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NCT Number: NCT02625974

A Study to Learn How Well Nifurtimox Works and How Safe it is in Children Aged 0 to 17 Years With Chagas' Disease, an Inflammatory, Infectious Disease Caused by the Parasite Trypanosoma Cruzi

Researchers are looking for a better way to treat children who have an infectious disease caused by the parasite Trypanosoma cruzi (Chagas' disease).

Chagas'disease is an inflammatory, infectious disease caused by the parasite Trypanosoma cruzi. This parasite is mainly spread by insects called triatomine bug. If Chagas' disease is left untreated, it can later cause serious heart and digestive problems.

The study treatment nifurtimox has been used for more than 50 years to treat Chagas' disease. When used early after infection, it kills the parasite. In people who have long-term Chagas' disease, it's no longer possible to kill the parasite. However, nifurtimox may help slow the progression of the disease and its most serious complications.

Nifurtimox was developed for use in adults only, but has also been used in children (off-label) for over 40 years. Currently it is available for doctors to give to adults and to children. However, there are not enough data about nifurtimox in children.

The main purpose of this study is to learn how well nifurtimox works in children aged 8 months to less than 18 years with Chagas' disease. To answer this, the researchers will compare the amount of antibodies against the parasite Trypanosoma cruzi in the serum (fluid from blood without the clotting factors) between children treated with nifurtimox for 60 days with untreated children from the past (control group):

* 12 months and * 4 years after the end of treatment. The data for the control group will come from 2 previous studies conducted in children.

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Key information

Conditions

Chagas Disease Euglenozoa Infections Infections Parasitic Diseases Protozoan Infections Trypanosomiasis Vector Borne Diseases

Age range

Up to 17 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Phase 3

Primary location

La Plata, Buenos Aires, Argentina

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Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

Part 1:

  • Male and female pediatric subjects aged 0 days to younger than 18 years
  • Chagas' disease diagnosed/ confirmed for a) Subjects < 8 months of age at randomization must demonstrate direct observation of Trypanosoma cruzi by concentration test; b) Subjects ≥ 8 months to < 18 years of age at randomization must demonstrate a positive conventional ELISA result for both recombinant ELISA and total purified antigen ELISA

Part 2:

  • Male and female subjects who were randomized and received at least one dose of their assigned 60- or 30-day regimen of nifurtimox treatment

Exclusion criteria

Part 1:

  • Subjects aged 0 to 27 days who, at birth, were pre-term, weighed less than 2500 g, or had a maximum Apgar score < 7 at 5 minutes
  • Known evidence of Chagas' disease-related cardiomyopathy/ Chagas' heart disease
  • Known evidence of Chagas' disease-related gastrointestinal dysfunction (e.g. megaoesophagus, megacolon, or both) or Chagas' digestive disease
  • Serious manifestations of acute Chagas' disease, including myocarditis, meningoencephalitis, or pneumonitis
  • Known evidence of Chagas' disease-related damage to the peripheral nervous system or peripheral neuropathy
  • Clinically significant psychiatric disorder (e.g. moderate to severe depression, severe anxiety, or psychosis) or epilepsy
  • Subjects with contraindications/ warnings to nifurtimox administration, or with conditions that may increase the risk of the undesirable effects of nifurtimox
  • Subjects who have had previous treatment with trypanocidal agents or an accepted indication for antiparasitic therapy (e.g. reactivation of Chagas' infection due to immunosuppression by several diseases or treatment with steroids)
  • Subjects living in housing conditions where there is no active or effective vector control to Trypanosoma cruzi reinfection as determined by Ministry of Health guidelines in each country

Part 2:

  • Subjects with acute or chronic health conditions or congenital disorders which, in the opinion of the investigator, would make them unsuitable for participation in the clinical study
  • Subjects living in housing conditions where there is no active or effective vector-control to Trypanosoma cruzi reinfection as determined by Ministry of Health guideline of the respective country
  • Subjects with clinical manifestations of Chagas' disease-related gastrointestinal dysfunction or serious manifestations of acute Chagas' disease
  • Immuno-compromised subjects (e.g. with human immunodeficiency virus or treated with immunosuppressive drugs)

Treatment and study plan

Nifurtimox (Lampit, BAYA2502)

Drug

For pediatric participants with body weight ≤ 40 kg: dosage 10 to 20 mg/kg/day in three divided doses.

