment of onchocerciasis in patients older than 12 years.

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• Prichard RK
• Geary TG

Perspectives on the utility of moxidectin for the control of parasitic nematodes in the face of developing anthelmintic resistance.

Evidence from previous trials

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• Hofmann D
• Sayasone S
• Sengngam K
• Chongvilay B
• Hattendorf J
• Keiser J

Efficacy and safety of ascending doses of moxidectin against Strongyloides stercoralis infections in adults: a randomised, parallel-group, single-blinded, placebo-controlled, dose-ranging, phase 2a trial.

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²²

• Opoku NO
• Bakajika DK
• Kanza EM
• et al.

Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind phase 3 trial.

^, 

²³

• Keller L
• Palmeirim MS
• Ame SM
• et al.

Efficacy and safety of ascending dosages of moxidectin and moxidectin-albendazole against Trichuris trichiura in adolescents: a randomized controlled trial.

shows that moxidectin might be a good candidate for combination treatment against soil-transmitted helminth infections. Moreover, moxidectin is also active against Strongyloides stercoralis; however, non-inferiority has not yet been shown.

²⁴

• Barda B
• Sayasone S
• Phongluxa K
• et al.

Efficacy of moxidectin versus ivermectin against Strongyloides stercoralis infections: a randomized, controlled noninferiority trial.

Studies comparing moxidectin versus ivermectin against S stercoralis are ongoing (NCT04056325 and NCT04848688). Additionally, ivermectin is being considered as a drug used in potential mass drug administration schemes against scabies and the efficacy of moxidectin against the ectoparasite is under investigation.

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• Engelman D
• Cantey PT
• Marks M
• et al.

The public health control of scabies: priorities for research and action.

We aimed to assess the efficacy and safety of moxidectin and albendazole compared with ivermectin and albendazole against T trichiura in adolescents living on Pemba Island, Tanzania. To measure long-term effects of moxidectin due to the longer half-life (20–35 days vs 18 h for ivermectin), follow-up was conducted at 14–21 days, 5–6 weeks, and 3 months after treatment.

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• Cotreau MM
• Warren S
• Ryan JL
• et al.

The antiparasitic moxidectin: safety, tolerability, and pharmacokinetics in humans.

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²⁷

• Guzzo CA
• Furtek CI
• Porras AG
• et al.

Safety, tolerability, and pharmacokinetics of escalating high doses of ivermectin in healthy adult subjects.

Methods

Study design and participants

This open-label, non-inferiority, randomised, controlled, phase 2/3 trial was done in four secondary schools (Kilindi, Kwale, Ndagoni [Chake Chake District], and Kiuyu [Wete District]) on Pemba Island, Tanzania. Adolescents aged 12–19 years who tested positive for T trichiura in at least two of four Kato-Katz slides with a mean infection intensity of 48 eggs per gram (EPG) of stool or higher were considered for inclusion. On treatment day, adolescents eligible based on stool examination were invited to undergo a clinical examination. Participants presenting with anaemia (lower than 80 g/L haemoglobin), a body temperature higher than 38°C, severe chronic or acute systemic illness (as determined by study physicians), those who received anthelmintic treatment in the past 4 weeks, had a positive pregnancy test, or were planning to become pregnant were not eligible.

The trial was conducted in compliance with the Declaration of Helsinki and Good Clinical Practice guidelines. Ethical approval was obtained from the Zanzibar Health Research Institute (NO.ZAHREC/03/PR/OCT/2020/23) and Ethics Committee Northwest and Central Switzerland (EKNZ, AO_2020–00042). Participants aged 18 years or older provided written informed consent, whereas those younger than 18 years were asked to provide written assent and a guardian or parent provided written informed consent. The trial protocol including the study design and methods were published elsewhere.

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• Welsche S
• Mrimi EC
• Keller L
• et al.

Efficacy and safety of moxidectin and albendazole compared to ivermectin and albendazole co-administration in adolescents infected with Trichuris trichiura: a randomized controlled trial protocol.

