A Phase 2 interventional study of Benznidazole and Nifurtimox in Trypanosoma Cruzi Infection and Chagas Disease, sponsored by University of Texas, El Paso. Completed at 3 sites in Bolivia. Open to participants aged 18 Years to 50 Years. Per ClinicalTrials.gov, last updated 2024-07-17.
Sponsored by University of Texas, El Paso · Phase 2, Interventional, and Treatment
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:
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.
73 studies on the registry are indexed under Chagas Disease; 5 are open to participants now.
This study's enrollment of 450 is above the median of 87 across 49 interventional studies indexed under Chagas Disease.
Browse Chagas Disease studies →University of Texas, El Paso is the lead sponsor of 21 studies on the registry; 11 are open to participants now.
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Go through the criteria one by one — yes, no or not sure — and take the list to your doctor or the study team. Kept in this browser only.
Exclusion Criteria:
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 *:
Less than 3 complete spontaneous stools per week
Underlined terms in the criteria open these too. Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
The US National Cancer Institute’s scale of how severe an adverse event is — any unwanted medical event during a study, such as a symptom, an illness or an abnormal test result, whether or not a treatment caused it. Whether it did is judged separately.
“Side effects of earlier treatment resolved to grade 1 or less” means they have settled to mild or gone.
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
You can keep asking questions during the study, you are told of new information that matters, and you can choose to leave at any time.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ECG (electrocardiogram)
A recording of the heart’s electrical activity, taken with stickers on the chest, arms and legs. It takes a few minutes and does not hurt.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
QT and QTc
On an ECG, the QT interval is the time the heart’s lower chambers take to activate electrically and recover in each beat. QTc is that time adjusted for heart rate (QTcF by Fridericia’s formula, QTcB by Bazett’s). Some medicines lengthen it, and a long QTc can raise the risk of a dangerous heart rhythm.
The study may name a correction formula and a limit in milliseconds, often around 450–480.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Hypersensitivity
An allergy, or another reaction of the immune system, to a substance. “Hypersensitivity to the study drug” means a known allergic reaction to it — not every side effect a medicine can have.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Excipients
The other ingredients in a medicine besides the active drug, such as fillers, colours or preservatives.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraindication
A reason a treatment, test or procedure should not be given to a particular person, such as an allergy, another illness or a medicine they take.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Childbearing potential
Able to become pregnant: from the first period until menopause, unless permanently unable to through surgery (removal of the womb, or of both ovaries or both fallopian tubes).
Criteria for people of childbearing potential usually ask for a negative pregnancy test and for contraception during the study and for a time after it.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Contraception
Ways of preventing pregnancy. “Highly effective” methods fail less than 1% of the time a year when used correctly — for example an IUD or an implant.
Criteria usually say which methods count and how long to keep using them after the last dose, sometimes for male participants too. Some studies accept a partner’s vasectomy if it was confirmed successful and that person is the participant’s only sexual partner.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
ALT and AST (liver enzymes)
Two enzymes measured in a routine blood test of the liver. Higher levels can mean the liver is under strain or damaged. SGPT and SGOT are older names for ALT and AST.
Criteria usually give a limit as a multiple of the upper limit of normal (ULN), often higher when cancer has spread to the liver.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
CTCAE grade
The US National Cancer Institute’s scale of how severe an adverse event is — any unwanted medical event during a study, such as a symptom, an illness or an abnormal test result, whether or not a treatment caused it. Whether it did is judged separately.
“Side effects of earlier treatment resolved to grade 1 or less” means they have settled to mild or gone.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
Bilirubin
A yellow substance made when red blood cells are broken down, which the liver clears. A high level can mean a problem with the liver or the bile ducts.
Criteria often allow more for people with Gilbert’s syndrome, a harmless inherited condition that raises bilirubin.
Explained by clinicaltrials.gg, not part of the registry record. The study team decides who can take part.
150 mg twice a day for 60 days.
Drug: Benznidazole
150 mg once a day for 30 days.
Drug: Benznidazole
150 mg once a day for 90 days.
