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    Clinical Trial Results:
    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

    Summary
    EudraCT number
    		 2022-001504-17
    Trial protocol
    		 Outside EU/EEA  
    Global end of trial date
    10 Aug 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Aug 2022
    First version publication date
    31 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    16027
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02625974
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Bayer AG
    Sponsor organisation address
    Kaiser-Wilhelm-Allee, Leverkusen, Germany, 51368
    Public contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Scientific contact
    Therapeutic Area Head, Bayer AG, clinical-trials-contact@bayer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-003134-PIP01-21
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    10 Aug 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Aug 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study consists of two parts: Part 1 (CHICO) comprised the treatment with nifurtimox including the 1-year follow up, and Part 2 (CHICO SECURE) comprises additional 3 years of follow-up after end of Part 1. The primary objective of Part 1 was to assess the superiority of a 60-day regimen of nifurtimox to historical untreated control at the 12-month follow-up (360 days from end of treatment [EOT]) as: - sero-reduction (defined as a ≥20% reduction in OD compared to baseline in subjects ≥8 months to <18 years of age at randomization; or - sero-conversion (defined as negative IgG concentration) in all subjects The primary objective of Part 2 was to assess the incidence of seronegative conversion in subjects who were randomized and received at least one dose of the 60-day nifurtimox treatment regimen in Part 1, compared to an external control group of historical placebo patients with Chagas’ disease at the 4-year follow-up.
    Protection of trial subjects
    The conduct of this clinical study met all local legal and regulatory requirements. The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Before entering the study, the informed consent form was read by and explained to all subjects. Participating subjects signed informed consent form and could withdraw from the study at any time without any disadvantage and without having to provide a reason for this decision. Only investigators qualified by training and experience were selected as appropriate experts to investigate the study drug.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    27 Jan 2016
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 4 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 178
    Country: Number of subjects enrolled
    Bolivia, Plurinational State of: 62
    Country: Number of subjects enrolled
    Colombia: 90
    Worldwide total number of subjects
    330
    EEA total number of subjects
    0
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    7
    Infants and toddlers (28 days-23 months)
    37
    Children (2-11 years)
    146
    Adolescents (12-17 years)
    140
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Part 1 of the study was conducted from 27 JAN 2016 (First subject first visit) to 25 JUL 2018 (Last subject last visit) in Argentina, Bolivia and Colombia. Part 2 of the study was conducted from 26 SEP 2018 (First subject first visit) to 10 AUG 2021 (Last subject last visit) in Argentina, Bolivia and Colombia.

    Pre-assignment
    Screening details
    		 Part 1: 330 subjects who were eligible to participate in the study were randomized in a 2:1 ratio to either a 60-Day or 30-Day regimen with nifurtimox tablets. 308 subjects completed treatment in Part 1, and 318 subjects completed Part 1. Part 2: Of the 318 subjects completed Part 1, 295 subjects were included in Part 2.

    Period 1
    Period 1 title
    Part 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nifurtimox 60 days / Arm 1
    Arm description
    		 Nifurtimox tablets administered three times daily for 60 days (Days 1 – 60, active nifurtimox treatment)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nifurtimox
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nifurtimox tablets administered 3 times daily for 60 days (Days 1 – 60, active treatment, Treatment Group 1)

    Arm title
    		 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Arm description
    		 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)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nifurtimox
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nifurtimox tablets administered 3 times daily for 30 days (Days 1 – 30, active treatment; Treatment Group 2)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo administered 3 times daily for 30 days (Days 31 – 60, placebo; Treatment Group 2)

    Number of subjects in period 1
    		Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Started
    219
    111
    Received treatment
    219
    111
    Completed
    210
    108
    Not completed
    9
    3
         Lost to follow-up
    9
    3
    Period 2
    Period 2 title
    Part 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Nifurtimox 60 days / Arm 1
    Arm description
    		 Nifurtimox tablets administered three times daily for 60 days (Days 1 – 60, active nifurtimox treatment) Treatment administered in Part 1; no study drug was administered in Part 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nifurtimox
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nifurtimox tablets administered 3 times daily for 60 days (Days 1 – 60, active treatment, Treatment Group 1)

    Arm title
    		 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Arm description
    		 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) Treatment administered in Part 1; no study drug was administered in Part 2
    Arm type
    		 Experimental

    Investigational medicinal product name
    Nifurtimox
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Nifurtimox tablets administered 3 times daily for 30 days (Days 1 – 30, active treatment; Treatment Group 2)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Matching placebo administered 3 times daily for 30 days (Days 31 – 60, placebo; Treatment Group 2)

    Number of subjects in period 2 [1]
    		Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Started
    197
    98
    Completed
    191
    91
    Not completed
    6
    7
         Other, including due to the COVID-19 Pandemic
    2
    1
         Lost to follow-up
    4
    6
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Of the 318 subjects completed Part 1, 295 subjects were included in Part 2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Nifurtimox 60 days / Arm 1
    Reporting group description
    		 Nifurtimox tablets administered three times daily for 60 days (Days 1 – 60, active nifurtimox treatment)

    Reporting group title
    Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Reporting group description
    		 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)

    Reporting group values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2 Total
    Number of subjects
    		 219 111 330
    Age Categorical
    Units: Subjects
        0 to 27 days
    		 4 3 7
        28 days to younger than 8 months
    		 8 4 12
        8 months to younger than 2 years
    		 17 8 25
        2 years to younger than 18 years
    		 190 96 286
    Sex: Female, Male
    Units: Subjects
        Female
    		 119 59 178
        Male
    		 100 52 152
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 155 81 236
        American Indian or Alaska native
    		 64 30 94
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 217 108 325
        Not Hispanic or Latino
    		 2 3 5
        Unknown or Not Reported
    		 0 0 0
    Total Purified Antigen enzyme-linked immunosorbent assay (ELISA) test results
    Chagas disease diagnosed by direct observation of T. cruzi by concentration test (subjects <8 months of age at randomization) or positive conventional ELISA results for both recombinant ELISA and total purified antigen ELISA (subjects ≥8 months to younger than 18 years of age at randomization) as determined by local laboratory test results were eligible for enrollment.
    Units: Subjects
        Reactive
    		 219 110 329
        Non Reactive
    		 0 1 1
    Recombinant ELISA test results
    Chagas disease diagnosed by direct observation of T. cruzi by concentration test (subjects <8 months of age at randomization) or positive conventional ELISA results for both recombinant ELISA and total purified antigen ELISA (subjects ≥8 months to younger than 18 years of age at randomization) as determined by local laboratory test results were eligible for enrollment.
    Units: Subjects
        Reactive
    		 219 110 329
        Non Reactive
    		 0 1 1
    Non conventional ELISA-F29 test results
    The non-conventional ELISA-F29 test is considered an early marker of treatment efficacy in chronic Chagas disease.
    Units: Subjects
        Reactive
    		 142 72 214
        Non Reactive
    		 77 39 116
    Concentration test for T. cruzi
    Chagas disease diagnosed by direct observation of T. cruzi by concentration test (subjects <8 months of age at randomization).
    Units: Subjects
        Positive
    		 12 7 19
        Negative
    		 0 0 0
        Missing
    		 207 104 311
    Total Purified Antigen ELISA optical density (OD) values
    Units: No dimension
        arithmetic mean (standard deviation)
    		 1.474 ( 0.553 ) 1.532 ( 0.533 ) -
    Recombinant ELISA OD values
    Units: No dimension
        arithmetic mean (standard deviation)
    		 2.735 ( 0.640 ) 2.765 ( 0.605 ) -

