New Therapies and Biomarkers for Chagas Infection — TESEO  

Chagas Disease Clinical Trial

Official title: New Chemotherapy Regimens and Biomarkers for Chagas Disease

Status Active, not recruiting

Clinical Trial Summary

Chagas disease (CD) is an endemic zoonotic disease with a significant global impact. Current approved treatments for CD (benznidazole (BZN) and nifurtimox (NFX)) were developed in the 1970s with regimens and dosing intervals derived from decades-old patient series and with very limited direct comparisons. Treatment recommendations vary significantly from country to country and the comparative evidence-base with the current treatment regimens is limited.

The reported efficacy of both drugs in patients with T. cruzi infection is variable and depends on the disease stage, the drug dose, the age of patients, and the infecting T. cruzi strain or genotype. Due to a therapeutic failure of at least 20% after 12 months in chronic patients and the high rate of adverse events, together with the recent data that suggest that we may be overdosing patients, we propose to test new dosing regimens of these two old compounds.

Hypotheses:

• Lowering the frequency of drug dosing of BZN and NFX, the plasma drug levels of the drugs within the therapeutic range will be maintained.

• The duration of treatment with BZN or NFX may be related to the effectiveness of these drugs.

• Blood levels of the proposed biomarkers will significantly diminish or became negative after a relatively short interval after treatment.

Clinical Trial Description

Chagas disease (CD) is an endemic zoonotic disease caused by the protozoan parasite, T. cruzi. It affects 8-10 million people in Latin America and is a worldwide public health issue due to migratory flows. CD has a significant economic impact. Recently, a study showed that the global costs for CD are US$7-19 billion per year, similar or even higher to those of other important diseases such as rotavirus infection or cervical cancer. Treatment of chronic CD (CCD) has been hampered, unlike other illnesses, by the paramount importance given to the autoimmune theory of the disease that prevailed for many years. As a result, several generations of health professionals were trained in the belief that CCD had no treatment. As a consequence, currently, most (>99%) chronically infected people are still not treated with specific antiparasitic drugs, and the research and development for new, more effective drugs was overlooked for many years, until very recently. Nowadays, the key role of the parasite persistence in the pathophysiology of CD is recognized, as well as the need for specific treatment.

Current approved specific treatments for CD include nifurtimox (NFX) and benznidazole (BZN) and the recommended dosing regimens are 5 mg/Kg/day divided into two doses (2.5 mg/Kg b.i.d) given for 60 days for BZN, and 8 mg/Kg divided into three equal daily doses (2.7 mg/Kg t.i.d.) given for 90 days for NFX. The efficacy of both drugs in patients with T. cruzi infection is highly variable and depends on the disease stage, the drug dose, the age of patients, and the infecting T. cruzi strain or genotype. Moreover, the high rate of adverse events hampers their standard use in the field. Recent studies show that at the current doses of both drugs, more than 70% of patients suffer mild/moderate reactions and around 10-27% experience serious ones, forcing patients to stop the treatment and take appropriate medications for the adverse events. Data on the pharmacokinetics (PK) of BZN and NFX are limited and there are no recent data on PK of NFX in adults with chronic CD. Moreover, due to a lack of early BMKs of therapeutic efficacy, the true efficacy of these drugs remains unknown. Seroconversion using conventional serology (CS) is often long-term (~10-20 years) or incomplete, and a reduction in T. cruzi-specific antibody titers often takes many years, rendering the evaluation of response to treatment insensitive and lengthy, and therefore impractical in clinical settings. The need for new, safer, and more efficacious drugs against T. cruzi as well as early BMKS of therapeutic efficacy are the major challenges in the treatment of CD, particularly in chronic adults.

With this project, the investigators aim to achieve specific knowledge about the safety and efficacy of new dosing regimens for BZN and NFX. The proposed new regimens for these drugs are based on recent data that suggest that with half of the dosing frequency the levels of BZN can be maintained in the therapeutic range of this drug, which could conceivably reduce the appearance of adverse events while maintaining antiparasitic efficacy. At the same time, the investigators plan to evaluate whether the drug efficacy will be maintained if the investigators reduce the length of treatment with BZN or NFX to 30 days. Furthermore, the investigators also plan to evaluate whether the efficacy of the treatment with BZN or NFX is improved by increasing its duration to 90 days and to evaluate novel potential BMKs of response to specific treatment and eventual parasitological cure in CCD patients. The information obtained in this study would also allow for better-designed clinical trials with drug combinations, in which NFX and BZN will have a central role.

The results will be disseminated via publications in peer-reviewed journals, conferences, and reports to the NIH, FDA, and participating institutions. The investigators of this study are aware of and have agreed to abide by the principles for sharing research resources as described by NIH in "Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Programs." Accordingly, resources developed in this study will be available to the scientific community as soon as the intellectual property of these resources and/or research tools have been protected or disclosed in publications. In the event that a specific research tool is requested from the TESEO investigators and is available, it will be shared with members of the scientific community. Data sharing not applicable as no datasets have been generated and/or analysed for this study yet. However, once the datasets resulting from this study are available, they will be disseminated via publications in peer-reviewed journals, national and international conferences, and reports to the NIH, FDA, and participating institutions. ;

Related Conditions & MeSH terms

• Chagas Disease
• Infections
• Trypanosoma Cruzi Infection

• NCT number: NCT03981523
• Study type: Interventional
• Source: University of Texas, El Paso
• Status: Active, not recruiting
• Phase: Phase 2
• Start date: December 18, 2019
• Completion date: July 31, 2025