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

NCT02625974 | Completed Phase 3 Results DMC

• 2 other identifiers: 160272022-001504-17
• Study Type: interventional
• Target: 330
• Locations: 3 countries
• Sites: 25

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.

Conditions

Chagas Disease

Outcome Measures

Primary Outcomes (2)

• Part 1 - Percentage of Sero-reduction or Sero-conversion (Cured Subjects)

  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.

  At 12 months post-treatment

• Part 2 - Incidence Rate of Seronegative Conversion in Subjects Received at Least One Dose of the 60-day Nifurtimox Treatment Regimen.

  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.

  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

Secondary Outcomes (34)

• 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

• 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

• 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

• 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

• 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

Other Outcomes (6)

• Part 1: Number of Participants Cured With 60-day Regimen Compared With Historical Active Control (Benznidazole)

  Up to 420 days (Visit 11 post-treatment)

• Part 1 - Relationship of Conventional Serology (Total Purified Antigen ELISA) and qPCR Testing by Visit

  Up to 420 days (Visit 11 post-treatment)

• Part 1 - Relationship of Conventional Serology (Total Purified Antigen ELISA) and Non-conventional (ELISA-F29) Serologic Testing by Visit

  Up to 420 days (Visit 11 post-treatment)

Study Arms (2)

Nifurtimox 60 days / Arm 1

EXPERIMENTAL

Nifurtimox tablets administered three times daily for 60 days (Days 1 - 60, active nifurtimox treatment)

Drug: Nifurtimox (Lampit, BAYA2502)

Nifurtimox 30 days / Arm 2

EXPERIMENTAL

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 (Lampit, BAYA2502); Drug: Placebo

Interventions

Nifurtimox (Lampit, BAYA2502) DRUG

For pediatric participants with body weight ≤ 40 kg: dosage 10 to 20 mg/kg/day in three divided doses. For pediatric participants with body weight \> 40 kg: 8 - 10 mg/kg/day in three divided doses. 60 days or 30 days of nifurtimox treatment

Nifurtimox 30 days / Arm 2; Nifurtimox 60 days / Arm 1

Placebo DRUG

Matching placebo

Nifurtimox 30 days / Arm 2

Eligibility Criteria

• Age: Up to 17 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17)

You may qualify if:

• 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

You may not qualify if:

• 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)

Sponsors & Collaborators

• Bayer: lead

Study Sites (25)

Unknown Facility

La Plata, Buenos Aires, 1900, Argentina

Location

Unknown Facility

Buenos Aires, Ciudad Auton. de Buenos Aires, 1281, Argentina

Location

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Buenos Aires, Ciudad Auton. de Buenos Aires, C1270AAN, Argentina

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Buenos Aires, Ciudad Auton. de Buenos Aires, C1425AGP, Argentina

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Buenos Aires, Ciudad Auton. de Buenos Aires, C1425EFD, Argentina

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San Salvador de Jujuy, Jujuy Province, 4600, Argentina

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Posadas, Misiones Province, Argentina

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Rosario, Santa Fe Province, 2000, Argentina

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Corrientes, W3400CBI, Argentina

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Formosa, P3600HZL, Argentina

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La Rioja, Argentina

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Mendoza, 5500, Argentina

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Mendoza, 5535, Argentina

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Salta, 4400, Argentina

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Salta, A4400ESE, Argentina

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San Juan, 5400, Argentina

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San Miguel de Tucumán, 4000, Argentina

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Santiago del Estero, 4202, Argentina

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Cochabamba, Bolivia

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Punata, Bolivia

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Tarija, Bolivia

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Soledad, Atlántico, Colombia

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Yopal, Casanare Department, 0, Colombia

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Santa Marta, Magdalena Department, 0, Colombia

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Floridablabca, Santander Department, 681011, Colombia

Location

Related Publications (5)

• 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. doi: 10.4269/ajtmh.1998.59.526.

  PMID: 9790423 RESULT

• 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. doi: 10.1016/s0140-6736(96)04128-1.

  PMID: 8937280 RESULT

• Altcheh J, Castro L, Dib JC, Grossmann U, Huang E, Moscatelli G, Pinto Rocha JJ, Ramirez 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.

  PMID: 33412557 RESULT

• Rivero R, Esteva MI, Huang E, Colmegna L, Altcheh J, Grossmann U, Ruiz AM; CHICO and CHICO SECURE Study Groups. ELISA F29 -A therapeutic efficacy biomarker in Chagas disease: Evaluation in pediatric patients treated with nifurtimox and followed for 4 years post-treatment. PLoS Negl Trop Dis. 2023 Jun 23;17(6):e0011440. doi: 10.1371/journal.pntd.0011440. eCollection 2023 Jun.

  PMID: 37352322 DERIVED

• Altcheh J, Sierra V, Ramirez T, Pinto Rocha JJ, Grossmann U, Huang E, Moscatelli G, Ding O. Efficacy and Safety of Nifurtimox in Pediatric Patients with Chagas Disease: Results at 4-Year Follow-Up in a Prospective, Historically Controlled Study (CHICO SECURE). Antimicrob Agents Chemother. 2023 Apr 18;67(4):e0119322. doi: 10.1128/aac.01193-22. Epub 2023 Mar 28.

  PMID: 36975790 DERIVED

Related Links

• 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.
• Related Info

MeSH Terms

Conditions

Chagas Disease

Interventions

Nifurtimox

Condition Hierarchy (Ancestors)

Trypanosomiasis; Euglenozoa Infections; Protozoan Infections; Parasitic Diseases; Infections; Vector Borne Diseases

Intervention Hierarchy (Ancestors)

Nitrofurans; Nitro Compounds; Organic Chemicals; Thiazines; Sulfur Compounds; Furans; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Limitations and Caveats

Abnormal findings on neurological examination by physical examination after Screening will be documented as AEs.

Results Point of Contact

• Title: Therapeutic Area Head
• Organization: Bayer AG

clinical-trials-contact@bayer.com

1-888-8422937

Study Officials

• Bayer Study Director

  Bayer

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: LTE60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 7, 2015
• First Posted: December 9, 2015
• Study Start: January 27, 2016
• Primary Completion: July 25, 2018
• Study Completion: August 10, 2021
• Last Updated: August 19, 2024
• Results First Posted: October 29, 2019

Record last verified: 2024-03

Locations

CO (4); BO (3); AR (18)