    End points

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    End points reporting groups
    Reporting group title
    Nifurtimox 60 days / Arm 1
    Reporting group description
    		 Nifurtimox tablets administered three times daily for 60 days (Days 1 – 60, active nifurtimox treatment)

    Reporting group title
    Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Reporting group description
    		 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)
    Reporting group title
    Nifurtimox 60 days / Arm 1
    Reporting group description
    		 Nifurtimox tablets administered three times daily for 60 days (Days 1 – 60, active nifurtimox treatment) Treatment administered in Part 1; no study drug was administered in Part 2

    Reporting group title
    Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Reporting group description
    		 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) Treatment administered in Part 1; no study drug was administered in Part 2

    Subject analysis set title
    Nifurtimox 60 days Reactive Detectable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Reactive Conventional Serologic Testing and Detectable qPCR

    Subject analysis set title
    Nifurtimox 60 days Reactive Non-detectable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Reactive Conventional Serologic Testing and Non-detectable qPCR

    Subject analysis set title
    Nifurtimox 60 days Non-reactive Detectable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Non-reactive Conventional Serologic Testing and Detectable qPCR

    Subject analysis set title
    Nifurtimox 60 days Non-reactive Non-detectable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Non-reactive Conventional Serologic Testing and Non-detectable qPCR

    Subject analysis set title
    Nifurtimox 60 days Reactive Non evaluable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Reactive Conventional Serologic Testing and Non evaluable qPCR

    Subject analysis set title
    Nifurtimox 60 days Reactive qPCR Missing
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Reactive Conventional Serologic Testing and missing qPCR

    Subject analysis set title
    Nifurtimox 30 days Reactive Detectable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with Reactive Conventional Serologic Testing and Detectable qPCR

    Subject analysis set title
    Nifurtimox 30 days Reactive Non-detectable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with Reactive Conventional Serologic Testing and Non-detectable qPCR

    Subject analysis set title
    Nifurtimox 30 days Non-reactive Detectable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with Non-reactive Conventional Serologic Testing and Detectable qPCR

    Subject analysis set title
    Nifurtimox 30 days Non-reactive Non-detectable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with Non-reactive Conventional Serologic Testing and Non-detectable qPCR

    Subject analysis set title
    Nifurtimox 30 days Reactive Non evaluable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with Reactive Conventional Serologic Testing and Non evaluable qPCR

    Subject analysis set title
    Nifurtimox 30 days Missing Conventional testing Non-detectable
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with missing Conventional Serologic Testing and Non-detectable qPCR

    Subject analysis set title
    Nifurtimox 60 days Reactive and Reactive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Reactive Conventional Serologic Testing and Reactive Non-conventional Serologic Testing

    Subject analysis set title
    Nifurtimox 60 days Reactive and Non-reactive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Reactive Conventional Serologic Testing and Non-reactive Non-conventional Serologic Testing

    Subject analysis set title
    Nifurtimox 60 days Non-reactive and Reactive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Non-reactive Conventional Serologic Testing and Reactive Non-conventional Serologic Testing

    Subject analysis set title
    Nifurtimox 60 days Non-reactive and Non-reactive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 60 days with Non-reactive Conventional Serologic Testing and Non-reactive Non-conventional Serologic Testing

    Subject analysis set title
    Nifurtimox 30 days Reactive and Reactive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with Reactive Conventional Serologic Testing and Reactive Non-conventional Serologic Testing

    Subject analysis set title
    Nifurtimox 30 days Reactive and Non-reactive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with Reactive Conventional Serologic Testing and Non-reactive Non-conventional Serologic Testing

    Subject analysis set title
    Nifurtimox 30 days Non-reactive and Reactive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with Non-reactive Conventional Serologic Testing and Reactive Non-conventional Serologic Testing

    Subject analysis set title
    Nifurtimox 30 days Non-reactive and Non-reactive
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Nifurtimox 30 days with Non-reactive Conventional Serologic Testing and Non-reactive Non-conventional Serologic Testing

    Subject analysis set title
    Non-reactive ELISA and Non-reactive IHA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: Non-reactive IHA results: Non-reactive

    Subject analysis set title
    Non-reactive ELISA and reactive IHA decrease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: Non-reactive IHA results: reactive with decreasing in titers

    Subject analysis set title
    Non-react ELISA and react IHA Nochange
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: Non-reactive IHA results: reactive without change in titers

    Subject analysis set title
    Reactive ELISA: Sero-reduction and Non-react IHA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: reactive, Sero-reduction IHA results: Non-reactive

    Subject analysis set title
    Reactive ELISA: Sero reduction and reactive IHA decrease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: reactive, Sero-reduction IHA results: reactive with decreasing in titers

    Subject analysis set title
    Reactive ELISA: Sero-reduction and reactive IHA Nochange
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: reactive, Sero-reduction IHA results: reactive without Change in titers

    Subject analysis set title
    Reactive ELISA: Others and Non-reactive IHA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: reactive, Others IHA results: Non-reactive

    Subject analysis set title
    Reactive ELISA: Others and react IHA decrease
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: reactive, Other IHA: reactive with decreasing in titers

    Subject analysis set title
    Reactive ELISA: Others and react IHA Nochange
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: reactive, Other IHA results: reactive without Change in titers

    Subject analysis set title
    Reactive ELISA: Others and Missing IHA
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    ELISA results: reactive, Others IHA results: Missing

    Subject analysis set title
    Cure and Non reactive/reactive decreasing
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Elisa results: Cure IHA results: Non reactive or reactive but decreasing in titer

    Subject analysis set title
    Cure and reactive non-decreasing
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Elisa results: Cure IHA results: reactive but non-decreasing in titer

    Subject analysis set title
    No Cure and Non reactive/reactive decreasing
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Elisa results: No Cure IHA results: Non reactive or reactive but decreasing in titer

    Subject analysis set title
    No Cure and reactive non-decreasing
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Elisa results: No Cure IHA results: reactive but non-decreasing in titer

    Subject analysis set title
    No Cure and Missing IHA Testing
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Elisa results: No Cure IHA results: Missing

    Subject analysis set title
    Nifurtimox 60 days: Chagas-related cardiomyopathy = Yes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Serological response measured by two types of assays and ECG evaluation for signs of established Chagas-related cardiomyopathy by visit

    Subject analysis set title
    Nifurtimox 60 days: Chagas-related cardiomyopathy = No
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Serological response measured by two types of assays and ECG evaluation for signs of established Chagas-related cardiomyopathy by visit

    Subject analysis set title
    Nifurtimox 60 days: Chagas-related cardiomyopathy = Missing
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Serological response measured by two types of assays and ECG evaluation for signs of established Chagas-related cardiomyopathy by visit

    Subject analysis set title
    Nifurtimox 30 days: Chagas-related cardiomyopathy = Yes
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Serological response measured by two types of assays and ECG evaluation for signs of established Chagas-related cardiomyopathy by visit

    Subject analysis set title
    Nifurtimox 30 days: Chagas-related cardiomyopathy = No
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Serological response measured by two types of assays and ECG evaluation for signs of established Chagas-related cardiomyopathy by visit

    Subject analysis set title
    Nifurtimox 30 days: Chagas-related cardiomyopathy = Missing
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Serological response measured by two types of assays and ECG evaluation for signs of established Chagas-related cardiomyopathy by visit

    Subject analysis set title
    Historical Benznidazole 1998 - Sosa Estani et al. (1998)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    istorical Benznidazole 1998, publication from Sosa Estani et al. (1998), 4-year follow-up data.

