Clinical trial NCT02625974: 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
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Chagas Disease
Lead sponsor: Bayer
Sponsor class: INDUSTRY
First posted: 2015-12-09
Enrollment: 330
Sex: ALL
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.


Eligibility 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 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)

Primary outcomes:
measure: Part 1 - Percentage of Sero-reduction or Sero-conversion (Cured Subjects)
timeFrame: At 12 months post-treatment
measure: Part 2 - Incidence Rate of Seronegative Conversion in Subjects Received at Least One Dose of the 60-day Nifurtimox Treatment Regimen.
timeFrame: 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:
measure: Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 2
timeFrame: At Visit 2 (Day 1): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours
measure: Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 3
timeFrame: At Visit 3 (Day 7): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours
measure: Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 6
timeFrame: At Visit 6 (Day 30): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours
measure: Part 1 - Nifurtimox Concentration Over Time in Plasma at Visit 8
timeFrame: At Visit 8 (Day 60): Pre-dose and Post-dose at 5-10 minutes, 10-120 minutes, 2-4 hours, and 4-8 hours
measure: Part 2 - Incidence Rate of Seronegative Conversion in Subjects Who Received at Least One Dose of the 30-day Nifurtimox Treatment Regimen
timeFrame: 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
measure: Part 2 - ECG Signs of Established Chagas-related Cardiomyopathy
timeFrame: 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
measure: Part 2 - Serological Response of Established Chagas-related Cardiomyopathy
timeFrame: 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
measure: Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Total Purified Antigen ELISA
timeFrame: Baseline and 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
measure: Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Recombinant ELISA
timeFrame: Baseline and 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
measure: Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 1
timeFrame: At Visit 1 (before treatment started)
measure: Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 3
timeFrame: Up to 7 days (Visit 3)
measure: Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 6
timeFrame: Up to 30 days (Visit 6)
measure: Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 8
timeFrame: Up to 60 days (Visit 8; end of treatment)
measure: Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 9
timeFrame: Up to 90 days (Visit 9 post-treatment)
measure: Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 10
timeFrame: Up to 240 days (Visit 10 post-treatment)
measure: Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 11
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Positive Results in Concentration Test for T. Cruzi (for Subjects <8 Months of Age)
timeFrame: Up to 90 days (Visit 9 post-treatment)
measure: Part 1 - Number of Subjects With a Positive Serological Response Using Non-conventional Enzyme-linked Immunosorbent Assay-F29 (ELISAF29) Test
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Positive Quantitative Polymerase Chain Reaction (qPCR) Results
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: up to 7 days after last application of study drug
measure: Part 2 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
timeFrame: 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
measure: Part 1 - Number of Subjects With Treatment-emergent High Blood Chemistry Abnormalities by Treatment
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Treatment-emergent Low Blood Chemistry Abnormalities by Treatment
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Treatment-emergent High Hematology Abnormalities by Treatment
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Treatment-emergent Low Hematology Abnormalities by Treatment
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Treatment-emergent High Coagulation Abnormalities by Treatment
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Treatment-emergent Low Coagulation Abnormalities by Treatment
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Abnormal Urinalysis Findings Considered as Clinically Significant or Reported as Adverse Events (AEs)
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Number of Subjects With Abnormal ECG Findings Considered as Clinically Significant by Investigators
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Mean Changes in Vital Signs (Systolic Blood Pressure) Between the Treatment Groups From Baseline
timeFrame: Baseline and up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Mean Changes in Vital Signs (Diastolic Blood Pressure) Between the Treatment Groups From Baseline
timeFrame: Baseline and up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Mean Changes in Vital Signs (Respiratory Rate) Between the Treatment Groups From Baseline
timeFrame: Baseline and up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Mean Changes in Vital Signs (Heart Rate) Between the Treatment Groups From Baseline
timeFrame: Baseline and up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Mean Changes in Vital Signs (Body Temperature) Between the Treatment Groups From Baseline
timeFrame: Baseline and up to 420 days (Visit 11 post-treatment)
Other outcomes:
measure: Part 1: Number of Participants Cured With 60-day Regimen Compared With Historical Active Control (Benznidazole)
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Relationship of Conventional Serology (Total Purified Antigen ELISA) and qPCR Testing by Visit
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Relationship of Conventional Serology (Total Purified Antigen ELISA) and Non-conventional (ELISA-F29) Serologic Testing by Visit
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Relationship of Conventional Serology (Recombinant ELISA) and Non-conventional (ELISA-F29) Serologic Testing by Visit
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Relationship of Conventional Serology (ELISA) to Indirect Hemagglutination Assay (IHA) Results
timeFrame: Up to 420 days (Visit 11 post-treatment)
measure: Part 1 - Relationship Between Conventional ELISA Results in Terms of Cure or No Cure and IHA Results in All Patients
timeFrame: Up to 420 days (Visit 11 post-treatment)
Locations:
city: La Plata
country: Argentina
state: Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. De Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. De Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. De Buenos Aires
city: Buenos Aires
country: Argentina
state: Ciudad Auton. De Buenos Aires
city: San Salvador de Jujuy
country: Argentina
state: Jujuy
city: Posadas
country: Argentina
state: Misiones
city: Rosario
country: Argentina
state: Santa Fe
city: Corrientes
country: Argentina
city: Formosa
country: Argentina
city: La Rioja
country: Argentina
city: Mendoza
country: Argentina
city: Mendoza
country: Argentina
city: Salta
country: Argentina
city: Salta
country: Argentina
city: San Juan
country: Argentina
city: Santiago del Estero
country: Argentina
city: Tucuman
country: Argentina
city: Cochabamba
country: Bolivia
city: Punata
country: Bolivia
city: Tarija
country: Bolivia
city: Soledad
country: Colombia
state: Atlántico
city: Yopal
country: Colombia
state: Casanare
city: Santa Marta
country: Colombia
state: Magdalena
city: Floridablabca
country: Colombia
state: Santander
Study officials:
affiliation: Bayer
name: Bayer Study Director
role: STUDY_DIRECTOR
References:
citation: 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.
citation: 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.
citation: 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.