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Efficacy and safety of tribendimidine versus praziquantel against Opisthorchis viverrini in Laos: an open-label, randomised, non-inferiority, phase 2 trial

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Summary

Background

Praziquantel is the only option for treatment of the liver fluke infection Opisthorchis viverrini. Tribendimidine could be an alternative drug. We aimed to assess the efficacy and safety of a single, oral dose of tribendimidine, compared with praziquantel administered in two doses, in participants with O viverrini infection.

Method

We did an open-label, randomised, non-inferiority, phase 2 trial in children (8–14 years) and adolescents and adults (≥15 years) in Champasack province, southern Laos. Participants infected with O viverrini were randomly assigned (1:1), via a computer-generated block-randomisation procedure (block sizes of two, four, and six), to receive a single, oral dose of tribendimidine (200 mg for children, 400 mg for adolescents and adults) or two oral doses of praziquantel (50 mg/kg bodyweight and 25 mg/kg bodyweight, 6 h apart). Physicians assessing adverse events and laboratory personnel were masked to treatment allocation, but the investigators administering treatment and the participants could have recognised the treatment group based on differences in the number, appearance, and odour of the tablets. The primary outcomes were cure rate, defined as no parasite eggs in stool at 3 weeks' follow-up, and egg reduction rate. We did available-case analysis of all participants with primary endpoint data. The non-inferiority margin for the difference in cure rates between the groups was pre-specified as −3 percentage points. Adverse events were monitored at 3 h and 24 h after treatment. This trial is registered, number ISRCTN96948551.

Findings

Between Feb 1, and April 30, 2014, we assigned 607 participants with confirmed O viverrini infection to receive tribendimidine (n=300) or praziquantel (n=307). 11 participants (five in the tribendimidine group and six in the praziquantel group) did not provide stool samples at 3 weeks' follow-up and were excluded from the available-case analysis. 276 (93·6%) of 295 participants in the tribendimidine group were cured compared with 293 (97·3%) of 301 participants in the praziquantel group. The difference in cure rates between the two groups was −3·8 percentage points (95% CI −7·1 to −0·4), thus the lower limit of the confidence interval exceeded the non-inferiority margin. In both treatment groups, egg reduction rates were 99·9%. Adverse events were of mild and moderate intensity and were more frequent in the praziquantel group than in the tribendimidine group (odds ratio 4·5, 95% CI 3·2–6·3; p<0·0001). The most frequent adverse events were headache, vertigo, nausea, and fatigue.

Interpretation

Tribendimidine has a slightly lower cure rate than praziquantel and non-inferiority was not shown. However, tribendimidine has a similar egg reduction rate to praziquantel and leads to fewer adverse events and thus might complement praziquantel in O viverrini control programmes, particularly in settings co-endemic for hookworm.

Funding

Joint Global Health Trials scheme from the Wellcome Trust, Department for International Development, and Medical Research Council.

Introduction

The liver fluke Opisthorchis viverrini is a major public health problem in southeast Asia, particularly in Thailand, Laos, and Cambodia.1 Consumption of raw and fermented fish containing O viverrini in infectious parasite stages is the main route of infection.2 O viverrini infection causes serious hepatobiliary diseases, such as obstructive jaundice and ascending cholangitis.3 Studies4, 5, 6 have implicated O viverrini infection in cholangiocarcinoma, a potentially fatal bile duct cancer. It has been estimated that 67·3 million people are at risk of acquiring an O viverrini infection7, 8 and 10 million people are infected with O viverrini, 2 million of whom live in Laos.1 High prevalences of more than 50% are observed in rural communities in the central and southern provinces of the country.9, 10 Praziquantel is the only available treatment for infection.

In 2004, tribendimidine was registered for use in human beings by the Chinese Food and Drug Administration against infections with hookworm and Ascaris lumbricoides.11 Tribendimidine is highly efficacious against these nematode infections and has a good safety profile when used at the recommended single oral doses of 200 mg for children aged between 4 years and 14 years and 400 mg for adolescents and adults aged 15 years or older.11 In the past decade, tribendimidine has shown promising activity against the liver flukes O viverrini and Clonorchis sinensis in preclinical laboratory studies.12, 13 Furthermore, tribendimidine has shown satisfactory efficacy and good safety profiles in open-label, exploratory, proof-of-concept trials.14, 15 A single, oral dose of 400 mg tribendimidine cured 19 (79%) of 24 adult participants with O viverrini infection (compared with praziquantel, which cured 14 [64%] of 22 participants).14 In a similar trial,15 a single, oral dose of tribendimidine cured 11 (44%) of 24 adults infected with the closely related liver fluke C sinensis (compared with praziquantel, which cured 14 [56%] of 25 participants).