    Subject analysis set title
    Historical Benznidazole 1996, Andrade et al. (1996)
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Historical Benznidazole 1996, publication from de Andrade et al. (1996), 3-year follow-up data.

    Primary: Part 1 - Percentage of sero-reduction or sero-conversion (cured subjects)

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    End point title
    		 Part 1 - Percentage of sero-reduction or sero-conversion (cured subjects)
    End point description
    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.
    End point type
    Primary
    End point timeframe
    At 12 months post-treatment
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Percentage of subjects
        number (confidence interval 95%)
    32.9 (26.4 to 39.3)
    18.9 (11.2 to 26.7)
    Statistical analysis title
    		 Historical Cure Rates
    Statistical analysis description
    Historical Cure Rates for Placebo Publication 1: De Andrade et al 1996. Age range (years): 7-12. Sero-conversion rate (95% CI) in placebo patients: 3/65 = 5% (1%, 13%) Publication 2: Sosa et al 1998. Age range (years): 6-12. Sero-conversion rate (95% CI) in placebo patients: 2/44 = 5% (1%, 16%). CI = confidence interval
    Comparison groups
    Nifurtimox 60 days / Arm 1 v Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects included in analysis
    330
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    Method
    Parameter type
    		 Difference in cure rate
    Point estimate
    14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 3.7
         upper limit
    		 24.2
    Notes
    [1] - A direct comparison

    Primary: Part 2 - Incidence rate of seronegative conversion in subjects received at least one dose of the 60-day nifurtimox treatment regimen.

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    End point title
    		 Part 2 - Incidence rate of seronegative conversion in subjects received at least one dose of the 60-day nifurtimox treatment regimen. [2]
    End point description
    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.
    End point type
    Primary
    End point timeframe
    4 years after end of treatment
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistics only
    End point values
    		 Nifurtimox 60 days / Arm 1
    Number of subjects analysed
    197
    Units: Incidence rate
        number (confidence interval 95%)
    2.12 (1.21 to 3.45)
    No statistical analyses for this end point

    Secondary: Part 2 - Incidence rate of seronegative conversion in subjects who received at least one dose of the 30-day nifurtimox treatment regimen

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    End point title
    		 Part 2 - Incidence rate of seronegative conversion in subjects who received at least one dose of the 30-day nifurtimox treatment regimen
    End point description
    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 30-day nifurtimox treatment regimen. 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.
    End point type
    Secondary
    End point timeframe
    4 years after end of treatment
    End point values
    		 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    98
    Units: Incidence rate
        number (confidence interval 95%)
    2.11 (0.91 to 4.16)
    No statistical analyses for this end point

    Secondary: Part 2 - Serological response and ECG signs of established Chagas-related cardiomyopathy

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    End point title
    		 Part 2 - Serological response and ECG signs of established Chagas-related cardiomyopathy
    End point description
    Summary of subjects by serological response and evidence of established Chagas-related cardiomyopathy as measured by electrocardiogram (ECG). Evidence of established Chagas-related cardiomyopathy: Total
    End point type
    Secondary
    End point timeframe
    4 years after end of treatment
    End point values
    		 Nifurtimox 60 days: Chagas-related cardiomyopathy = Yes Nifurtimox 60 days: Chagas-related cardiomyopathy = No Nifurtimox 60 days: Chagas-related cardiomyopathy = Missing Nifurtimox 30 days: Chagas-related cardiomyopathy = Yes Nifurtimox 30 days: Chagas-related cardiomyopathy = No Nifurtimox 30 days: Chagas-related cardiomyopathy = Missing
    Number of subjects analysed
    197
    197
    197
    98
    98
    98
    Units: Subjects
    number (not applicable)
        Year 2: Non Reactive
    0
    10
    0
    0
    3
    1
        Year 2: Reactive
    0
    177
    1
    0
    87
    0
        Year 2: Missing
    0
    0
    9
    0
    1
    6
        Year 3: Non Reactive
    0
    12
    0
    0
    5
    1
        Year 3: Reactive
    0
    163
    0
    0
    79
    0
        Year 3: Missing
    0
    0
    22
    0
    0
    13
        Year 4: Non-Reactive
    0
    14
    0
    0
    6
    0
        Year 4: Reactive
    0
    174
    2
    0
    83
    1
        Year 4: Missing
    0
    1
    6
    0
    1
    7
    No statistical analyses for this end point

    Secondary: Part 1 + Part 2 - Serial reduction of optical density values measured by Total Purified Antigen ELISA

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    End point title
    		 Part 1 + Part 2 - Serial reduction of optical density values measured by Total Purified Antigen ELISA
    End point description
    Summary and change from baseline of optical density values measured by total purified antigen ELISA.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 years after end of treatment
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    197
    98
    Units: Optical density
    arithmetic mean (standard deviation)
        Part 1 - Baseline (Visit 1)
    1.47 ( 0.55 )
    1.52 ( 0.55 )
        Part 1 - Up to 420 days post-treatment (Visit 11)
    1.24 ( 0.62 )
    1.30 ( 0.61 )
        Part 1 - Change from Baseline (Visit 11)
    -0.24 ( 0.29 )
    -0.23 ( 0.41 )
        Part 2 - Year 2: (FU Visit 1)
    1.23 ( 0.59 )
    1.29 ( 0.61 )
        Part 2 - Year 2: Change from Baseline (FU Visit 1)
    -0.25 ( 0.41 )
    -0.23 ( 0.49 )
        Part 2 - Year 3 (FU Visit 3)
    1.16 ( 0.58 )
    1.23 ( 0.58 )
        Part 2 - Year 3: Change from Baseline (FU Visit 3)
    -0.30 ( 0.42 )
    -0.30 ( 0.50 )
        Part 2 - Year 4 (FU Visit 5)
    1.12 ( 0.57 )
    1.23 ( 0.59 )
        Part 2 - Year 4: Change from Baseline (FU Visit 5)
    -0.35 ( 0.40 )
    -0.30 ( 0.46 )
    No statistical analyses for this end point

    Secondary: Part 1 + Part 2 - Serial reduction of optical density values measured by Recombinant ELISA