For pediatric participants with body weight > 40 kg: 8 - 10 mg/kg/day in three divided doses.

60 days or 30 days of nifurtimox treatment

Placebo

Drug

Matching placebo

Primary outcomes

  1. Part 1 - Percentage of Sero-reduction or Sero-conversion (Cured Subjects)

    Time frame: At 12 months post-treatment

    Cure is defined as sero-reduction (in subjects ≥8 months to <18 years of age at randomization) or sero-conversion (in all subjects). Sero-reduction is defined as a ≥20% reduction in optical density [OD]) measured by two conventional ELISA serology tests and sero-conversion is defined as negative Immunoglobulin G (IgG) concentration measured by two conventional ELISA serology tests.

    Subjects who have missing conventional serology results at the 12 month time point were treated as failures (ie, no cure).

    For the primary objective in the study, superiority over placebo was confirmed if the lower limit of the 95% Confidence Interval (CI) for the nifurtimox (60-day regimen) cure rate is greater than 16%, the larger of the upper limits of the 95% CIs for historical placebo control.

  2. Part 2 - Incidence Rate of Seronegative Conversion in Subjects Received at Least One Dose of the 60-day Nifurtimox Treatment Regimen.

    Time frame: Subjects participating in Part 2 were followed up for another 3 years, for a total follow-up period of 4 years after end of nifurtimox treatment in Part 1

    Seronegative conversion measured by two types of assay (recombinant ELISA and indirect hemagglutination assay [IHA]) in subjects who were randomized and received at least one dose of the 60-day nifurtimox treatment regimen compared to an external control group of historical placebo patients with Chagas' disease. Incidence rate is the number of new cases of seronegative conversion over the study period (i.e., 4 years after end of nifurtimox treatment) divided by the person-time at risk. It was modelled using a Poisson distribution with a 2-sided 95% exact CI.

    Number of participants with events were reported.

Secondary outcomes

  1. Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 2

    Time frame: At Visit 2 (Day 1): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours

    Measured in sub-population.

  2. Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 3

    Time frame: At Visit 3 (Day 7): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours

    Measured in sub-population.

  3. Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 6

    Time frame: At Visit 6 (Day 30): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours

    The evaluation was based on clinical examinations. Measured in sub-population.

  4. Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 8

    Time frame: At Visit 8 (Day 60): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours

    Measured in sub-population.

  5. Part 2 - Incidence Rate of Seronegative Conversion in Subjects Who Received at Least One Dose of the 30-day Nifurtimox Treatment Regimen

    Time frame: Subjects participating in Part 2 were followed up for another 3 years, for a total follow-up period of 4 years after end of nifurtimox treatment in Part 1

    Seronegative conversion measured by two types of assay (recombinant ELISA and indirect hemagglutination assay [IHA]) in subjects who were randomized and received at least one dose of the 30-day nifurtimox treatment regimen. Incidence rate is the number of new cases of seronegative conversion over the study period (i.e., 4 years after end of nifurtimox treatment) divided by the person-time at risk. It was modelled using a Poisson distribution with a 2-sided 95% exact CI.

    Number of participants with events were reported.

  6. Part 2 - ECG Signs of Established Chagas-related Cardiomyopathy

    Time frame: Subjects participating in Part 2 were followed up for another 3 years, for a total follow-up period of 4 years after end of nifurtimox treatment in Part 1

    Summary of subjects by evidence of established Chagas-related cardiomyopathy as measured by electrocardiogram (ECG).

