New Therapies and Biomarkers for Chagas Infection

NCT03981523 | Completed Phase 2 DMC FDA Drug

• 2 other identifiers: 743474U01AI129783
• Study Type: interventional
• Target: 450
• Locations: 1 country
• Sites: 3

Brief 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.

Conditions

Trypanosoma Cruzi Infection; Chagas Disease

Keywords

Chagas disease; Trypanosoma cruzi; Chemotherapy; Benznidazole; Nifurtimox; Biomarkers; Bolivia; Antiparasitic Agents; Parasitic Diseases

Outcome Measures

Primary Outcomes (1)

• Sustained Parasitological Clearance by qPCR at End of Follow-Up (36 months)

  The primary efficacy endpoint or measure is a binary 'cured' (success), 'not-cured' (failure) variable based on a total of eight qPCR timepoints from end-of-treatment (EOT) up to 36 months of follow-up. Each of the timepoints includes a total of three sequential qPCR examinations on blood samples collected during one visit. Therefore, for a patient to be considered "cured", a total of 24 negative qPCR results should be documented. Blood samples to be collected at EOT (30, 60, or 90 days), and at 4, 6, 12, 18, 24, 30 and 36 months of follow-up (with a window period of +/- 7 days from 4 to 12 months and +/- 14 days from 18 to 36 months).

  up to 36 months

Secondary Outcomes (9)

• Changes Over Time in the blood parasitic load by qPCR

  Days 14-17, 59-62; EOT-30, EOT-60, and EOT-90; and months 4, 6, 12, 18, 24, 30, and 36 during follow-up (with a window period of +/- 7 days from 4 to 12 months and +/- 14 days from 18 to 36 months).

• Changes Over Time in the Conventional Serology using parasite antigenic mixture

  Day -28; EOT-30, EOT-60, and EOT-90; and months 4, 6, 12, 18, 24, 30, and 36 (with a window period of +/- 7 days from 4 to 12 months and +/- 14 days from 18 to 36 months) during follow-up.

• Changes Over Time in the Conventional Serology using recombinant parasite antigens

  Day -28; EOT-30, EOT-60, and EOT-90; and months 4, 6, 12, 18, 24, 30, and 36 (with a window period of +/- 7 days from 4 to 12 months and +/- 14 days from 18 to 36 months) during follow-up.

• Changes Over Time in the Non-Conventional Serology Biomarker "Lytic Anti-α-Gal Antibodies"

  Days 0, 14-17, 59-62; EOT-30, EOT-60, and EOT-90; and at months 4, 6, 12, 18, 24, 30, and 36 during follow-up (with a window period of +/- 7 days from 4 to 12 months and +/- 14 days from 18 to 36 months).

• Changes Over Time in the Non-Conventional Serology Biomarker "Anti-KMP11 Antibodies"

  Days 0, 14-17, 59-62; EOT-30, EOT-60, and EOT-90; and at months 4, 6, 12, 18, 24, 30, and 36 during follow-up (with a window period of +/- 7 days from 4 to 12 months and +/- 14 days from 18 to 36 months).

Study Arms (6)

BZN-60

EXPERIMENTAL

150 mg twice a day for 60 days.

Drug: Benznidazole

BZN-30

EXPERIMENTAL

150 mg once a day for 30 days.

Drug: Benznidazole

BZN-90

EXPERIMENTAL

150 mg once a day for 90 days.

Drug: Benznidazole

NFX-60

EXPERIMENTAL

240 mg twice a day for 60 days.

Drug: Nifurtimox

NFX-30

EXPERIMENTAL

240 mg twice a day for 30 days.

Drug: Nifurtimox

NFX-90

EXPERIMENTAL

240 mg once a day for 90 days.

Drug: Nifurtimox

Interventions

Benznidazole DRUG

50 mg and 100 mg tablet taken orally

Also known as: P01CA02, Abarax, Radanil, Rochagan

BZN-30; BZN-60; BZN-90

Nifurtimox DRUG

120 mg tablet taken orally

Also known as: Lampit, P01CC01, QP51AC01

NFX-30; NFX-60; NFX-90

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Adults, 18-50 years.
• Weight: 88-198 pounds (40-90 Kg).
• 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.
• Patient classified as being in the indeterminate form (without clinical manifestations) or early cardiac form (Kushnir 1) of chronic Chagas disease.
• Signed informed consent form (ICF).

You may not qualify if:

• 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).
• History of Chagas disease treatment with BZN or NFX or any triazole drug(s) in the last five years.
• 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 \*:
• Excessive exertion in at least 25% of bowel movements
• Hard stools in at least 25% of stools (type 1-2 of Bristol)
• Feeling of incomplete evacuation in at least 25% of bowel movements
• Feeling of obstruction or anorectal block in at least 25% of bowel movements
• Manual maneuvers to facilitate defecation in at least 25% of bowel movements
• 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.
• Hypersensitivity to the active substances (BZN or NFX) or to the excipient.
• Previous diagnosis of porphyria.
• 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.
• Formal contraindication to BZN or NFX.
• Any concomitant or anticipated use of drugs that are contraindicated with the use of BZN or NFX.

Sponsors & Collaborators

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

Study Sites (3)

Platform for the Comprehensive Care of Patients with Chagas Disease

Cochabamba, Cercado, Bolivia

Location

Platform for the Comprehensive Care of Patients with Chagas Disease

Tarija, Cercado, Bolivia

Location

Platform for the Comprehensive Care of Patients with Chagas Disease

Sucre, Bolivia

Location

Related Publications (20)

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  BACKGROUND

• Alonso-Vega C, Urbina JA, Sanz S, Pinazo MJ, Pinto JJ, Gonzalez VR, Rojas G, Ortiz L, Garcia W, Lozano D, Soy D, Maldonado RA, Nagarkatti R, Debrabant A, Schijman A, Thomas MC, Lopez MC, Michael K, Ribeiro I, Gascon J, Torrico F, Almeida IC. 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. BMJ Open. 2021 Dec 31;11(12):e052897. doi: 10.1136/bmjopen-2021-052897.

  PMID: 34972765 DERIVED

MeSH Terms

Conditions

Chagas Disease; Parasitic Diseases

Interventions

benzonidazole; Nifurtimox

Condition Hierarchy (Ancestors)

Trypanosomiasis; Euglenozoa Infections; Protozoan Infections; Infections; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Nitrofurans; Nitro Compounds; Organic Chemicals; Thiazines; Sulfur Compounds; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Study Officials

• Igor C Almeida, D.Sc.

  The University of Texas at El Paso (UTEP)

  PRINCIPAL INVESTIGATOR

• Faustino Torrico, M.D., Ph.D

  Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente (CEADES)

  PRINCIPAL INVESTIGATOR

• Joaquim Gascon, M.D., Ph.D

  Barcelona Institute for Global Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor

Model Details: Three of 6 parallel groups will receive one of three different oral benznidazole (BZN) dosing regimens and the other three will receive one of the three different nifurtimox (NFX) regimens.

Study Record Dates

• First Submitted: April 8, 2019
• First Posted: June 11, 2019
• Study Start: December 18, 2019
• Primary Completion: May 29, 2024
• Study Completion: May 31, 2024
• Last Updated: July 17, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

BO (3)