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    End point title
    		 Part 1 + Part 2 - Serial reduction of optical density values measured by Recombinant ELISA
    End point description
    Summary and change from baseline of optical density values measured by recombinant ELISA.
    End point type
    Secondary
    End point timeframe
    Baseline and 4 years after end of treatment
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    197
    98
    Units: Optical density
    arithmetic mean (standard deviation)
        Part 1 - Baseline (Visit 1)
    2.74 ( 0.63 )
    2.73 ( 0.63 )
        Part 1 - Up to 420 days post-treatment (Visit 11)
    2.27 ( 0.98 )
    2.31 ( 1.00 )
        Part 1 - Change from Baseline (Visit 11)
    -0.47 ( 0.74 )
    -0.41 ( 0.79 )
        Part 2 - Year 2: (FU Visit 1)
    2.5 ( 0.95 )
    2.57 ( 0.88 )
        Part 2 - Year 2: Change from Baseline (FU Visit 1)
    -0.23 ( 0.87 )
    -0.17 ( 0.90 )
        Part 2 - Year 3 (FU Visit 3)
    2.17 ( 0.98 )
    2.25 ( 0.91 )
        Part 2 - Year 3: Change from Baseline (FU Visit 3)
    -0.56 ( 0.86 )
    -0.45 ( 0.87 )
        Part 2 - Year 4 (FU Visit 5)
    2.09 ( 1.01 )
    2.22 ( 1.00 )
        Part 2 - Year 4: Change from Baseline (FU Visit 5)
    -0.64 ( 0.89 )
    -0.48 ( 0.87 )
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 1

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    End point title
    		 Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 1
    End point description
    The evaluation was based on clinical examinations.
    End point type
    Secondary
    End point timeframe
    At Visit 1 (before treatment started)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        Known ECG abnormality
    2
    0
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 3

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    End point title
    		 Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 3
    End point description
    The evaluation was based on clinical examinations.
    End point type
    Secondary
    End point timeframe
    Up to 7 days (Visit 3)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    110
    Units: Subjects
        Anemia
    1
    0
        Chagas disease
    2
    0
        Hepatomegaly
    1
    0
        Known ECG abnormality
    4
    0
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 6

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    End point title
    		 Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 6
    End point description
    The evaluation was based on clinical examinations.
    End point type
    Secondary
    End point timeframe
    Up to 30 days (Visit 6)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    215
    110
    Units: Subjects
        Known ECG abnormality
    1
    0
        Romana sign
    0
    1
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 8

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    End point title
    		 Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 8
    End point description
    The evaluation was based on clinical examinations.
    End point type
    Secondary
    End point timeframe
    Up to 60 days (Visit 8; end of treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    217
    109
    Units: Subjects
        Anemia
    1
    0
        Chagas disease
    1
    0
        Known ECG abnormality
    1
    0
        Lymphadenopathy
    1
    0
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 9

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    End point title
    		 Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 9
    End point description
    The evaluation was based on clinical examinations.
    End point type
    Secondary
    End point timeframe
    Up to 90 days (Visit 9 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    213
    107
    Units: Subjects
        Known ECG abnormality
    1
    0
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 10

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    End point title
    		 Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 10
    End point description
    The evaluation was based on clinical examinations.
    End point type
    Secondary
    End point timeframe
    Up to 240 days (Visit 10 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    212
    109
    Units: Subjects
        Known ECG abnormality
    1
    0
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 11

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    End point title
    		 Part 1 - Number of subjects with Clinical signs/ symptoms of Chagas disease at Visit 11
    End point description
    The evaluation was based on clinical examinations.
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    210
    108
    Units: Subjects
        Known ECG abnormality
    3
    3
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with positive results in concentration test for T. cruzi (for subjects <8 months of age)

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    End point title
    		 Part 1 - Number of subjects with positive results in concentration test for T. cruzi (for subjects <8 months of age)
    End point description
    End point type
    Secondary
    End point timeframe
    Up to 90 days (Visit 9 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    12
    7
    Units: Subjects
        Visit 1|Positive
    12
    7
        Visit 3|Positive
    1
    1
        Visit 6|Positive
    0
    0
        Visit 8|Positive
    0
    0
        Visit 9|Positive
    1
    0
        Visit 1|Negative
    0
    0
        Visit 3|Negative
    11
    5
        Visit 6|Negative
    12
    7
        Visit 8|Negative
    12
    7
        Visit 9|Negative
    11
    7
        Visit 1|Missing
    0
    0
        Visit 3|Missing
    0
    1
        Visit 6|Missing
    0
    0
        Visit 8|Missing
    0
    0
        Visit 9|Missing
    0
    0
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with a positive serological response using non-conventional enzyme-linked immunosorbent assay-F29 (ELISAF29) test

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    End point title
    		 Part 1 - Number of subjects with a positive serological response using non-conventional enzyme-linked immunosorbent assay-F29 (ELISAF29) test
    End point description
    The non-conventional ELISA-F29 test is considered an early marker of treatment efficacy in chronic Chagas disease.
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        Visit 1|Reactive
    142
    72
        Visit 3|Reactive
    133
    64
        Visit 6|Reactive
    131
    67
        Visit 8|Reactive
    124
    63
        Visit 10|Reactive
    110
    61
        Visit 11|Reactive
    96
    54
        Visit 1|Non-reactive
    77
    39
        Visit 3|Non-reactive
    85
    44
        Visit 6|Non-reactive
    83
    43
        Visit 8|Non-reactive
    91
    44
        Visit 10|Non-reactive
    101
    48
        Visit 11|Non-reactive
    114
    54
        Visit 1|Missing
    0
    0
        Visit 3|Missing
    1
    3
        Visit 6|Missing
    5
    1
        Visit 8|Missing
    4
    4
        Visit 10|Missing
    8
    2
        Visit 11|Missing
    9
    3
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with positive quantitative polymerase chain reaction (qPCR) results

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    End point title
    		 Part 1 - Number of subjects with positive quantitative polymerase chain reaction (qPCR) results
    End point description
    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
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        Visit 1|Non-detectable
    99
    53
        Visit 3|Non-detectable
    171
    86
        Visit 6|Non-detectable
    207
    105
        Visit 8|Non-detectable
    210
    105
        Visit 10|Non-detectable
    206
    105
        Visit 11|Non-detectable
    205
    102
        Visit 1|Detectable
    117
    57
        Visit 3|Detectable
    46
    21
        Visit 6|Detectable
    4
    3
        Visit 8|Detectable
    3
    1
        Visit 10|Detectable
    3
    2
        Visit 11|Detectable
    3
    5
        Visit 1|Non-evaluable
    1
    1
        Visit 3|Non-evaluable
    0
    1
        Visit 6|Non-evaluable
    3
    2
        Visit 8|Non-evaluable
    2
    2
        Visit 10|Non-evaluable
    2
    2
        Visit 11|Non-evaluable
    1
    1
        Visit 1|Missing
    2
    0
        Visit 3|Missing
    2
    3
        Visit 6|Missing
    5
    1
        Visit 8|Missing
    4
    3
        Visit 10|Missing
    8
    2
        Visit 11|Missing
    10
    3
    No statistical analyses for this end point

    Secondary: Part 1 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Part 1 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    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
    End point type
    Secondary
    End point timeframe
    up to 7 days after last application of study drug
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        Any treatment-emergent adverse event (TEAE)
    147
    66
        Any Serious TEAE
    6
    3
    No statistical analyses for this end point

    Secondary: Part 2 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)