Drug: Benznidazole
240 mg twice a day for 60 days.
Drug: Nifurtimox
240 mg twice a day for 30 days.
Drug: Nifurtimox
240 mg once a day for 90 days.
Drug: Nifurtimox
50 mg and 100 mg tablet taken orally
Also known as: P01CA02, Abarax, Radanil, Rochagan
120 mg tablet taken orally
Also known as: Lampit, P01CC01, QP51AC01
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).
Time frame: up to 36 months
Changes Over Time in the blood parasitic load by qPCR
Evaluate changes over time in blood parasitic load as measured by qPCR. The unit for the qPCR is parasite equivalents/milliliter of blood (Par. Eq./mL). The limit of detection (LOD) and limit of quantification (LOQ) for the qPCR assay is 0.69 and 1.5 Par. Eq./mL blood, respectively. Kaplan-Meier survival curves will be drawn to depict the time-to-reappearance of blood parasitic load for patients who have cleared blood parasitic load at EOT (as such this is a time-to-relapse for 'success' patients) across treatment groups. A discrete-time survival model will be used to analyze this event time data. Change in parasite load over time assessed at days 14-17, 59-62, and EOT (30, 60, or 90 days), according to the treatment arm, and months 4, 6, 12, 18, 24, 30, and 36 of follow-up (with a window period of +/- 7 days from 4 to 12 months and +/- 14 days from 18 to 36 months), as measured by qPCR.
Time frame: 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
Evaluate changes over time in serological titers and incidence of negative seroconversion through conventional serology. Chagas disease serology commercial kit using a parasite antigenic mixture (lysate) will be used to perform this analysis. Serum samples from all timepoints in the study for each patient will be analyzed in the same ELISA plate to avoid bias due to interassay variations. Generalized linear mixed-effects models will be used to evaluate the conventional serological response over time. The dependent variable in both models will be a binary conventional serology parameter. The treatment arm will be included in the model as a fixed effect. The significance of the treatment covariate will be tested at the 0.05 two-sided significance level with Likelihood Ratio Test.
Time frame: 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
Evaluate changes over time in serological titers and incidence of negative seroconversion through conventional serology. Chagas disease serology commercial kit using recombinant parasite antigens will be used to perform this analysis. Serum samples from all timepoints in the study for each patient will be analyzed in the same ELISA plate to avoid bias due to interassay variations. Generalized linear mixed-effects models will be used to evaluate the conventional serological response over time. The dependent variable in both models will be a binary conventional serology parameter. The treatment arm will be included in the model as a fixed effect. The significance of the treatment covariate will be tested at the 0.05 two-sided significance level with Likelihood Ratio Test.
Time frame: 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"
Evaluate changes over time in the non-conventional serology biomarker (BMK) "Lytic Anti-α-Gal Antibodies" and incidence of negative seroconversion for it, as measured by chemiluminescent (CL)-ELISA using T. cruzi tGPI-mucins as antigens. CL-ELISA unit is the Titer (T). T is the ratio of the relative luminescence units (RLU) of the tested serum to the cutoff value (CV). The CV is calculated by defining the upper prediction limit (as standard deviation, SD), multiplied by a factor according to the number of negative controls (NC) and a confidence interval of 99.5%. For each test plate in which six NC are included, the CV is defined as the NC mean plus 4.355 times the SD. A serum sample is positive when T = or \>1.000; negative when T = or \< 0.900; and inconclusive when T \> 0.900, \< 1.000. Generalized linear mixed-effects models (GLMM) will define how this BMK affects binary outcomes of parasite clearance. The BMK variable will be included in the model, with repeated measures.
