Clinical trial NCT03981523: New Therapies and Biomarkers for Chagas Infection
Official title: New Chemotherapy Regimens and Biomarkers for Chagas Disease
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Trypanosoma Cruzi Infection
Chagas Disease
Keywords: Chagas disease
Trypanosoma cruzi
Chemotherapy
Benznidazole
Nifurtimox
Biomarkers
Bolivia
Antiparasitic Agents
Parasitic Diseases
Lead sponsor: University of Texas, El Paso
Sponsor class: OTHER
Collaborators: name: Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente (CEADES)
name: Barcelona Institute for Global Health
name: Institute of Parasitology and Biomedicine Lopez Neyra
name: U.S. Food and Drug Administration (FDA)
name: Drugs for Neglected Diseases
name: Mundo Sano Foundation
name: National Institute of Allergy and Infectious Diseases (NIAID)
First posted: 2019-06-11
Enrollment: 450
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: 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.
Primary purpose: TREATMENT

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.

Detailed 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.

Eligibility 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).

Primary outcomes:
measure: Sustained Parasitological Clearance by qPCR at End of Follow-Up (36 months)
timeFrame: up to 36 months
Secondary outcomes:
measure: Changes Over Time in the blood parasitic load by qPCR
timeFrame: 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).
measure: Changes Over Time in the Conventional Serology using parasite antigenic mixture
timeFrame: 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.
measure: Changes Over Time in the Conventional Serology using recombinant parasite antigens
timeFrame: 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.
measure: Changes Over Time in the Non-Conventional Serology Biomarker "Lytic Anti-α-Gal Antibodies"
timeFrame: 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).
measure: Changes Over Time in the Non-Conventional Serology Biomarker "Anti-KMP11 Antibodies"
timeFrame: 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).
measure: Changes in the Non-Conventional Serology Biomarker "Anti-HSP70 Antibodies"
timeFrame: 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).
measure: Changes Over Time in the Non-Conventional Serology Biomarker "Anti-PFR2 Antibodies"
timeFrame: 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).
measure: Changes Over Time in the Non-Conventional Serology Biomarker "Anti-Peptide 3973 Antibodies"
timeFrame: Days 0, 14-17, 59-62; EOT-30, EOT-600, 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).
measure: Changes Over Time in the Non-Conventional Serology Biomarker "Trypomastigote Excreted/Secreted Antigens (TESA)"
timeFrame: 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).
Other outcomes:
Locations:
city: Cochabamba
country: Bolivia
facility: Platform for the Comprehensive Care of Patients with Chagas Disease
state: Cercado
city: Tarija
country: Bolivia
facility: Platform for the Comprehensive Care of Patients with Chagas Disease
state: Cercado
city: Sucre
country: Bolivia
facility: Platform for the Comprehensive Care of Patients with Chagas Disease
Study officials:
affiliation: The University of Texas at El Paso (UTEP)
name: Igor C Almeida, D.Sc.
role: PRINCIPAL_INVESTIGATOR
affiliation: Fundación Ciencia y Estudios Aplicados para el Desarrollo en Salud y Medio Ambiente (CEADES)
name: Faustino Torrico, M.D., Ph.D
role: PRINCIPAL_INVESTIGATOR
affiliation: Barcelona Institute for Global Health
name: Joaquim Gascon, M.D., Ph.D
role: PRINCIPAL_INVESTIGATOR
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