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    End point title
    		 Part 2 - Number of Subjects With Treatment-emergent Adverse Events (TEAEs) and Treatment-emergent Serious Adverse Events (TESAEs)
    End point description
    TEAEs comprised events which first occurred or worsened at study start up to end of study in part 2. In Part 2, only AEs considered at least possibly related to nifurtimox (administered in part 1) and those caused by protocol-related procedures were reported.
    End point type
    Secondary
    End point timeframe
    up to 3 years after start of study part 2
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    197
    98
    Units: Subjects
        Any AE
    0
    0
        Any study drug-related AE
    0
    0
        Any AE related to protocol
    0
    0
        Any SAE
    0
    0
        Any study drug-related SAE
    0
    0
        Any SAE related to protocol
    0
    0
        AE with outcome death
    0
    0
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with treatment-emergent high blood chemistry abnormalities by treatment

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    End point title
    		 Part 1 - Number of subjects with treatment-emergent high blood chemistry abnormalities by treatment
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        Creatinine (mg/dL)
    3
    2
        Albumin (g/dL)
    49
    21
        Alkaline Phosphatase (U/L)
    11
    3
        Alanine Aminotransferase (U/L)
    19
    7
        Aspartate Aminotransferase (U/L)
    27
    7
        Bilirubin (mg/dL)
    19
    9
        Direct Bilirubin (mg/dL)
    21
    9
        Blood Urea Nitrogen (mg/dL)
    11
    3
        Urate (mg/dL)
    7
    1
        Glucose (mg/dL)
    15
    13
        Protein (g/dL)
    42
    14
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with treatment-emergent low blood chemistry abnormalities by treatment

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    End point title
    		 Part 1 - Number of subjects with treatment-emergent low blood chemistry abnormalities by treatment
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        Creatinine (mg/dL)
    22
    10
        Albumin (g/dL)
    14
    4
        Alkaline Phosphatase (U/L)
    4
    4
        Alanine Aminotransferase (U/L)
    6
    3
        Aspartate Aminotransferase (U/L)
    1
    5
        Bilirubin (mg/dL)
    7
    3
        Direct Bilirubin (mg/dL)
    0
    0
        Blood Urea Nitrogen (mg/dL)
    31
    15
        Urate (mg/dL)
    32
    18
        Glucose (mg/dL)
    29
    18
        Protein (g/dL)
    17
    15
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with treatment-emergent high hematology abnormalities by treatment

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    End point title
    		 Part 1 - Number of subjects with treatment-emergent high hematology abnormalities by treatment
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        Hematocrit (%)
    19
    8
        Hemoglobin (g/dL)
    15
    3
        Erythrocytes (T/L) in Blood
    21
    9
        Ery. Mean Corpuscular Volume (fL) in Blood
    20
    7
        Ery. Mean Corpuscular Hemoglobin (pg) in Blood
    14
    5
        Ery. Mean Corpuscular HGB Conc. (g/dL) in Blood
    23
    6
        Leukocytes (GIGA/L) in Blood
    41
    16
        Neutrophils/Leukocytes (%)
    38
    12
        Neutrophils (GIGA/L)
    36
    8
        Lymphocytes/Leukocytes (%)
    35
    17
        Lymphocytes (GIGA/L)
    21
    7
        Monocytes/Leukocytes (%)
    33
    17
        Monocytes (GIGA/L)
    17
    15
        Eosinophils/Leukocytes (%)
    58
    26
        Eosinophils (GIGA/L)
    53
    22
        Basophils/Leukocytes (%)
    20
    7
        Basophils (GIGA/L)
    10
    2
        Platelets (GIGA/L) in Blood
    27
    13
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with treatment-emergent low hematology abnormalities by treatment

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    End point title
    		 Part 1 - Number of subjects with treatment-emergent low hematology abnormalities by treatment
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Participants
        Hematocrit (%)
    30
    17
        Hemoglobin (g/dL)
    23
    17
        Erythrocytes (T/L) in Blood
    15
    9
        Ery. Mean Corpuscular Volume (fL) in Blood
    16
    6
        Ery. Mean Corpuscular Hemoglobin (pg) in Blood
    19
    10
        Ery. Mean Corpuscular HGB Conc. (g/dL) in Blood
    29
    21
        Leukocytes (GIGA/L) in Blood
    39
    18
        Neutrophils/Leukocytes (%)
    53
    27
        Neutrophils (GIGA/L)
    46
    25
        Lymphocytes/Leukocytes (%)
    40
    9
        Lymphocytes (GIGA/L)
    5
    0
        Monocytes/Leukocytes (%)
    54
    28
        Monocytes (GIGA/L)
    33
    22
        Eosinophils/Leukocytes (%)
    13
    5
        Eosinophils (GIGA/L)
    14
    5
        Basophils/Leukocytes (%)
    1
    2
        Basophils (GIGA/L)
    1
    2
        Platelets (GIGA/L) in Blood
    6
    3
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with treatment-emergent high coagulation abnormalities by treatment

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    End point title
    		 Part 1 - Number of subjects with treatment-emergent high coagulation abnormalities by treatment
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        Prothrombin Time (sec) in Plasma
    38
    23
        Activated Partial Thromboplastin
    9
    10
        Time in Plasma Prothrombin Intl. Normalized Ratio
    21
    13
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with treatment-emergent low coagulation abnormalities by treatment

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    End point title
    		 Part 1 - Number of subjects with treatment-emergent low coagulation abnormalities by treatment
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Participants
        Prothrombin Time (sec) in Plasma
    10
    5
        Activated Partial Thromboplastin
    15
    2
        Time in Plasma Prothrombin Intl. Normalized Ratio
    14
    5
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with abnormal Urinalysis findings considered as clinically significant or reported as Adverse Events (AEs)

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    End point title
    		 Part 1 - Number of subjects with abnormal Urinalysis findings considered as clinically significant or reported as Adverse Events (AEs)
    End point description
    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.
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        abnormal Urinalysis findings
    0
    0
    No statistical analyses for this end point

    Secondary: Part 1 - Number of subjects with abnormal ECG findings considered as clinically significant by investigators

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    End point title
    		 Part 1 - Number of subjects with abnormal ECG findings considered as clinically significant by investigators
    End point description
    Clinical significance of abnormal ECG was based on the judgement of the investigator
    End point type
    Secondary
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: Subjects
        abnormal ECG findings
    0
    0
    No statistical analyses for this end point

    Secondary: Part 1 - Mean changes in vital signs (Systolic Blood Pressure) between the treatment groups from baseline

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    End point title
    		 Part 1 - Mean changes in vital signs (Systolic Blood Pressure) between the treatment groups from baseline
    End point description
    Systolic Blood Pressure
    End point type
    Secondary
    End point timeframe
    Baseline and up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: mmHg
    arithmetic mean (standard deviation)
        VISIT 1
    1.09 ( 7.79 )
    0.69 ( 7.85 )
        VISIT 2
    -3.75 ( 7.50 )
    -5.00 ( 7.07 )
        VISIT 3
    1.08 ( 9.98 )
    -0.50 ( 8.45 )
        VISIT 6
    -0.74 ( 10.70 )
    -1.12 ( 9.89 )
        VISIT 8
    -0.41 ( 11.01 )
    0.48 ( 11.24 )
        VISIT 9
    -0.13 ( 11.11 )
    -0.45 ( 10.49 )
        VISIT 10
    -0.02 ( 10.46 )
    -1.48 ( 10.95 )
        VISIT 11
    1.20 ( 11.52 )
    1.57 ( 10.70 )
    No statistical analyses for this end point