    Evidence of established Chagas-related cardiomyopathy: Total

  7. Part 2 - Serological Response of Established Chagas-related Cardiomyopathy

    Time frame: Subjects participating in Part 2 were followed up for another 3 years, for a total follow-up period of 4 years after end of nifurtimox treatment in Part 1

    Summary of subjects by evidence of established Chagas-related cardiomyopathy as measured by Serological response.

    Evidence of established Chagas-related cardiomyopathy: Total

  8. Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Total Purified Antigen ELISA

    Time frame: Baseline and Subjects participating in Part 2 were followed up for another 3 years, for a total follow-up period of 4 years after end of nifurtimox treatment in Part 1

    Summary and change from baseline of optical density values measured by total purified antigen ELISA.

    Optical density is the measure of absorbance, and is defined as the ratio of the intensity of light falling upon a material and the intensity transmitted.

  9. Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Recombinant ELISA

    Time frame: Baseline and Subjects participating in Part 2 were followed up for another 3 years, for a total follow-up period of 4 years after end of nifurtimox treatment in Part 1

    Summary and change from baseline of optical density values measured by recombinant ELISA.

    Optical density is the measure of absorbance, and is defined as the ratio of the intensity of light falling upon a material and the intensity transmitted.

  10. Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 1

    Time frame: At Visit 1 (before treatment started)

    The evaluation was based on clinical examinations.

  11. Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 3

    Time frame: Up to 7 days (Visit 3)

    The evaluation was based on clinical examinations.

  12. Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 6

    Time frame: Up to 30 days (Visit 6)

    The evaluation was based on clinical examinations.

  13. Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 8

    Time frame: Up to 60 days (Visit 8; end of treatment)

    The evaluation was based on clinical examinations.

  14. Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 9

    Time frame: Up to 90 days (Visit 9 post-treatment)

    The evaluation was based on clinical examinations.

  15. Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 10

    Time frame: Up to 240 days (Visit 10 post-treatment)

    The evaluation was based on clinical examinations.

  16. Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 11

    Time frame: Up to 420 days (Visit 11 post-treatment)

    The evaluation was based on clinical examinations.

  17. Part 1 - Number of Subjects With Positive Results in Concentration Test for T. Cruzi (for Subjects <8 Months of Age)

    Time frame: Up to 90 days (Visit 9 post-treatment)

  18. Part 1 - Number of Subjects With a Positive Serological Response Using Non-conventional Enzyme-linked Immunosorbent Assay-F29 (ELISAF29) Test

    Time frame: Up to 420 days (Visit 11 post-treatment)

    The non-conventional ELISA-F29 test is considered an early marker of treatment efficacy in chronic Chagas disease.

  19. Part 1 - Number of Subjects With Positive Quantitative Polymerase Chain Reaction (qPCR) Results

    Time frame: Up to 420 days (Visit 11 post-treatment)

    The qPCR is molecular technique, considered a tool to diagnose acute and congenital Chagas disease, as well as a marker to measure treatment failure when demonstrating positive (detectable) results

  20. Part 1 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

    Time frame: up to 7 days after last application of study drug

    TEAEs comprised events which first occurred or worsened at or after first application of study drug during the course of the study up to and including 7 days after last application of study drug

  21. Part 2 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

    Time frame: Subjects participating in Part 2 were followed up for another 3 years, for a total follow-up period of 4 years after end of nifurtimox treatment in Part 1

    TEAEs comprised events which first occurred or worsened at study start up to end of study in part 2.

    In Part 2, only AEs considered at least possibly related to nifurtimox (administered in part 1) and those caused by protocol-related procedures were reported.

  22. Part 1 - Number of Subjects With Treatment-emergent High Blood Chemistry Abnormalities by Treatment

    Time frame: Up to 420 days (Visit 11 post-treatment)

    The Number Analyzed represents the number of subjects at baseline with a normal or lower than normal laboratory assessment who also had at least one valid laboratory value after start of treatment.

    The number of subjects represents subjects with at least one high laboratory assessment after start of treatment who had a normal or lower than normal laboratory assessment at baseline.

