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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
330
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
Matching placebo
Unnamed facility
La Plata, Buenos Aires, Argentina
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Buenos Aires, Ciudad Auton. de Buenos Aires, Argentina
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Buenos Aires, Ciudad Auton. de Buenos Aires, Argentina
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Buenos Aires, Ciudad Auton. de Buenos Aires, Argentina
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Buenos Aires, Ciudad Auton. de Buenos Aires, Argentina
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San Salvador de Jujuy, Jujuy Province, Argentina
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Posadas, Misiones Province, Argentina
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Rosario, Santa Fe Province, Argentina
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Corrientes, Argentina
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Formosa, Argentina
...and 15 more locations
Part 1 - Percentage of Sero-reduction or Sero-conversion (Cured Subjects)
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.
Time frame: At 12 months post-treatment
Part 2 - Incidence Rate of Seronegative Conversion in Subjects Received at Least One Dose of the 60-day Nifurtimox Treatment Regimen.
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.
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
Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 2
Measured in sub-population.
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
Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 3
Measured in sub-population.
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
Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 6
The evaluation was based on clinical examinations. Measured in sub-population.
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
Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 8
Measured in sub-population.
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
Part 2 - Incidence Rate of Seronegative Conversion in Subjects Who Received at Least One Dose of the 30-day Nifurtimox Treatment Regimen
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.
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
Part 2 - ECG Signs of Established Chagas-related Cardiomyopathy
Summary of subjects by evidence of established Chagas-related cardiomyopathy as measured by electrocardiogram (ECG). Evidence of established Chagas-related cardiomyopathy: Total
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
Part 2 - Serological Response of Established Chagas-related Cardiomyopathy
Summary of subjects by evidence of established Chagas-related cardiomyopathy as measured by Serological response. Evidence of established Chagas-related cardiomyopathy: Total
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
Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Total Purified Antigen ELISA
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.
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
Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Recombinant ELISA
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.
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
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 1
The evaluation was based on clinical examinations.
Time frame: At Visit 1 (before treatment started)
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 3
The evaluation was based on clinical examinations.
Time frame: Up to 7 days (Visit 3)
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 6
The evaluation was based on clinical examinations.
Time frame: Up to 30 days (Visit 6)
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 8
The evaluation was based on clinical examinations.
Time frame: Up to 60 days (Visit 8; end of treatment)
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 9
The evaluation was based on clinical examinations.
Time frame: Up to 90 days (Visit 9 post-treatment)
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 10
The evaluation was based on clinical examinations.
Time frame: Up to 240 days (Visit 10 post-treatment)
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 11
The evaluation was based on clinical examinations.
Time frame: Up to 420 days (Visit 11 post-treatment)
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)
Part 1 - Number of Subjects With a Positive Serological Response Using Non-conventional Enzyme-linked Immunosorbent Assay-F29 (ELISAF29) Test
The non-conventional ELISA-F29 test is considered an early marker of treatment efficacy in chronic Chagas disease.
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Number of Subjects With Positive Quantitative Polymerase Chain Reaction (qPCR) Results
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
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
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
Time frame: up to 7 days after last application of study drug
Part 2 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
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.
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
Part 1 - Number of Subjects With Treatment-emergent High Blood Chemistry Abnormalities by 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.
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Number of Subjects With Treatment-emergent Low Blood Chemistry Abnormalities by 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.
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Number of Subjects With Treatment-emergent High Hematology Abnormalities by 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.
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Number of Subjects With Treatment-emergent Low Hematology Abnormalities by 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.
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Number of Subjects With Treatment-emergent High Coagulation Abnormalities by 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.
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Number of Subjects With Treatment-emergent Low Coagulation Abnormalities by 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.
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Number of Subjects With Abnormal Urinalysis Findings Considered as Clinically Significant or Reported as Adverse Events (AEs)
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.
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Number of Subjects With Abnormal ECG Findings Considered as Clinically Significant by Investigators
Clinical significance of abnormal ECG was based on the judgement of the investigator
Time frame: Up to 420 days (Visit 11 post-treatment)
Part 1 - Mean Changes in Vital Signs (Systolic Blood Pressure) Between the Treatment Groups From Baseline
Systolic Blood Pressure
Time frame: Baseline and up to 420 days (Visit 11 post-treatment)
Part 1 - Mean Changes in Vital Signs (Diastolic Blood Pressure) Between the Treatment Groups From Baseline
Diastolic Blood Pressure
Time frame: Baseline and up to 420 days (Visit 11 post-treatment)
Part 1 - Mean Changes in Vital Signs (Respiratory Rate) Between the Treatment Groups From Baseline
Respiratory Rate
Time frame: Baseline and up to 420 days (Visit 11 post-treatment)
Part 1 - Mean Changes in Vital Signs (Heart Rate) Between the Treatment Groups From Baseline
Heart Rate
Time frame: Baseline and up to 420 days (Visit 11 post-treatment)
Part 1 - Mean Changes in Vital Signs (Body Temperature) Between the Treatment Groups From Baseline
Temperature
Time frame: Baseline and up to 420 days (Visit 11 post-treatment)
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