    Secondary: Part 1 - Mean changes in vital signs (Diastolic Blood Pressure) between the treatment groups from baseline

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    End point title
    		 Part 1 - Mean changes in vital signs (Diastolic Blood Pressure) between the treatment groups from baseline
    End point description
    Diastolic Blood Pressure
    End point type
    Secondary
    End point timeframe
    Baseline and up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: mmHg
    arithmetic mean (standard deviation)
        VISIT 1
    1.00 ( 7.72 )
    0.90 ( 7.90 )
        VISIT 2
    -1.25 ( 2.50 )
    -1.00 ( 2.00 )
        VISIT 3
    0.76 ( 8.36 )
    0.26 ( 8.05 )
        VISIT 6
    0.26 ( 10.87 )
    -0.14 ( 10.21 )
        VISIT 8
    0.08 ( 9.91 )
    0.93 ( 10.17 )
        VISIT 9
    -0.68 ( 8.81 )
    -0.21 ( 10.03 )
        VISIT 10
    0.99 ( 9.90 )
    0.85 ( 9.53 )
        VISIT 11
    2.30 ( 11.06 )
    3.25 ( 10.95 )
    No statistical analyses for this end point

    Secondary: Part 1 - Mean changes in vital signs (Respiratory Rate) between the treatment groups from baseline

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    End point title
    		 Part 1 - Mean changes in vital signs (Respiratory Rate) between the treatment groups from baseline
    End point description
    Respiratory Rate
    End point type
    Secondary
    End point timeframe
    Baseline and up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: BREATHS/MIN
    arithmetic mean (standard deviation)
        VISIT 1
    0.12 ( 4.10 )
    0.47 ( 2.91 )
        VISIT 2
    -1.50 ( 3.42 )
    -1.00 ( 1.15 )
        VISIT 3
    -0.05 ( 3.15 )
    -0.14 ( 3.91 )
        VISIT 6
    -0.57 ( 4.16 )
    -0.06 ( 3.87 )
        VISIT 8
    -0.77 ( 4.04 )
    0.04 ( 4.58 )
        VISIT 9
    -1.01 ( 4.06 )
    -0.50 ( 3.76 )
        VISIT 10
    -1.36 ( 4.50 )
    -0.24 ( 3.60 )
        VISIT 11
    -1.93 ( 5.10 )
    -0.74 ( 4.61 )
    No statistical analyses for this end point

    Secondary: Part 1 - Mean changes in vital signs (Heart Rate) between the treatment groups from baseline

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    End point title
    		 Part 1 - Mean changes in vital signs (Heart Rate) between the treatment groups from baseline
    End point description
    Heart Rate
    End point type
    Secondary
    End point timeframe
    Baseline and up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: BEATS/MIN
    arithmetic mean (standard deviation)
        VISIT 1
    -1.08 ( 10.19 )
    0.26 ( 11.37 )
        VISIT 2
    -6.75 ( 2.22 )
    -0.75 ( 2.99 )
        VISIT 3
    0.04 ( 10.11 )
    -0.51 ( 11.46 )
        VISIT 6
    -0.78 ( 11.49 )
    -0.75 ( 11.92 )
        VISIT 8
    -1.27 ( 11.65 )
    -1.34 ( 11.03 )
        VISIT 9
    -1.26 ( 11.97 )
    -1.63 ( 10.56 )
        VISIT 10
    -3.28 ( 11.87 )
    -3.28 ( 11.61 )
        VISIT 11
    -3.57 ( 12.57 )
    -4.66 ( 14.73 )
    No statistical analyses for this end point

    Secondary: Part 1 - Mean changes in vital signs (Body Temperature) between the treatment groups from baseline

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    End point title
    		 Part 1 - Mean changes in vital signs (Body Temperature) between the treatment groups from baseline
    End point description
    Temperature
    End point type
    Secondary
    End point timeframe
    Baseline and up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    219
    111
    Units: °C
    arithmetic mean (standard deviation)
        VISIT 1
    0.01 ( 0.39 )
    0.04 ( 0.36 )
        VISIT 2
    -0.35 ( 0.45 )
    -0.03 ( 0.39 )
        VISIT 3
    -0.10 ( 0.36 )
    0.04 ( 0.43 )
        VISIT 6
    -0.06 ( 0.44 )
    0 ( 0.44 )
        VISIT 8
    -0.06 ( 0.45 )
    0.05 ( 0.42 )
        VISIT 9
    -0.03 ( 0.44 )
    0.02 ( 0.47 )
        VISIT 10
    -0.07 ( 0.49 )
    -0.01 ( 0.52 )
        VISIT 11
    -0.14 ( 0.51 )
    -0.10 ( 0.50 )
    No statistical analyses for this end point

    Secondary: Part 1 - Nifurtimox concentration over time in plasma at Visit 2

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    End point title
    		 Part 1 - Nifurtimox concentration over time in plasma at Visit 2
    End point description
    Measured in sub-population. 00000 = data not available.
    End point type
    Secondary
    End point 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
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    40
    23
    Units: ug/L
    median (full range (min-max))
        Predose
    00000 (00000 to 26.8)
    00000 (00000 to 00000)
        5 - 10 MIN POST
    00000 (00000 to 154.8)
    21.1 (00000 to 695.0)
        10 - 120 MIN POST
    78.2 (5.8 to 847.5)
    49.0 (00000 to 524.3)
        2 - 4 HOURS POST
    215.4 (77.9 to 516.3)
    300.7 (106.9 to 533.5)
        4 - 8 HOURS POST
    267.6 (40.2 to 508.1)
    289.6 (103.2 to 301.0)
    No statistical analyses for this end point

    Secondary: Part 1 - Nifurtimox concentration over time in plasma at Visit 3

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    End point title
    		 Part 1 - Nifurtimox concentration over time in plasma at Visit 3
    End point description
    Measured in sub-population. 00000 = data not available.
    End point type
    Secondary
    End point 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
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    40
    22
    Units: ug/L
    median (full range (min-max))
        Predose
    47.7 (00000 to 407.6)
    38.3 (00000 to 472.3)
        5 - 10 MIN POST
    82.6 (00000 to 561.6)
    56.0 (00000 to 442.8)
        10 - 120 MIN POST
    250.6 (13.8 to 1035.6)
    232.3 (13.9 to 706.3)
        2 - 4 HOURS POST
    497.2 (57.1 to 1027.4)
    257.7 (46.3 to 660.2)
        4 - 8 HOURS POST
    427.5 (141.2 to 778.2)
    267.0 (00000 to 339.6)
    No statistical analyses for this end point