Time frame: 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"
This BMK is measured by Enzyme-Linked Immunosorbent Assay (ELISA), whose unit is Optical Density (OD) at 492 nm. Cutoff: A negative result will be considered when OD values = or \<0.200, and positive when OD values \>0.300, at 1/200 serum dilution; indeterminate results will be OD values comprised between 0.200 and 0.300. Therapeutic efficacy will imply a continuous and substantial drop in the reactivity after treatment. A substantial decrease has to be at least 40% compared with the reactivity at T0 (before treatment). A slight increase (= or \<20%) in the reactivity against the BMK shortly after treatment versus OD at T0 will be allowed. Generalized linear mixed-effects models (GLMM) will define how this BMK affects binary outcomes of parasite clearance. The BMK variable will be included in the model, with repeated measures.
Time frame: 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 in the Non-Conventional Serology Biomarker "Anti-HSP70 Antibodies"
This BMK is measured by Enzyme-Linked Immunosorbent Assay (ELISA), whose unit is Optical Density (OD) at 492 nm. Cutoff: A negative result will be considered when OD values = or \<0.300, and positive when OD values \>0.450, at 1/200 serum dilution; indeterminate results will be OD values comprised between 0.300 and 0.450. Therapeutic efficacy will imply a continuous and substantial drop in the reactivity after treatment. A substantial decrease has to be at least 30% compared with the reactivity at T0 (before treatment). A slight increase (= or \< 20%) in the reactivity against the BMK shortly after treatment versus OD at T0 will be allowed.
Time frame: 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-PFR2 Antibodies"
This BMK is measured by Enzyme-Linked Immunosorbent Assay (ELISA), whose unit is Optical Density (OD) at 492 nm. Cutoff: A negative result will be considered when OD values = or \<0.250 at 1/400 dilution, and positive when OD values \>0.350, at 1/400 serum dilution; indeterminate results will be OD values comprised between 0.250 and 0.350. Therapeutic efficacy will imply a continuous and substantial drop in the reactivity after treatment. A substantial decrease has to be at least 40% compared with the reactivity at T0 (before treatment). A slight increase (= or \<20%) in the reactivity against the BMK shortly after treatment versus OD at T0 will be allowed. Generalized linear mixed-effects models (GLMM) will define how this BMK affects binary outcomes of parasite clearance. The BMK variable will be included in the model, with repeated measures.
Time frame: 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-Peptide 3973 Antibodies"
This BMK is measured by Enzyme-Linked Immunosorbent Assay (ELISA), whose unit is Optical Density (OD) at 492 nm. Cutoff: A negative result will be considered when OD values = or \<0.250, and positive when OD values \>0.350, at 1/400 serum dilution; indeterminate results will be OD values comprised between 0.250 and 0.350. Therapeutic efficacy will imply a continuous and substantial drop in the reactivity after treatment. A substantial decrease has to be at least 40% compared with the reactivity at T0 (before treatment). A slight increase (= or \<20%) in the reactivity against the BMK shortly after treatment versus OD at T0 will be allowed. Generalized linear mixed-effects models (GLMM) will define how this BMK affects binary outcomes of parasite clearance. The BMK variable will be included in the model, with repeated measures.
Time frame: 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).
Changes Over Time in the Non-Conventional Serology Biomarker "Trypomastigote Excreted/Secreted Antigens (TESA)"
Evaluate changes over time in the non-conventional serology biomarker (BMK) "Trypomastigote Excreted/Secreted Antigens (TESA)" and incidence of negative seroconversion for it, as measured by the aptamer assay. The unit of the aptamer assay is relative fluorescence unit (RFU). A Signal to Cutoff (S/CO) ratio is calculated for each clinical specimen by dividing the RFU value of the test sample by the cutoff (CO). The CO is the highest RFU value obtained from the endemic control specimens included in each run. The S/CO of a positive control included in the same run must meet pre-established acceptance criteria to be valid. A specimen with an S/CO \> 1.0 is interpreted as positive for the presence of the BMK (=infected). A specimen with an S/CO \< 1 is interpreted as negative (=non-infected). Generalized linear mixed-effects models (GLMM) will define how this BMK affects binary outcomes of parasite clearance. The BMK variable will be included in the model, with repeated measures.
Time frame: 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).
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Studies of the drugs tested here: Benzonidazole · Nifurtimox
University of Texas, El Paso