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

Phase 3

Completed

• Conditions: Chagas Disease
• Interventions: Drug: Nifurtimox (Lampit, BAYA2502); Drug: Placebo

• Registration Number: NCT02625974
• Lead Sponsor: Bayer

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2015-12-07
• Study First Submitted QC: 2015-12-07
• Study First Posted: 2015-12-09
• Study Start: 2016-01-27
• Primary Completion: 2018-07-25
• Results First Submitted: 2019-07-22
• Results First Submitted QC: 2019-10-10
• Results First Posted: 2019-10-29
• Study Completion: 2021-08-10
• Status Verified: 2024-03
• Last Update Submitted: 2024-03-21
• Last Update Posted: 2024-08-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 330

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

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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)

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Nifurtimox 30 days / Arm 2	Placebo	Nifurtimox tablets administered three times daily for 30 days, followed by placebo administered three times daily for 30 days (Days 1 - 30, active nifurtimox treatment; Days 31 - 60, placebo)
Nifurtimox 60 days / Arm 1	Nifurtimox (Lampit, BAYA2502)	Nifurtimox tablets administered three times daily for 60 days (Days 1 - 60, active nifurtimox treatment)
Nifurtimox 30 days / Arm 2	Nifurtimox (Lampit, BAYA2502)	Nifurtimox tablets administered three times daily for 30 days, followed by placebo administered three times daily for 30 days (Days 1 - 30, active nifurtimox treatment; Days 31 - 60, placebo)

Primary Outcome Measures

Name	Time	Method
Part 1 - Percentage of Sero-reduction or Sero-conversion (Cured Subjects)	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.
Part 2 - Incidence Rate of Seronegative Conversion in Subjects Received at Least One Dose of the 60-day Nifurtimox Treatment Regimen.	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 Outcome Measures

Name	Time	Method
Part 2 - Incidence Rate of Seronegative Conversion in Subjects Who Received at Least One Dose of the 30-day Nifurtimox Treatment Regimen	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.
Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Recombinant ELISA	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.
Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 6	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.
Part 2 - Serological Response of Established Chagas-related Cardiomyopathy	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
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 9	Up to 90 days (Visit 9 post-treatment)	The evaluation was based on clinical examinations.
Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 2	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.
Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 3	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.
Part 2 - ECG Signs of Established Chagas-related Cardiomyopathy	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
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 6	Up to 30 days (Visit 6)	The evaluation was based on clinical examinations.
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 1	At Visit 1 (before treatment started)	The evaluation was based on clinical examinations.
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 10	Up to 240 days (Visit 10 post-treatment)	The evaluation was based on clinical examinations.
Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Total Purified Antigen ELISA	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.
Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 8	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.
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 3	Up to 7 days (Visit 3)	The evaluation was based on clinical examinations.
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 11	Up to 420 days (Visit 11 post-treatment)	The evaluation was based on clinical examinations.
Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 8	Up to 60 days (Visit 8; end of treatment)	The evaluation was based on clinical examinations.
Part 1 - Number of Subjects With Positive Results in Concentration Test for T. Cruzi (for Subjects <8 Months of Age)	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	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.
Part 1 - Number of Subjects With Positive Quantitative Polymerase Chain Reaction (qPCR) Results	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
Part 1 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	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
Part 2 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)	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.
Part 1 - Number of Subjects With Treatment-emergent High Blood Chemistry Abnormalities by Treatment	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.
Part 1 - Number of Subjects With Treatment-emergent Low Blood Chemistry Abnormalities by Treatment	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.
Part 1 - Number of Subjects With Treatment-emergent High Hematology Abnormalities by Treatment	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.
Part 1 - Number of Subjects With Treatment-emergent Low Hematology Abnormalities by Treatment	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.
Part 1 - Number of Subjects With Treatment-emergent High Coagulation Abnormalities by Treatment	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.
Part 1 - Number of Subjects With Treatment-emergent Low Coagulation Abnormalities by Treatment	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.
Part 1 - Number of Subjects With Abnormal Urinalysis Findings Considered as Clinically Significant or Reported as Adverse Events (AEs)	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.
Part 1 - Number of Subjects With Abnormal ECG Findings Considered as Clinically Significant by Investigators	Up to 420 days (Visit 11 post-treatment)	Clinical significance of abnormal ECG was based on the judgement of the investigator
Part 1 - Mean Changes in Vital Signs (Systolic Blood Pressure) Between the Treatment Groups From Baseline	Baseline and up to 420 days (Visit 11 post-treatment)	Systolic Blood Pressure
Part 1 - Mean Changes in Vital Signs (Diastolic Blood Pressure) Between the Treatment Groups From Baseline	Baseline and up to 420 days (Visit 11 post-treatment)	Diastolic Blood Pressure
Part 1 - Mean Changes in Vital Signs (Respiratory Rate) Between the Treatment Groups From Baseline	Baseline and up to 420 days (Visit 11 post-treatment)	Respiratory Rate
Part 1 - Mean Changes in Vital Signs (Heart Rate) Between the Treatment Groups From Baseline	Baseline and up to 420 days (Visit 11 post-treatment)	Heart Rate
Part 1 - Mean Changes in Vital Signs (Body Temperature) Between the Treatment Groups From Baseline	Baseline and up to 420 days (Visit 11 post-treatment)	Temperature