Prospective Study of a Pediatric Nifurtimox Formulation for Chagas' Disease

Study Overview
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Brief Summary
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The study consists of two parts. Part I (CHICO) was designed to develop a better understanding of the efficacy, safety and pharmacokinetics of nifurtimox in children with a diagnosis of Chagas' disease (Trypanosoma cruzi infection) using pediatric formulations. Part II (CHICO SECURE) was designed at request of the FDA to assess the incidence of sero-negative conversion in children with diagnosis of Chagas' disease treated with nifurtimox.

Official Title
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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

Conditions
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Chagas Disease

Intervention / Treatment
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* Drug: Nifurtimox (Lampit, BAYA2502)
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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)

Ages Eligible for Study
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Maximum Age: 17 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Nifurtimox 60 days / Arm 1<br>Nifurtimox tablets administered three times daily for 60 days (Days 1 - 60, active nifurtimox treatment) | Drug: Nifurtimox (Lampit, BAYA2502)<br>* For pediatric subjects with body weight ≤ 40 kg: dosage 10 to 20 mg/kg/day in three divided doses. For pediatric subjects with body weight > 40 kg: 8 - 10 mg/kg/day in three divided doses. 60 days of nifurtimox treatment<br>|
| Other: Nifurtimox 30 days / Arm 2<br>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) | Drug: Placebo<br>* Matching placebo<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants Cured | 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 from the two publications. | At 12 months post-treatment | 
| Incidence Rate of Seronegative Conversion for Subjects Received at Least One Dose of the 60-day Nifurtimox Treatment Regimen.(Part 2) | 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. | Up to 4 years after end of treatment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 1 | The evaluation was based on clinical examinations. | At Visit 1 (before treatment started) | 
| Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 3 | The evaluation was based on clinical examinations. | Up to 7 days (Visit 3) | 
| Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 6 | The evaluation was based on clinical examinations. | Up to 30 days (Visit 6) | 
| Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 8 | The evaluation was based on clinical examinations. | Up to 60 days (Visit 8) end of treatment | 
| Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 9 | The evaluation was based on clinical examinations. | Up to 90 days (Visit 9) post treatment | 
| Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 10 | The evaluation was based on clinical examinations. | Up to 240 days (Visit 10) post treatment | 
| Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 11 | The evaluation was based on clinical examinations. | Up to 420 days (Visit 11) post-treatment | 
| 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 | 
| 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. | Up to 420 days (Visit 11) post-treatment | 
| 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 | Up to 420 days (Visit 11) post-treatment | 
| 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 | Up to 420 days (Visit 11) post-treatment | 
| Number of Subjects With Treatment-emergent High Blood Chemistry Abnormalities by Treatment (Part 1) | 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. | Up to 420 days (Visit 11) post-treatment | 
| Number of Subjects With Treatment-emergent Low Blood Chemistry Abnormalities by Treatment (Part 1) | 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. | Up to 420 days (Visit 11) post-treatment | 
| Number of Subjects With Treatment-emergent High Hematology Abnormalities by Treatment (Part 1) | 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. | Up to 420 days (Visit 11) post-treatment | 
| Number of Subjects With Treatment-emergent Low Hematology Abnormalities by Treatment (Part 1) | 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. | Up to 420 days (Visit 11) post-treatment | 
| Number of Subjects With Treatment-emergent High Coagulation Abnormalities by Treatment (Part 1) | 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. | Up to 420 days (Visit 11) post-treatment | 
| Number of Subjects With Treatment-emergent Low Coagulation Abnormalities by Treatment (Part 1) | 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. | Up to 420 days (Visit 11) post-treatment | 
| 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. | Up to 420 days (Visit 11) post-treatment | 
| Number of Subjects With Abnormal ECG Findings Considered as Clinically Significant by Investigators (Part 1) | Clinical significance of abnormal ECG was based on the judgement of the investigator | Up to 420 days (Visit 11) post-treatment | 
| Mean Changes in Vital Signs (Systolic Blood Pressure) Between the Treatment Groups From Baseline (Part 1) | Systolic Blood Pressure | Baseline and up to 420 days (Visit 11) post-treatment | 
| Mean Changes in Vital Signs (Diastolic Blood Pressure) Between the Treatment Groups From Baseline (Part 1) | Diastolic Blood Pressure | Baseline and up to 420 days (Visit 11) post-treatment | 
| Mean Changes in Vital Signs (Respiratory Rate) Between the Treatment Groups From Baseline (Part 1) | Respiratory Rate | Baseline and up to 420 days (Visit 11) post-treatment | 
| Mean Changes in Vital Signs (Heart Rate) Between the Treatment Groups From Baseline (Part 1) | Heart Rate | Baseline and up to 420 days (Visit 11) post-treatment | 
| Mean Changes in Vital Signs(Temperature) Between the Treatment Groups From Baseline (Part 1) | Temperature | Baseline and up to 420 days (Visit 11) post-treatment | 
| Nifurtimox Concentration Over Time in Plasma at Visit 2 (Part 1) | Measured in sub-population. | At Visit 2 (Day 1): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours | 
| Nifurtimox Concentration Over Time in Plasma at Visit 3 (Part 1) | Measured in sub-population. | At Visit 3 (Day 7): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours | 
| Nifurtimox Concentration Over Time in Plasma at Visit 6 (Part 1) | Measured in sub-population. | At Visit 6 (Day 30): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours | 
| Nifurtimox Concentration Over Time in Plasma at Visit 8 (Part 1) | Measured in sub-population. | At Visit 8 (Day 60): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours | 
| Incidence of Seronegative Conversion Received at Least One Dose of the 30-day Nifurtimox Treatment Regimen. (Part 2) | Measured once per year by two types of assays (recombinant ELISA and IHA) in subjects received at least one dose of 30-day nifurtimox treatment regimen. | Up to 4 years after end of treatment | 
| Proportion of Responders With Seronegative Conversion and no Evidence of Cardiomyopathy (Part 2) | Seronegative conversion measured by two types of assays (recombinant ELISA and IHA). Cardiomyopathy as evaluated by electrocardiogram. | Up to 4 years after end of treatment | 
| Antibody Titer in Plasma Over Time in All Subjects (Part 2) | Measured once per year by recombinant ELISA and total purified antigen ELISA in subjects treated either with the 60- or 30-day nifurtimox treatment regimen. | Up to 4 years after end of treatment |