Randomisation and masking

Eligible participants were randomly assigned (21:21:2:2:8) to five treatment groups (moxidectin and albendazole, ivermectin and albendazole, albendazole, ivermectin, or moxidectin) using a computer-generated randomisation code by order of arrival to treatment, resulting in a minimum block size of 54. Two levels of baseline T trichiura infection intensity (ie, light at ≤999 EPG and moderate or heavy at ≥1000 EPG) served as a basis for stratification. The trial statistician generating the randomisation sequence was not involved in any field activities. To ensure an allocation close to the anticipated ratio—even when the number of participants in a stratum was low—we developed a randomisation procedure with elements from block randomisation, biased coin design, and covariate constraint randomisation (appendix pp 7–8). Sealed, opaque, and sequentially numbered envelopes containing the treatment group assignment were prepared before the trial start by team members who were not further involved in the trial. Laboratory technicians as primary outcome assessors were masked to treatment allocation. Due to the varying doses and size of tablets, study site investigators and participants were not masked to study treatment. However, allocation was concealed to participants and treatment was handed out individually. Personal data and stool samples were coded with a 4-digit unique identifier for analysis and evaluation.

Procedures

Participants were asked to provide two stool samples at baseline on two consecutive days, with a maximum 5-day interval. Kato-Katz thick smears using 41·7 mg of stool were prepared in duplicate for each sample and assessed by experienced laboratory technicians under a light microscope. Egg counts of A lumbricoides, T trichiura, and hookworm were noted and entered using tablets via a data entry mask predefined in CommCare (Dimagi, Cambridge, MA, USA). Approximately 10% Kato-Katz slides were randomly chosen for quality control of T trichiura and A lumbricoides results. An additional slide was prepared from 10% of samples for immediate quality control of hookworm egg counts.

Participants received either 8 mg moxidectin and 400 mg albendazole (group 1), 200 μg/kg ivermectin and 400 mg albendazole (group 2), 400 mg albendazole (group 3), 200 μg/kg ivermectin (group 4), or 8 mg moxidectin (group 5). Moxidectin (Medicines Development for Global Health, Melbourne, VIC, Australia) was available in tablets of 2 mg with participants receiving 4 tablets each. Ivermectin (Merck Sharp & Dohme, Readington, NJ, USA) was administered in 3 mg tablets as a weight-dependent dose. Albendazole (GlaxoSmithKline, London, UK) was given as a single tablet of 400 mg.

On the treatment day, study physicians performed a physical examination (including a rapid assessment of haemoglobin concentrations to rule out anaemia, measurement of body temperature, and the medical history to assess baseline conditions) of all eligible participants to ensure inclusion criteria were met. Females were tested for pregnancy and asked to confirm that no pregnancy was planned throughout the duration of the study. Study physicians assessed adverse events at 3 h and 24 h after treatment. At the three follow-up timepoints of 14–21 days, 5–6 weeks, and 3 months after treatment, adverse events were assessed retrospectively by trained study team members and considered as possibly related when causality could not be ruled out by other conditions. Severity grading was categorised according to the US National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE; version 5.0).

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National Cancer Institute
Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

When symptoms prevailed at follow-up assessments, participants were taken to a study physician or Chake Chake hospital, provided with the prescribed treatment, and followed up by the study team until symptoms resolved.

A subsample of 60 participants were asked to provide blood samples collected by a finger prick for the assessment of pharmacokinetic parameters between day 0 and 7 after treatment. Pharmacokinetic results will be published elsewhere. Efficacy was assessed 14–21 days after treatment by quadruplicate Kato-Katz from two stool samples collected using the same procedures as for baseline sampling. The same procedures were applied at the other timepoints to determine long-term treatment efficacy. At the end of the study, participants who were still positive for soil-transmitted helminth infections were offered the best available treatment option—ie, ivermectin and albendazole.

Outcomes

The primary outcome was egg reduction rate (ERR) of T trichiura 14–21 days after treatment in the available case population. Secondary outcomes were cure rates (defined as the proportion of participants converted from egg-positive at baseline to egg-negative after treatment) of combination therapy groups compared with monotherapy groups for T trichiura 14–21 days after treatment; egg reduction rates and cure rates for A lumbricoides and hookworm assessed at 14–21 days, 5–6 weeks, and 3 months after treatment; and tolerability of treatment assessed by type, number, and severity of adverse events. Secondary outcomes were assessed in the available case population.

Statistical analysis

The primary hypothesis was that moxidectin and albendazole combination treatment is not inferior to ivermectin and albendazole. Simulations using data based on a study by Barda and colleagues

³⁰

• Barda B
• Ame SM
• Ali SM
• et al.

