Efficacy and safety of fexinidazole for treatment of chronic indeterminate Chagas disease (FEXI-12): a multicentre, randomised, double-blind, phase 2 trial.

BACKGROUND: More than six million people worldwide, particularly in vulnerable communities in Latin America, are infected with Trypanosoma cruzi, the causative agent of Chagas disease. Only a small portion have access to diagnosis and treatment. Both drugs used to treat this chronic, neglected infection, benznidazole and nifurtimox, were developed more than 50 years ago, and adverse drug reactions during treatment pose a major barrier, causing 20% of patients to discontinue therapy. Fexinidazole proved efficacious in an earlier, interrupted clinical trial, but the doses evaluated were not well tolerated. The present study evaluated fexinidazole at lower doses and for shorter treatment durations. METHODS: In this randomised, double-blind, phase 2 trial, we included adult patients (18-60 years old) with confirmed T cruzi infection by serology and PCR and without signs of organ involvement. We evaluated three regimens of fexinidazole-600 mg once daily for 10 days (6·0 g total dose), 1200 mg daily for 3 days (3·6 g), and 600 mg daily for 3 days followed by 1200 mg daily for 4 days (6·6 g)-and compared them with a historical placebo control group (n=47). The primary endpoint was sustained negative results by PCR at end of treatment and on each visit up to four months of follow-up. This study is registered with ClinicalTrials.gov, NCT03587766, and EudraCT, 2016-004905-15. FINDINGS: Between Oct 16, 2017, and Aug 7, 2018, we enrolled 45 patients (n=15 for each group), of whom 43 completed the study. Eight (19%) of 43 fexinidazole-treated patients reached the primary endpoint, compared with six (13%) of 46 in the historical control group. Mean parasite load decreased sharply following treatment but rebounded beginning 10 weeks after treatment. Five participants had seven grade 3 adverse events: carpal tunnel, sciatica, device infection, pneumonia, staphylococcal infection, and joint and device dislocation. Two participants discontinued treatment due to adverse events unrelated to fexinidazole. INTERPRETATION: The fexinidazole regimens in this study had an acceptable safety profile but did not prove effective against T cruzi infection. Development of fexinidazole monotherapy for treating T cruzi infection has been stopped. FUNDING: The Drugs for Neglected Diseases initiative.

Preventing chronic malnutrition in children under 2 years in rural Angola (MuCCUA trial): protocol for the economic evaluation of a three-arm community cluster randomised controlled trial.

INTRODUCTION: Chronic malnutrition is a serious problem in southern Angola with a prevalence of 49.9% and 37.2% in the provinces of Huila and Cunene, respectively. The MuCCUA (Mother and Child Chronic Undernutrition in Angola) trial is a community-based randomised controlled trial (c-RCT) which aims to evaluate the effectiveness of a nutrition supplementation plus standard of care intervention and a cash transfer plus standard of care intervention in preventing stunting, and to compare them with a standard of care alone intervention in southern Angola. This protocol describes the planned economic evaluation associated with the c-RCT. METHODS AND ANALYSIS: We will conduct a cost-efficiency and cost-effectiveness analysis nested within the MuCCUA trial with a societal perspective, measuring programme, provider, participant and household costs. We will collect programme costs prospectively using a combined calculation method including quantitative and qualitative data. Financial costs will be estimated by applying activity-based costing methods to accounting records using time allocation sheets. We will estimate costs not included in accounting records by the ingredients approach, and indirect costs incurred by beneficiaries through interviews, household surveys and focus group discussions. Cost-efficiency will be estimated as cost per output achieved by combining activity-specific cost data with routine data on programme outputs. Cost-effectiveness will be assessed as cost per stunting case prevented. We will calculate incremental cost-effectiveness ratios comparing the additional cost per improved outcome of the different intervention arms and the standard of care. We will perform sensitivity analyses to assess robustness of results. ETHICS AND DISSEMINATION: This economic evaluation will provide useful information to the Angolan Government and other policymakers on the most cost-effective intervention to prevent stunting in this and other comparable contexts. The protocol was approved by the República de Angola Ministério da Saúde Comité de Ética (27C.E/MINSA.INIS/2022). The findings of this study will be disseminated within academia and the wider policy sphere. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT05571280).