Research in context

Evidence before this study

We searched PubMed without language restrictions between Jan 1, 1970, and March 1, 2017, using the search term “tribendimidine” in combination with “opisthorchiasis”, “clonorchiasis”, and “liver fluke”. Previous studies included exploratory clinical trials and dose-finding studies of liver fluke infections. These studies showed promising efficacy for tribendimidine against Opisthorchis viverrini and Clonorchis sinensis. The drug was found to be well tolerated.

Added value of this study

We investigated the efficacy and safety of tribendimidine (single oral dose of 200 mg for children aged 8–14 years and 400 mg for adults and adolescents aged ≥15 years) compared with praziquantel (75 mg/kg bodyweight in two doses) against O viverrini infection. 293 (97·3%) of 301 participants treated with praziquantel and 276 (93·6%) of 295 participants treated with tribendimidine were cured. The difference in cure rates between the groups was −3·8 percentage points (95% CI −7·1 to −0·4). We set our non-inferiority margin at −3 percentage points; thus, non-inferiority for tribendimidine could not be shown because the lower bound of the 95% CI for the difference in cure rates between the groups exceeded this margin. Both treatments resulted in high egg reduction rates (>99%). Participants treated with tribendimidine had significantly fewer and milder adverse events than participants treated with praziquantel. This study is the first direct comparison of the two drugs, showing that tribendimidine has a superior safety profile and similar efficacy to praziquantel.

Implications of all the available evidence

Tribendimidine is a potential candidate to complement praziquantel in the treatment of O viverrini infection. Given that the evidence has come from individuals with light O viverrini infections, further studies are needed in people with moderate and severe liver fluke infections.

In 2016, we presented the results of two randomised, dose-ranging, phase 2 trials assessing the efficacy and safety of tribendimidine against O viverrini.16 In adult and adolescent participants, high cure rates (>80%) and egg reduction rates (>99%) were observed with doses of 200–600 mg tribendimidine. In children, single oral doses between 100 mg and 400 mg resulted in cure rates of greater than 77% and egg reduction rates of 99%. All treatment doses in adults and children were well tolerated. Adverse events were transient and mostly mild.

We aimed to investigate the efficacy and safety of a single, oral dose of tribendimidine (400 mg in adolescents and adults aged ≥15 years and 200 mg in children aged 8–14 years), compared with two doses of praziquantel (50 mg/kg bodyweight followed by 25 mg/kg bodyweight), against O viverrini infection.

Section snippets

Study design and participants

We did a phase 2, two-group, randomised, open-label, non-inferiority trial in three villages (Pakhuay, Morphu, and Phakpheo) in Champasack province, southern Laos. 2 days before screening, participants were invited to join a meeting held at the village pagoda in the presence of the directors of the provincial health department, district health office, provincial malaria station, and the village authority. After the meeting, eligible participants (aged >8 years) were invited to participate and

Results

Between Feb 1, and April 30, 2014, we enrolled 1800 children, adolescents, and adults, 1169 of whom were present during the registration process and gave informed consent (figure). 685 participants were infected with O viverrini and 607 were randomly assigned to receive either tribendimidine (n=300) or praziquantel (n=307). 11 participants (five in the tribendimidine group and six in the praziquantel group) were lost to follow-up. 48 participants did not receive the second dose of praziquantel

Discussion

Praziquantel is the only drug available to treat the liver fluke infection O viverrini. Alternative drugs are urgently needed, but no candidates are in development. One exception is the Chinese anthelmintic tribendimidine, which has activity against nematodes and the liver flukes O viverrini and C sinensis. This head-to-head comparison of tribendimidine with praziquantel is the latest in a series of clinical trials of tribendimidine against liver fluke infections.

We did not show non-inferiority

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