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

• 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 (BAYA2502); Drug: Nifurtimox (BAYA2502) followed by 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 (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
Placebo Comparator: 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: Nifurtimox (BAYA2502) followed by Placebo; 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. 30 days of nifurtimox treatment followed by 30 days of placebo

Outcome Measures

Primary Outcome Measures :

1. Incidence rate of seronegative conversion for all subjects (Part 1) [ Time Frame: 360 days from end of treatment ]

   Sero-conversion defined as negative antibody concentration to Trypanosoma cruzi.

   Binary variables: CURE (negative enzyme-linked immune sorbent assay [ELISA] result) / NO CURE (positive ELISA result).

2. Incidence rate of sero-reduction for subjects ≥ 8 months to <18 years of age (Part 1) [ Time Frame: 360 days from end of treatment ]

   Sero-reduction defined as recombinant ELISA serology tests based upon a target of ≥ 20% decrease in antibody concentration to Trypanosoma cruzi.

   Binary variables: CURE (≥ 20% reduction in antibody) / NO CURE (< 20% reduction in antibody).

3. Incidence rate of seronegative conversion for all subjects (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. Comparability of a 30-day regimen of nifurtimox to a 60-day regimen of nifurtimox as sero-reduction or sero-conversion and to quantitative polymerase chain reaction (PCR) (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
   Binary variables: CURE (negative ELISA result, ≥ 20% reduction in antibody concentration, or non-reactive PCR test) / NO CURE (positive ELISA result, < 20% reduction in antibody, or reactive PCR test).
2. Safety profile of nifurtimox by assessing the number of participants with Adverse Event (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
3. Safety profile of nifurtimox by laboratory parameters (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
   Hematology Blood chemistry Urinalysis
4. Safety profile of nifurtimox by electrocardiogram (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
5. Safety profile of nifurtimox by vital signs (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
   Blood pressure Heart rate Respiratory rate Temperature
6. Safety profile of nifurtimox by physical examination (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
   Neurological examinations
7. Nifurtimox concentration over time in plasma (Part 1) [ Time Frame: Up to 60 days (Visit 8) ]
   Measured in sub-population.
8. Incidence of seronegative conversion in all subjects (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 treated with the 30-day nifurtimox treatment regimen.
9. 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.
10. 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. Comparability of a 60-day regimen of nifurtimox to historical active control (benznidazole) as sero-reduction or sero-conversion (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
   Binary variables: CURE (negative ELISA result or ≥ 20% reduction in antibody concentration) / NO CURE (positive ELISA result or < 20% reduction in antibody).
2. Relationship of conventional serology (as sero-reduction or sero-conversion) to quantitative PCR using frequencies of matches and mismatches to assess agreement (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
   Comparison of CURE / NO CURE results for ELISA tests and PCR tests.
3. Relationship of non-conventional serology to conventional serology (Part 1) [ Time Frame: Up to 420 days (Visit 11) post-treatment ]
   Compare CURE / NO CURE results for non-conventional ELISA and conventional ELISA 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 immunosuppresive 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

More Information

• Responsible Party: Bayer
• ClinicalTrials.gov Identifier: NCT02625974 History of Changes
• Other Study ID Numbers: 16027
• First Posted: December 9, 2015
• Last Update Posted: March 18, 2019
• Last Verified: March 2019

• 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