New Therapies and Biomarkers for Chagas Infection

• Status: Active, not recruiting
• Trial end date: 2024-07-31
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Texas, El Paso
• Collaborators: Barcelona Institute for Global Health; Drugs for Neglected Diseases; Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente (CEADES); Institute of Parasitology and Biomedicine Lopez Neyra; Mundo Sano Foundation; National Institute of Allergy and Infectious Diseases (NIAID); U.S. Food and Drug Administration (FDA)
• Treatments: Benzonidazole; Nifurtimox

Criteria

Inclusion Criteria:

1. Adults, 18-50 years.

2. Weight: 88-198 pounds (40-90 Kg).

3. Individuals diagnosed as being infected with T. cruzi by conventional serology (two positive tests with different antigens) with at least one positive qualitative RT-PCR assay out of three during the screening.

4. Patient classified as being in the indeterminate form (without clinical manifestations) or early cardiac form (Kushnir 1) of chronic Chagas disease.

5. Signed informed consent form (ICF).

Exclusion Criteria:

1. Clinical signs of dilated cardiomyopathy (dyspnea, legs' edema, syncope, pulmonary crackles). Patients with an EKG showing the following characteristics: sinus tachycardia or atrial fibrillation, ventricular arrhythmias, left atrial enlargement, left bundle-branch block (LBBB) accompanied by right axis deviation (RAD), and/or patients with Calculation of Fridericia's corrected QT interval (QTcF) > 450ms, a formula for calculating the QT interval on an electrocardiogram (ECG).

2. History of Chagas disease treatment with BZN or NFX or any triazole drug(s) in the last five years.

3. Clinical signs and/or symptoms of digestive form of Chagas disease, which is characterized by the presence of two or more of the following criteria *:

1. Excessive exertion in at least 25% of bowel movements

2. Hard stools in at least 25% of stools (type 1-2 of Bristol)

3. Feeling of incomplete evacuation in at least 25% of bowel movements

4. Feeling of obstruction or anorectal block in at least 25% of bowel movements

5. Manual maneuvers to facilitate defecation in at least 25% of bowel movements

6. Less than 3 complete spontaneous stools per week

• Criteria must be met for at least the last three months and symptoms must have been started for at least six months before diagnosis.

4. Hypersensitivity to the active substances (BZN or NFX) or to the excipient.

5. Previous diagnosis of porphyria.

6. Any other acute or chronic health conditions that in the opinion of the PI, may interfere with the efficacy and/or safety evaluation of the study drug.

7. Formal contraindication to BZN or NFX.

8. Any concomitant or anticipated use of drugs that are contraindicated with the use of BZN or NFX.

9. Individuals currently known to abuse alcohol and/or drugs. Furthermore, if throughout the course of the study the team becomes aware that a participant is using drugs/alcohol that participant will be excluded from the treatment but will continue with the follow-up visits. The study manual outlines how abuse and dependence will be measured for this study.

10. Pregnancy. Females of childbearing potential will be required to complete a pregnancy test prior to enrollment and throughout the course of treatment.

11. Women in reproductive age must have a negative serum pregnancy test at screening, must not be breastfeeding, and consistently use and/or have partner consistently use a highly effective contraceptive method during the entire treatment phase of the trial.

12. Transaminases (alanine aminotransferase-ALT and aspartate aminotransferase- AST). AST must be within the normal range, within an acceptable margin of 25% above the upper limit of normality for both, according to the insert of the biochemical kit being used in this study.

13. Creatinine must be within an acceptable range, within an acceptable margin of 10% above the upper limit of normality, according to the insert of the biochemical kit being used. The normal ranges of transaminases (ALT and AST) and creatinine are defined by the inserts of the commercial biochemical kits selected to be used in the present study. All treatment centers (Chagas Platforms in Cochabamba, Sucre, and Tarija) are going to use the same biochemical kits. The participating clinical laboratories at the Platforms (in Cochabamba, Sucre, and Tarija) will use the Common Terminology Criteria for Adverse Events (CTCAE, v.5.0; ttps://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick _reference_5x7.pdf).

14. Total bilirubin must be within the normal range, within an acceptable margin of 15% above the upper limit of normality for both sexes, according to the insert of the biochemical kit being used in this study.

15. For other standard exclusion criteria, a detailed explanation for each criterion is provided in the Manual of Operations and Procedures (MOP).