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Prospective Study of a Pediatric Nifurtimox Formulation for Chagas' Disease (CHICO)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02625974
Recruitment Status : Active, not recruiting
First Posted : December 9, 2015
Results First Posted : October 29, 2019
Last Update Posted : October 26, 2020
Sponsor:
Information provided by (Responsible Party):
Bayer

Brief Summary:
The study consists of two parts. Part I 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 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.

Condition or disease Intervention/treatment Phase
Chagas Disease Drug: Nifurtimox (Lampit, BAYA2502) Drug: Placebo Phase 3

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 330 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : January 27, 2016
Actual Primary Completion Date : July 25, 2018
Estimated Study Completion Date : August 9, 2021

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Chagas Disease

Arm Intervention/treatment
Experimental: Nifurtimox 60 days / Arm 1
Nifurtimox tablets administered three times daily for 60 days (Days 1 - 60, active nifurtimox treatment)
Drug: Nifurtimox (Lampit, BAYA2502)

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


Nifurtimox 30 days / Arm 2
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
Matching placebo




Primary Outcome Measures :
  1. Percentage of Participants Cured [ 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 from the two publications.


  2. Incidence Rate of Seronegative Conversion for Subjects Received at Least One Dose of the 60-day Nifurtimox Treatment Regimen.(Part 2) [ Time Frame: Up to 4 years after end of treatment ]
    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.


Secondary Outcome Measures :
  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.

  2. 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.

  3. 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.

  4. 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.

  5. 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.

  6. 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.

  7. 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.

  8. 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 ]
  9. 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.

  10. 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

  11. Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
    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

  12. Number of Subjects With Treatment-emergent High Blood Chemistry Abnormalities by Treatment (Part 1) [ 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.


  13. Number of Subjects With Treatment-emergent Low Blood Chemistry Abnormalities by Treatment (Part 1) [ 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.


  14. Number of Subjects With Treatment-emergent High Hematology Abnormalities by Treatment (Part 1) [ 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.


  15. Number of Subjects With Treatment-emergent Low Hematology Abnormalities by Treatment (Part 1) [ 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.


  16. Number of Subjects With Treatment-emergent High Coagulation Abnormalities by Treatment (Part 1) [ 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.


  17. Number of Subjects With Treatment-emergent Low Coagulation Abnormalities by Treatment (Part 1) [ 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.


  18. 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.

  19. Number of Subjects With Abnormal ECG Findings Considered as Clinically Significant by Investigators (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
    Clinical significance of abnormal ECG was based on the judgement of the investigator

  20. Mean Changes in Vital Signs (Systolic Blood Pressure) Between the Treatment Groups From Baseline (Part 1) [ Time Frame: Baseline and up to 420 days (Visit 11) post-treatment ]
    Systolic Blood Pressure

  21. Mean Changes in Vital Signs (Diastolic Blood Pressure) Between the Treatment Groups From Baseline (Part 1) [ Time Frame: Baseline and up to 420 days (Visit 11) post-treatment ]
    Diastolic Blood Pressure

  22. Mean Changes in Vital Signs (Respiratory Rate) Between the Treatment Groups From Baseline (Part 1) [ Time Frame: Baseline and up to 420 days (Visit 11) post-treatment ]
    Respiratory Rate

  23. Mean Changes in Vital Signs (Heart Rate) Between the Treatment Groups From Baseline (Part 1) [ Time Frame: Baseline and up to 420 days (Visit 11) post-treatment ]
    Heart Rate

  24. Mean Changes in Vital Signs(Temperature) Between the Treatment Groups From Baseline (Part 1) [ Time Frame: Baseline and up to 420 days (Visit 11) post-treatment ]
    Temperature

  25. Nifurtimox Concentration Over Time in Plasma at Visit 2 (Part 1) [ 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.

  26. Nifurtimox Concentration Over Time in Plasma at Visit 3 (Part 1) [ 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.

  27. Nifurtimox Concentration Over Time in Plasma at Visit 6 (Part 1) [ 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 ]
    Measured in sub-population.

  28. Nifurtimox Concentration Over Time in Plasma at Visit 8 (Part 1) [ 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.

  29. Incidence of Seronegative Conversion Received at Least One Dose of the 30-day Nifurtimox Treatment Regimen. (Part 2) [ Time Frame: Up to 4 years after end of treatment ]
    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.

  30. Proportion of Responders With Seronegative Conversion and no Evidence of Cardiomyopathy (Part 2) [ Time Frame: Up to 4 years after end of treatment ]
    Seronegative conversion measured by two types of assays (recombinant ELISA and IHA). Cardiomyopathy as evaluated by electrocardiogram.

  31. Antibody Titer in Plasma Over Time in All Subjects (Part 2) [ Time Frame: Up to 4 years after end of treatment ]
    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.


Other Outcome Measures:
  1. Number of Subjects 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. Relationship of Conventional Serology (Total Purified Antigen ELISA) and qPCR Testing by Visit (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
    Using frequencies of matches and mismatches to assess agreement

  3. Relationship of Conventional Serology (Total Purified Antigen ELISA) and Non-conventional (ELISA-F29) Serologic Testing by Visit (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
    Using frequencies of matches and mismatches to assess agreement

  4. Relationship of Conventional Serology (Recombinant ELISA) and Non-conventional (ELISA-F29) Serologic Testing by Visit (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
    Using frequencies of matches and mismatches to assess agreement

  5. 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.

  6. 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.




Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   up to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 who after completing nifurtimox treatment require treatment with an anti-trypanosomal agent
  • 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)

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02625974


Locations
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Argentina
La Plata, Buenos Aires, Argentina, 1900
Buenos Aires, Ciudad Auton. De Buenos Aires, Argentina, 1281
Buenos Aires, Ciudad Auton. De Buenos Aires, Argentina, C1270AAN
Buenos Aires, Ciudad Auton. De Buenos Aires, Argentina, C1425AGP
Buenos Aires, Ciudad Auton. De Buenos Aires, Argentina, C1425EFD
San Salvador de Jujuy, Jujuy, Argentina, 4600
Posadas, Misiones, Argentina
Rosario, Santa Fe, Argentina, 2000
Corrientes, Argentina, W3400CBI
Formosa, Argentina, P3600HZL
La Rioja, Argentina
Mendoza, Argentina, 5500
Mendoza, Argentina, 5535
Salta, Argentina, 4400
Salta, Argentina, A4400ESE
San Juan, Argentina, 5400
Santiago del Estero, Argentina, 4202
Tucuman, Argentina, 4000
Bolivia
Cochabamba, Bolivia
Punata, Bolivia
Tarija, Bolivia
Colombia
Barranquilla, Atlántico, Colombia
Yopal, Casanare, Colombia, 0
Santa Marta, Magdalena, Colombia, 0
Floridablanca, Santander, Colombia
Sponsors and Collaborators
Bayer
Investigators
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Study Director: Bayer Study Director Bayer
  Study Documents (Full-Text)

Documents provided by Bayer:
Statistical Analysis Plan  [PDF] February 16, 2018
Study Protocol  [PDF] May 11, 2018

Additional Information:
Publications of Results:
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Responsible Party: Bayer
ClinicalTrials.gov Identifier: NCT02625974    
Other Study ID Numbers: 16027
First Posted: December 9, 2015    Key Record Dates
Results First Posted: October 29, 2019
Last Update Posted: October 26, 2020
Last Verified: October 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Chagas Disease
Trypanosomiasis
Euglenozoa Infections
Protozoan Infections
Parasitic Diseases
Nifurtimox
Trypanocidal Agents
Antiprotozoal Agents
Antiparasitic Agents
Anti-Infective Agents