Efficacy and tolerability of moxidectin alone and in co-administration with albendazole and tribendimidine versus albendazole plus oxantel pamoate against Trichuris trichiura infections: a randomised, non-inferiority, single-blind trial.

were used to determine the sample size. We estimated that 160 participants would be needed per group to ensure a power of 90% that the upper limit of the two-sided 95% CIs would exclude a difference of more than 2 percentage points (the non-inferiority margin) in favour of the ivermectin and albendazole combination group, assuming a true ERR of 98% in both groups. Accounting for possible loss to follow-up of 10% and an additional safety margin of 20% due to uncertainties in the simulation assumptions, the aim was to enrol 210 participants in each combination treatment group. To test superiority of each combination treatment against respective monotherapies we assumed a cure rate of less than 25% for albendazole or ivermectin monotherapy and less than 40% for moxidectin monotherapy. To detect a statistically significant difference with 85–90% power, 20 participants needed to be enrolled in the albendazole group, 20 in the ivermectin group, and 80 in the moxidectin group. The aim was to enrol 540 participants across all five groups.

The primary non-inferiority analysis was done according to the intention-to-treat principles in the available case population (defined as all participants with any primary endpoint data), with a subsequent per-protocol analysis (defined as all participants with no major protocol deviations, excluding those who did not enter the study because they did not satisfy entry criteria, received no treatment, received the wrong treatment or an incorrect dose, or received concomitant therapy). Eggs per gram of stool were calculated from the geometric mean egg counts multiplied by a factor of 24. For each treatment group, ERRs were calculated using geometric mean egg counts assessed at baseline and 14–21 days after treatment according to the following formula:

${\text{ERR}}_{\text{geometric mean}}=1-\frac{e^{\frac{1}{\text{n}}\sum log(\text{EPGfollow}-\text{up}+1)}-1}{e^{\frac{1}{\text{n}}\sum log(\text{EPGbaseline}+1)}-1}$

To estimate the difference between ERRs and 95% CIs, a bootstrap resampling method with 5000 replicates was used. The geometric SD was calculated as; e^{(SD[log(EPG + 1)])}. Absolute differences between the cure rates were assessed using an exact melded binomial test with mid-p correction, relative differences were estimated using unadjusted regression. Logistic regression with adjustment for baseline infection intensity, age, sex, and weight was also performed. For each follow-up timepoint, ERRs and cure rates were calculated.

Adverse events are presented as frequencies without statistical testing, as recommended by Ioannidis and colleagues.

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• Ioannidis JP
• Evans SJ
• Gøtzsche PC
• et al.

Better reporting of harms in randomized trials: an extension of the CONSORT statement.

Data was analysed using R (version 4.0.3) and Stata (version 16). This study is registered with ClinicalTrials.gov, NCT04700423.

Role of the funding source

The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.

Results

Between March 1 and April 30, 2021, 771 participants were assessed for eligibility (figure 1). 706 (92%) participants provided two stool samples, 550 (71%) were positive for T trichiura and had at least 48 EPG infection intensity. 221 (29%) of 771 participants were ineligible and a further 14 (2%) were excluded. Between May 24 and June 3, 2021, 207 (39%) of 536 participants were randomly assigned to moxidectin and albendazole, 211 (39%) to ivermectin and albendazole, 19 (4%) to albendazole, 19 (4%) to ivermectin, and 80 (15%) to moxidectin.

Figure 1Trial profile

Show full caption

Timepoints refer to follow-up. *Assessed for adverse events at 3 h and 24 h after treatment. †Assessed for efficacy and adverse events.

Baseline characteristics are summarised in table 1. The mean age of participants ranged from 15·6 to 15·9 years with a mean of 15·8 years (SD 1·5). 394 (74%) were female and 142 (24%) were male students. Coinfections with other soil-transmitted helminths were common (292 [54%] of 536 were positive for A lumbricoides and 173 [32%] had a concomitant hookworm infection). Most T trichiura and all hookworm infections were light in intensity, whereas for A lumbricoides most participants harboured moderate to heavy infections. More female students were enrolled than males; however, the distribution across treatment groups was balanced.

Table 1Baseline characteristics of trial participants

Data are mean (SD) and n (%). EPG=eggs per gram.