    Secondary: Part 1 - Nifurtimox concentration over time in plasma at Visit 6

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    End point title
    		 Part 1 - Nifurtimox concentration over time in plasma at Visit 6
    End point description
    Measured in sub-population. 00000 = data not available.
    End point type
    Secondary
    End point 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
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    35
    24
    Units: ug/L
    median (full range (min-max))
        Predose
    23.8 (00000 to 459.3)
    40.8 (00000 to 284.3)
        5 - 10 MIN POST
    71.7 (00000 to 153.7)
    73.7 (00000 to 266.7)
        10 - 120 MIN POST
    135.0 (00000 to 932.4)
    172.7 (14.1 to 387.3)
        2 - 4 HOURS POST
    369.5 (92.1 to 1277.0)
    103.8 (12.3 to 1107.2)
        4 - 8 HOURS POST
    249.7 (70.9 to 504.3)
    165.2 (84.9 to 1089.3)
    No statistical analyses for this end point

    Secondary: Part 1 - Nifurtimox concentration over time in plasma at Visit 8

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    End point title
    		 Part 1 - Nifurtimox concentration over time in plasma at Visit 8
    End point description
    Measured in sub-population. 00000 = data not available.
    End point type
    Secondary
    End point 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
    End point values
    		 Nifurtimox 60 days / Arm 1 Nifurtimox 30 days, then Placebo 30 days / Arm 2
    Number of subjects analysed
    36
    19
    Units: ug/L
    median (full range (min-max))
        Predose
    00000 (00000 to 258.7)
    00000 (00000 to 00000)
        5 - 10 MIN POST
    92.4 (15.9 to 255.1)
    00000 (00000 to 00000)
        10 - 120 MIN POST
    139.1 (23.6 to 711.4)
    00000 (00000 to 21.5)
        2 - 4 HOURS POST
    395.6 (166.9 to 883.0)
    00000 (00000 to 00000)
        4 - 8 HOURS POST
    300.6 (28.5 to 1217.2)
    00000 (00000 to 00000)
    No statistical analyses for this end point

    Other pre-specified: Part 1: Number of subjects cured with 60-day regimen compared with historical active control (benznidazole)

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    End point title
    		 Part 1: Number of subjects cured with 60-day regimen compared with historical active control (benznidazole) [3]
    End point description
    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.
    End point type
    Other pre-specified
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    Notes
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistics only
    End point values
    		 Nifurtimox 60 days / Arm 1 Historical Benznidazole 1998 - Sosa Estani et al. (1998) Historical Benznidazole 1996, Andrade et al. (1996)
    Number of subjects analysed
    219
    53
    64
    Units: Subjects
    10
    4
    4
    No statistical analyses for this end point

    Other pre-specified: Part 1 - Relationship of conventional serology (total purified antigen ELISA) and qPCR testing by Visit

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    End point title
    		 Part 1 - Relationship of conventional serology (total purified antigen ELISA) and qPCR testing by Visit
    End point description
    Using frequencies of matches and mismatches to assess agreement Reactive = Reac ELISA Detectable = Detec qPCR Non-reactive = Nonreac ELISA Non-detectable = Nondetec qPCR Non evaluable = Noneval qPCR qPCR Missing = Miss qPCR Missing conventional testing = Miss ELISA
    End point type
    Other pre-specified
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days Reactive Detectable Nifurtimox 60 days Reactive Non-detectable Nifurtimox 60 days Non-reactive Detectable Nifurtimox 60 days Non-reactive Non-detectable Nifurtimox 60 days Reactive Non evaluable Nifurtimox 60 days Reactive qPCR Missing Nifurtimox 30 days Reactive Detectable Nifurtimox 30 days Reactive Non-detectable Nifurtimox 30 days Non-reactive Detectable Nifurtimox 30 days Non-reactive Non-detectable Nifurtimox 30 days Reactive Non evaluable Nifurtimox 30 days Missing Conventional testing Non-detectable
    Number of subjects analysed
    219 [4]
    219 [5]
    219 [6]
    219 [7]
    219 [8]
    219 [9]
    111 [10]
    111 [11]
    111 [12]
    111 [13]
    111 [14]
    111 [15]
    Units: Subjects
        Visit 1
    117
    99
    0
    0
    1
    2
    57
    52
    0
    1
    1
    0
        Visit 8
    3
    210
    0
    0
    2
    0
    1
    103
    0
    1
    2
    1
        Visit 10
    3
    195
    0
    11
    2
    0
    2
    99
    0
    6
    2
    0
        Visit 11
    3
    194
    0
    11
    1
    1
    5
    96
    0
    6
    1
    0
    Notes
    [4] - Nifurtimox 60 days with Reac ELISA and Detec qPCR
    [5] - Nifurtimox 60 days with Reac ELISA and Nondetec qPCR
    [6] - Nifurtimox 60 days with Nonreac ELISA and Detec qPCR
    [7] - Nifurtimox 60 days with Nonreac ELISA and Nondetec qPCR
    [8] - Nifurtimox 60 days with Reac ELISA and Non evaluable qPCR
    [9] - Nifurtimox 60 days with Reac ELISA and missing qPCR
    [10] - Nifurtimox 30 days with Reac ELISA and Detec qPCR
    [11] - Nifurtimox 30 days with Reac ELISA and Nondetec qPCR
    [12] - Nifurtimox 30 days with Nonreac ELISA and Detec qPCR
    [13] - Nifurtimox 30 days with Nonreac ELISA and Nondetec qPCR
    [14] - Nifurtimox 30 days with Reac ELISA and Non evaluable qPCR
    [15] - Nifurtimox 30 days with Miss ELISA and Nondetec qPCR
    No statistical analyses for this end point

    Other pre-specified: Part 1 - Relationship of conventional serology (total purified antigen ELISA) and non-conventional (ELISA-F29) serologic testing by visit

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    End point title
    		 Part 1 - Relationship of conventional serology (total purified antigen ELISA) and non-conventional (ELISA-F29) serologic testing by visit
    End point description
    Using frequencies of matches and mismatches to assess agreement Reactive = Reac ELISA Reactive = Reac F29 Non-reactive = Nonreac ELISA Non-reactive = Nonreac F29
    End point type
    Other pre-specified
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days Reactive and Reactive Nifurtimox 60 days Reactive and Non-reactive Nifurtimox 60 days Non-reactive and Reactive Nifurtimox 60 days Non-reactive and Non-reactive Nifurtimox 30 days Reactive and Reactive Nifurtimox 30 days Reactive and Non-reactive Nifurtimox 30 days Non-reactive and Reactive Nifurtimox 30 days Non-reactive and Non-reactive
    Number of subjects analysed
    219 [16]
    219 [17]
    219 [18]
    219 [19]
    111 [20]
    111 [21]
    111 [22]
    111 [23]
    Units: Subjects
        Visit 1
    142
    77
    0
    0
    72
    38
    0
    1
        Visit 3
    133
    85
    0
    0
    64
    43
    0
    1
        Visit 6
    131
    83
    0
    0
    67
    42
    0
    1
        Visit 8
    124
    91
    0
    0
    63
    43
    0
    1
        Visit 10
    108
    92
    2
    9
    61
    42
    0
    6
        Visit 11
    93
    106
    3
    8
    54
    48
    0
    6
    Notes
    [16] - Nifurtimox 60 days with Reac ELISA and Reac F29
    [17] - Nifurtimox 60 days with Reac ELISA and Nonreac F29
    [18] - Nifurtimox 60 days with Nonreac ELISA and Reac F29
    [19] - Nifurtimox 60 days with Nonreac ELISA and Nonreac F29
    [20] - Nifurtimox 30 days with Reac ELISA and Reac F29
    [21] - Nifurtimox 30 days with Reac ELISA and Nonreac F29
    [22] - Nifurtimox 30 days with Nonreac ELISA and Reac F29g
    [23] - Nifurtimox 30 days Nonreac ELISA and Nonreac F29
    No statistical analyses for this end point

