New chemotherapy regimens and biomarkers for Chagas disease: the rationale and design of the TESEO study, an open-label, randomised, prospective, phase-2 clinical trial in the Plurinational State of Bolivia

Abstract

IntroductionChagas disease (CD) affects ~7 million people worldwide. Benznidazole (BZN) and nifurtimox (NFX) are the only approved drugs for CD chemotherapy. Although both drugs are highly effective in acute and paediatric infections, their efficacy in adults with chronic CD (CCD) is lower and variable. Moreover, the high incidence of adverse events (AEs) with both drugs has hampered their widespread use. Trials in CCD adults showed that quantitative PCR (qPCR) assays remain negative for 12 months after standard-of-care (SoC) BZN treatment in ~80% patients. BZN pharmacokinetic data and the nonsynchronous nature of the proliferative mammal-dwelling parasite stage suggested that a lower BZN/NFX dosing frequency, combined with standard or extended treatment duration, might have the same or better efficacy than either drug SoC, with fewer AEs.Methods and analysisNew ThErapies and Biomarkers for ChagaS infEctiOn (TESEO) is an open-label, randomised, prospective, phase-2 clinical trial, with six treatment arms (75 patients/arm, 450 patients). Primary objectives are to compare the safety and efficacy of two new proposed chemotherapy regimens of BZN and NFX in adults with CCD with the current SoC for BZN and NFX, evaluated by qPCR and biomarkers for 36 months posttreatment and correlated with CD conventional serology. Recruitment of patients was initiated on 18 December 2019 and on 20 May 2021, 450 patients (study goal) were randomised among the six treatment arms. The treatment phase was finalised on 18 August 2021. Secondary objectives include evaluation of population pharmacokinetics of both drugs in all treatment arms, the incidence of AEs, and parasite genotyping.Ethics and disseminationThe TESEO study was approved by the National Institutes of Health (NIH), U.S. Food and Drug Administration (FDA), federal regulatory agency of the Plurinational State of Bolivia and the Ethics Committees of the participating institutions. The results will be disseminated via publications in peer-reviewed journals, conferences and reports to the NIH, FDA and participating institutions.Trial registration numberNCT03981523.

Specific Recognition of β-Galactofuranose-Containing Glycans of Synthetic Neoglycoproteins by Sera of Chronic Chagas Disease Patients

“…In adults, the kinetics of Ch anti-α-Gal Ab seroconversion seems to be slower, as observed after one-year follow-up in two recent clinical trials [14,15]. However, a long-term (three-year) follow-up of treated patients is currently being performed in an adult population using tGPI-mucins and synthetic α-Gal-based antigens to evaluate the seroconversion kinetics in adults with CCD [16]. Taken together, these studies suggest that the seroconversion of Abs against parasite-derived carbohydrate antigens could by useful for determining cure following chemotherapy.…”

A Branched and Double Alpha-Gal-Bearing Synthetic Neoglycoprotein as a Biomarker for Chagas Disease

“…Of course, this preliminary observation with NGP11b needs to be expanded with a larger cohort of treated patients to validate this NGP to be used in clinical settings. To this end, our ongoing phase II clinical trial in Bolivia, named TESEO (ClinicalTrials.gov identifier NCT03981523), will evaluate NGP11b and several other α-Gal-bearing NGPs in the coming years as BMK(s) for early assessment of therapeutic outcomes of CCD [ 52 ].…”

The endoplasmic reticulum of trypanosomatids: An unrevealed road for chemotherapy

“…Such treatments are usually indicated for acute cases but their efficacy in adults with chronic CD is lower and variable. Moreover, the high incidence of adverse events with both drugs has hampered their widespread use (Alonso-Veja et al, 2021) Leishmaniasis is a complex sandfly-borne disease caused by different species of protozoan belonging to the genus Leishmania. These illnesses infect 12 million people worldwide and are present in approximately 90 countries, in the tropic and subtropics regions of the Old World (Asia, the Middle East, Africa and southern Europe) and the New World (Mexico, Central America and South America) (Centers for Disease Control and Prevention, 2020;World Health Organization, 2022b).…”