Primary outcome data were available for all 536 participants (table 2). The geometric mean ERR of T trichiura after 14–21 days was 96·8% (95% CI 95·8 to 97·6) with moxidectin and albendazole and 99·0% (98·7 to 99·3) with ivermectin and albendazole. The difference of –2·2 percentage points (–4·2 to –1·4) was large enough to reject non-inferiority and show inferiority of moxidectin and albendazole over ivermectin and albendazole. No major protocol deviations were recorded; therefore, the per protocol population was identical to the available case population.

Table 2ERR and cure rates for T trichiura, hookworm, and A lumbricoides across different follow-up timepoints

Data are mean (95% CI), unless stated otherwise. ERR=egg reduction rate. EPG=eggs per gram.

A secondary analysis showed that ivermectin and albendazole was superior to moxidectin and albendazole in terms of the secondary outcome cure rate for T trichiura 14–21 days after treatment (54·0% vs 34·3%, difference of 19·7 percentage points [10·2 to 28·9]; pappendix p 4). The cure rate of moxidectin and albendazole was 8·0 percentage points higher (–15 to 25) than that of albendazole monotherapy; however, the difference was not statistically significant. The cure rate of moxidectin and albendazole was significantly higher than moxidectin monotherapy (difference of 23·0 percentage points [12·6 to 31·8]; pT trichiura between moxidectin and albendazole and ivermectin and albendazole during 5–6 weeks and 3 months after treatment.

The point estimate cure rates and ERRs for T trichiura infection were higher with combination treatments than with either of the three monotherapies across all three follow-up timepoints. Although the difference between cure rates of moxidectin and albendazole versus albendazole monotherapy was not statistically significant at any of the follow-up timepoints, the ERRs of moxidectin and albendazole were significantly higher at all three timepoints for T trichiura (table 2).

No serious adverse events of grade 3–5 were reported in all five treatment groups during the study. The number of participants reporting adverse events are shown in table 3. The type and distribution of adverse events are shown in figure 2 for the two combination treatment groups and in the appendix (pp 5–7) for all treatment groups. Adverse events were predominantly mild (385 [83%] of 465 total adverse events) and a few were moderate (80 [17%]; appendix pp 5–7).

Table 3Number of participants reporting adverse events at each timepoint per treatment group

Each participant could have more than one adverse event.

Figure 2Total number of adverse events

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Reported in the two combination treatment groups at 3h, 24h, 14–21 days, 5–6 weeks, and 3-month follow-up, stratified by mild or moderate adverse event severity. *Other includes self-reported fever, sleepiness, itching eyes, eye discharge, flu-like symptoms, and ear pain.

Before treatment, 18 (3%) of 536 participants reported symptoms (mainly headache, nausea, or rash). 132 adverse events were reported 24 h after treatment and 149 during the first follow-up after 14–21 days. The most reported adverse events were headache (160 [34%] of 465), abdominal pain (78 [17%]), itching (44 [9%]), and dizziness (26 [6%]). Additionally reported symptoms included itching or watering eyes and various flu-like symptoms, such as throat ache or ear pain (summarised as other; appendix pp 5–7).

Discussion

Preventive chemotherapy has been a cornerstone strategy in the fight against soil-transmitted helminth infections since the early 1990s. Nevertheless, soil-transmitted helminths remain a major public health problem, partly due to the absence of efficacious, broad-spectrum single-dose treatment options suitable for mass drug administration programmes. Moxidectin is readily available because of repurposing and is one of the few alternatives to albendazole and mebendazole and the combination of ivermectin and albendazole, which are widely used.

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• Hürlimann E
• Keller L
• Patel C
• et al.

Efficacy and safety of co-administered ivermectin and albendazole in school-aged children and adults infected with Trichuris trichiura in Côte d'Ivoire, Laos, and Pemba Island, Tanzania: a double-blind, parallel-group, phase 3, randomised controlled trial.

^, 

³²

• Palmeirim MS
• Hürlimann E
• Knopp S
• et al.

Efficacy and safety of co-administered ivermectin plus albendazole for treating soil-transmitted helminths: a systematic review, meta-analysis and individual patient data analysis.

Moxidectin might be a particularly interesting candidate because the neglected tropical disease community has voiced concerns regarding potential resistance against ivermectin because of its long history of use in mass drug administration programmes against filarial diseases.

¹⁸

• Tinkler SH

Preventive chemotherapy and anthelmintic resistance of soil-transmitted helminths—can we learn nothing from veterinary medicine?.

^,