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

• ClinicalTrials.gov Identifier: NCT02625974
• Recruitment Status: Active, not recruiting
• First Posted: December 9, 2015
• Results First Posted: October 29, 2019
• Last Update Posted: February 8, 2021
• Sponsor: Bayer
• Information provided by (Responsible Party): Bayer

Study Description

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

Study Design

• 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

Arms and Interventions

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

Outcome Measures

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.

Eligibility Criteria

• 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)

Contacts and Locations

Locations

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

• 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

More Information

Additional Information:

Click here to find information about studies related to Bayer Healthcare products conducted in Europe 

Click here to find results for studies related to Bayer products. 

Publications of Results:

Sosa Estani S, Segura EL, Ruiz AM, Velazquez E, Porcel BM, Yampotis C. Efficacy of chemotherapy with benznidazole in children in the indeterminate phase of Chagas' disease. Am J Trop Med Hyg. 1998 Oct;59(4):526-9.

de Andrade AL, Zicker F, de Oliveira RM, Almeida Silva S, Luquetti A, Travassos LR, Almeida IC, de Andrade SS, de Andrade JG, Martelli CM. Randomised trial of efficacy of benznidazole in treatment of early Trypanosoma cruzi infection. Lancet. 1996 Nov 23;348(9039):1407-13.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Altcheh J, Castro L, Dib JC, Grossmann U, Huang E, Moscatelli G, Pinto Rocha JJ, Ramírez TE; CHICO Study Group. Prospective, historically controlled study to evaluate the efficacy and safety of a new paediatric formulation of nifurtimox in children aged 0 to 17 years with Chagas disease one year after treatment (CHICO). PLoS Negl Trop Dis. 2021 Jan 7;15(1):e0008912. doi: 10.1371/journal.pntd.0008912. eCollection 2021 Jan.

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02625974
• Other Study ID Numbers: 16027
• First Posted: December 9, 2015
• Results First Posted: October 29, 2019
• Last Update Posted: February 8, 2021
• Last Verified: February 2021

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Chagas Disease; Trypanosomiasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Nifurtimox; Trypanocidal Agents; Antiprotozoal Agents; Antiparasitic Agents; Anti-Infective Agents