  23. Part 1 - Number of Subjects With Treatment-emergent Low Blood Chemistry Abnormalities by Treatment

    Time frame: Up to 420 days (Visit 11 post-treatment)

    The number analyzed represents the number of subjects at baseline with a normal or higher than normal laboratory assessment who also had at least one valid laboratory value after start of treatment.

    The number of subjects represents subjects with at least one low laboratory assessment after start of treatment who had a normal or higher than normal laboratory assessment at baseline.

  24. Part 1 - Number of Subjects With Treatment-emergent High Hematology Abnormalities by Treatment

    Time frame: Up to 420 days (Visit 11 post-treatment)

    The number analyzed represents the number of subjects at baseline with a normal or lower than normal laboratory assessment who also had at least one valid laboratory value after start of treatment. Subjects with missing or high abnormal values at baseline are not included in the number analyzed.

    The number of subjects represents subjects with at least one high laboratory assessment after start of treatment who had a normal or lower than normal laboratory assessment at baseline.

  25. Part 1 - Number of Subjects With Treatment-emergent Low Hematology Abnormalities by Treatment

    Time frame: Up to 420 days (Visit 11 post-treatment)

    The number analyzed represents the number of subjects at baseline with a normal or lower than normal laboratory assessment who also had at least one valid laboratory value after start of treatment. Subjects with missing or low abnormal values at baseline are not included in the number analyzed.

    The number of subjects represents subjects with at least one low laboratory assessment after start of treatment who had a normal or higher than normal laboratory assessment at baseline.

  26. Part 1 - Number of Subjects With Treatment-emergent High Coagulation Abnormalities by Treatment

    Time frame: Up to 420 days (Visit 11 post-treatment)

    The Number Analyzed represents the number of subjects at baseline with a normal or lower than normal laboratory assessment who also had at least one valid laboratory value after start of treatment.

    The number of subjects represents subjects with at least one high laboratory assessment after start of treatment who had a normal or lower than normal laboratory assessment at baseline.

  27. Part 1 - Number of Subjects With Treatment-emergent Low Coagulation Abnormalities by Treatment

    Time frame: Up to 420 days (Visit 11 post-treatment)

    The number analyzed represents the number of subjects at baseline with a normal or higher than normal laboratory assessment who also had at least one valid laboratory value after start of treatment.

    The number of subjects represents subjects with at least one low laboratory assessment after start of treatment who had a normal or higher than normal laboratory assessment at baseline.

  28. Part 1 - Number of Subjects With Abnormal Urinalysis Findings Considered as Clinically Significant or Reported as Adverse Events (AEs)

    Time frame: Up to 420 days (Visit 11 post-treatment)

    Urinalysis was performed and the following parameters evaluated: bilirubin, blood (red blood cells, white blood cells), chorionic gonadotropin β, glucose, ketones, leukocytes, nitrite, pH, protein, specific gravity, and urobilinogen.

  29. Part 1 - Number of Subjects With Abnormal ECG Findings Considered as Clinically Significant by Investigators

    Time frame: Up to 420 days (Visit 11 post-treatment)

    Clinical significance of abnormal ECG was based on the judgement of the investigator

  30. Part 1 - Mean Changes in Vital Signs (Systolic Blood Pressure) Between the Treatment Groups From Baseline

    Time frame: Baseline and up to 420 days (Visit 11 post-treatment)

    Systolic Blood Pressure

  31. Part 1 - Mean Changes in Vital Signs (Diastolic Blood Pressure) Between the Treatment Groups From Baseline

    Time frame: Baseline and up to 420 days (Visit 11 post-treatment)

    Diastolic Blood Pressure

  32. Part 1 - Mean Changes in Vital Signs (Respiratory Rate) Between the Treatment Groups From Baseline

    Time frame: Baseline and up to 420 days (Visit 11 post-treatment)

    Respiratory Rate

  33. Part 1 - Mean Changes in Vital Signs (Heart Rate) Between the Treatment Groups From Baseline

    Time frame: Baseline and up to 420 days (Visit 11 post-treatment)

