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
试验速览
- 阶段
- 3 期
- 状态
- 已完成
- 发起方
- Bayer
- 入组人数
- 330
- 主要终点
- Part 1 - Percentage of Sero-reduction or Sero-conversion (Cured Subjects)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
入排标准
- 年龄范围
- — 至 17 Years（Child）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •Male and female subjects who were randomized and received at least one dose of their assigned 60- or 30-day regimen of nifurtimox treatment
排除标准
- •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
- •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)
研究组 & 干预措施
Nifurtimox 60 days / Arm 1
Nifurtimox tablets administered three times daily for 60 days (Days 1 - 60, active nifurtimox treatment)
干预措施: Nifurtimox (Lampit, BAYA2502) (Drug)
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)
干预措施: Nifurtimox (Lampit, BAYA2502) (Drug)
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)
干预措施: Placebo (Drug)
结局指标
主要结局
Part 1 - Percentage of Sero-reduction or Sero-conversion (Cured Subjects)
时间窗: 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 for historical placebo control.
Part 2 - Incidence Rate of Seronegative Conversion in Subjects Received at Least One Dose of the 60-day Nifurtimox Treatment Regimen.
时间窗: 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
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.
次要结局
- 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)
- Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Recombinant ELISA(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)
- 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 2 - Serological Response of Established Chagas-related Cardiomyopathy(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)
- Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 9(Up to 90 days (Visit 9 post-treatment))
- 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 2 - ECG Signs of Established Chagas-related Cardiomyopathy(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)
- Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 6(Up to 30 days (Visit 6))
- Part 1 + Part 2 - Serial Reduction of Optical Density Values Measured by Total Purified Antigen ELISA(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)
- Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 1(At Visit 1 (before treatment started))
- Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 10(Up to 240 days (Visit 10 post-treatment))
- Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 3(Up to 7 days (Visit 3))
- 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 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 11(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Clinical Signs/ Symptoms of Chagas Disease at Visit 8(Up to 60 days (Visit 8; end of treatment))
- Part 1 - Number of Subjects With Positive Results in Concentration Test for T. Cruzi (for Subjects <8 Months of Age)(Up to 90 days (Visit 9 post-treatment))
- Part 1 - Number of Subjects With a Positive Serological Response Using Non-conventional Enzyme-linked Immunosorbent Assay-F29 (ELISAF29) Test(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Positive Quantitative Polymerase Chain Reaction (qPCR) Results(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)(up to 7 days after last application of study drug)
- Part 2 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)(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)
- Part 1 - Number of Subjects With Treatment-emergent High Blood Chemistry Abnormalities by Treatment(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Treatment-emergent Low Blood Chemistry Abnormalities by Treatment(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Treatment-emergent High Hematology Abnormalities by Treatment(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Treatment-emergent Low Hematology Abnormalities by Treatment(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Treatment-emergent High Coagulation Abnormalities by Treatment(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Treatment-emergent Low Coagulation Abnormalities by Treatment(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Abnormal Urinalysis Findings Considered as Clinically Significant or Reported as Adverse Events (AEs)(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Number of Subjects With Abnormal ECG Findings Considered as Clinically Significant by Investigators(Up to 420 days (Visit 11 post-treatment))
- Part 1 - Mean Changes in Vital Signs (Systolic Blood Pressure) Between the Treatment Groups From Baseline(Baseline and up to 420 days (Visit 11 post-treatment))
- Part 1 - Mean Changes in Vital Signs (Diastolic Blood Pressure) Between the Treatment Groups From Baseline(Baseline and up to 420 days (Visit 11 post-treatment))
- Part 1 - Mean Changes in Vital Signs (Respiratory Rate) Between the Treatment Groups From Baseline(Baseline and up to 420 days (Visit 11 post-treatment))
- Part 1 - Mean Changes in Vital Signs (Heart Rate) Between the Treatment Groups From Baseline(Baseline and up to 420 days (Visit 11 post-treatment))
- Part 1 - Mean Changes in Vital Signs (Body Temperature) Between the Treatment Groups From Baseline(Baseline and up to 420 days (Visit 11 post-treatment))