    Heart Rate

  34. Part 1 - Mean Changes in Vital Signs (Body Temperature) Between the Treatment Groups From Baseline

    Time frame: Baseline and up to 420 days (Visit 11 post-treatment)

    Temperature

Other outcomes

  1. Part 1: Number of Participants Cured With 60-day Regimen Compared With Historical Active Control (Benznidazole)

    Time frame: Up to 420 days (Visit 11 post-treatment)

    This exploratory efficacy analysis evaluated the cure rate assessed as seroconversion of nifurtimox after 1-year post-treatment follow-up with that of published data for benznidazole (Sosa Estani et al. 1998 and de Andrade et al. 1996) at 4- and 3-year post-treatment follow-up, respectively, used as historical control.

  2. Part 1 - Relationship of Conventional Serology (Total Purified Antigen ELISA) and qPCR Testing by Visit

    Time frame: Up to 420 days (Visit 11 post-treatment)

    Using frequencies of matches and mismatches to assess agreement

    Reactive = Reac ELISA Detectable = Detec qPCR Non-reactive = Nonreac ELISA Non-detectable = Nondetec qPCR Non evaluable = Noneval qPCR qPCR Missing = Miss qPCR Missing conventional testing = Miss ELISA

  3. Part 1 - Relationship of Conventional Serology (Total Purified Antigen ELISA) and Non-conventional (ELISA-F29) Serologic Testing by Visit

    Time frame: Up to 420 days (Visit 11 post-treatment)

    Using frequencies of matches and mismatches to assess agreement

    Reactive = Reac ELISA Reactive = Reac F29 Non-reactive = Nonreac ELISA Non-reactive = Nonreac F29

  4. Part 1 - Relationship of Conventional Serology (Recombinant ELISA) and Non-conventional (ELISA-F29) Serologic Testing by Visit

    Time frame: Up to 420 days (Visit 11 post-treatment)

    Using frequencies of matches and mismatches to assess agreement

    Reactive = Reac ELISA Reactive = Reac F29 Non-reactive = Nonreac ELISA Non-reactive= Nonreac F29

  5. Part 1 - Relationship of Conventional Serology (ELISA) to Indirect Hemagglutination Assay (IHA) Results

    Time frame: Up to 420 days (Visit 11 post-treatment)

    Sero-reduction is defined as a => 20% reduction in optical density [OD]) using two conventional ELISA serology tests in subjects => 8 months to < 18 years of age at randomization; Others: reactive results that are not sero-reduction in subjects => 8 months to < 18 years of age at randomization; or reactive results in subjects < 8 months of age at randomization.

    Non-reactive ELISA = Nonreac ELISA Non-reactive IHA = Nonreac IHA Reactive IHA decrease = Reac IHA dec React IHA nochange = Reac IHA nochange Reactive ELISA: seroreduction = Reac ELISA reduc Reactive ELISA: others = Reac ELISA other

  6. Part 1 - Relationship Between Conventional ELISA Results in Terms of Cure or No Cure and IHA Results in All Patients

    Time frame: Up to 420 days (Visit 11 post-treatment)

    Cure is defined as sero-reduction (in subjects => 8 months to < 18 years of age at randomization) or sero-conversion (in all subjects). Sero-reduction is defined as a => 20% reduction in optical density [OD]) measured by two conventional ELISA serology tests and sero-conversion is defined as negative Immunoglobulin G [IgG] concentration measured by two conventional ELISA serology tests.

    Cure = Cure Non reactive/reactive decreasing = Nonreac/reac dec Reactive non-decreasing = Reac nondec No cure = No Cure Missing IHA testing = IHA missing

Sponsors and collaborators

Lead sponsor

Bayer

Industry

Registry information

Official study title

Prospective, Historically Controlled Study to Evaluate the Efficacy and Safety of a New Pediatric Formulation of Nifurtimox in Children Aged 0 to 17 Years With Chagas' Disease

Important dates

Study start
2016
Primary completion
2018
Study completion
2021
First posted
Dec 9, 2015
Registry last updated
Aug 19, 2024

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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