    Other pre-specified: Part 1 - Relationship of conventional serology (recombinant ELISA) and non-conventional (ELISA-F29) serologic testing by visit

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    End point title
    		 Part 1 - Relationship of conventional serology (recombinant ELISA) and non-conventional (ELISA-F29) serologic testing by visit
    End point description
    Using frequencies of matches and mismatches to assess agreement Reactive = Reac ELISA Reactive = Reac F29 Non-reactive = Nonreac ELISA Non-reactive= Nonreac F29
    End point type
    Other pre-specified
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Nifurtimox 60 days Reactive and Reactive Nifurtimox 60 days Reactive and Non-reactive Nifurtimox 60 days Non-reactive and Reactive Nifurtimox 60 days Non-reactive and Non-reactive Nifurtimox 30 days Reactive and Reactive Nifurtimox 30 days Reactive and Non-reactive Nifurtimox 30 days Non-reactive and Reactive Nifurtimox 30 days Non-reactive and Non-reactive
    Number of subjects analysed
    219 [24]
    219 [25]
    219 [26]
    219 [27]
    111 [28]
    111 [29]
    111 [30]
    111 [31]
    Units: Subjects
        Visit 1
    142
    77
    0
    0
    72
    38
    0
    1
        Visit 3
    133
    85
    0
    0
    64
    43
    0
    1
        Visit 6
    131
    81
    0
    2
    67
    42
    0
    1
        Visit 8
    124
    90
    0
    1
    63
    43
    0
    1
        Visit 10
    108
    91
    2
    10
    59
    43
    2
    5
        Visit 11
    93
    106
    3
    8
    53
    48
    1
    6
    Notes
    [24] - Nifurtimox 60 days Reac ELISA and Reac F29
    [25] - Nifurtimox 60 days with Reac ELISA and Nonreac F29
    [26] - Nifurtimox 60 days with Nonreac ELISA and Reac F29
    [27] - Nifurtimox 60 days Nonreac ELISA and Nonreac F29
    [28] - Nifurtimox 30 days with Reactive ConvReac ELISA and Reac F29
    [29] - Nifurtimox 30 days with Reac ELISA and Nonreac F29
    [30] - Nifurtimox 30 days with Nonreac ELISA and Reac F29
    [31] - Nifurtimox 30 days with Nonreac ELISA and Nonreac F29
    No statistical analyses for this end point

    Other pre-specified: Part 1 - Relationship of conventional serology (ELISA) to Indirect hemagglutination assay (IHA) results

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    End point title
    		 Part 1 - Relationship of conventional serology (ELISA) to Indirect hemagglutination assay (IHA) results
    End point description
    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. Non-reactive ELISA = Nonreac ELISA Non-reactive IHA = Nonreac IHA Reactive IHA decrease = Reac IHA dec React IHA nochange = Reac IHA nochange Reactive ELISA: seroreduction = Reac ELISA reduc Reactive ELISA: others = Reac ELISA other
    End point type
    Other pre-specified
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Non-reactive ELISA and Non-reactive IHA Non-reactive ELISA and reactive IHA decrease Non-react ELISA and react IHA Nochange Reactive ELISA: Sero-reduction and Non-react IHA Reactive ELISA: Sero reduction and reactive IHA decrease Reactive ELISA: Sero-reduction and reactive IHA Nochange Reactive ELISA: Others and Non-reactive IHA Reactive ELISA: Others and react IHA decrease Reactive ELISA: Others and react IHA Nochange Reactive ELISA: Others and Missing IHA
    Number of subjects analysed
    318 [32]
    318 [33]
    318 [34]
    318 [35]
    318 [36]
    318 [37]
    318 [38]
    318 [39]
    318 [40]
    318 [41]
    Units: Subjects
        Nifurtimox 60 days
    8
    2
    0
    2
    40
    20
    1
    47
    89
    1
        Nifurtimox 30 days
    4
    1
    0
    0
    12
    4
    1
    30
    58
    0
    Notes
    [32] - Nonreac ELISA and Nonreac IHA
    [33] - Nonreac ELISA and Reac IHA dec
    [34] - Nonreac ELISA and Reac IHA nochange
    [35] - Reac ELISA and Nonreac IHA
    [36] - Reac ELISA reduc and Reac IHA dec
    [37] - Reac ELISA reduc and Reac IHA nochange
    [38] - Reac ELISA other and Nonreac IHA
    [39] - Reac ELISA other and Reac IHA dec
    [40] - Reac ELISA other and Reac IHA nochange
    [41] - Reac ELISA other and IHA missing
    No statistical analyses for this end point

    Other pre-specified: Part 1 - Relationship between conventional ELISA results in terms of Cure or No Cure and IHA results in all patients

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    End point title
    		 Part 1 - Relationship between conventional ELISA results in terms of Cure or No Cure and IHA results in all patients
    End point description
    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. Cure = Cure Non reactive/reactive decreasing = Nonreac/reac dec Reactive non-decreasing = Reac nondec No cure = No Cure Missing IHA testing = IHA missing
    End point type
    Other pre-specified
    End point timeframe
    Up to 420 days (Visit 11 post-treatment)
    End point values
    		 Cure and Non reactive/reactive decreasing Cure and reactive non-decreasing No Cure and Non reactive/reactive decreasing No Cure and reactive non-decreasing No Cure and Missing IHA Testing
    Number of subjects analysed
    318 [42]
    318 [43]
    318 [44]
    318 [45]
    318 [46]
    Units: Subjects
        Nifurtimox 60 days
    52
    20
    48
    89
    1
        Nifurtimox 30 days
    17
    4
    29
    58
    0
    Notes
    [42] - ELISA Cure and IHA Nonreac/reac dec
    [43] - ELISA Cure and IHA Reac nondec
    [44] - ELISA No Cure and IHA results: Nonreac/reac dec
    [45] - ELISA No Cure and IHA Reac nondec
    [46] - ELISA No Cure and IHA missing
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Part 1: From first application of study drug up to and including 7 days after last application of study drug Part 2: first occurred or worsened at start 0f study part 2 up to 3 years.
    Adverse event reporting additional description
    Part 1: TEAS first occurred or worsened after first application of study drug up to 7 days after last application. Part 2: only AEs considered at least possibly related to nifurtimox (administered in part 1) and those caused by protocol-related procedures were reported.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.0
    Reporting groups
    Reporting group title
    Nifurtimox 30 days
    Reporting group description
    		 Nifurtimox tablets administered three times daily for 30 days, followed by placebo administered three timesdaily for 30 days (Days 1 - 30, active nifurtimox treatment; Days 31 - 60, placebo)

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

    Serious adverse events
    		 Nifurtimox 30 days Nifurtimox 60 days
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 111 (2.70%)
    6 / 219 (2.74%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Nervous system disorders
    Febrile convulsion
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Apnoea
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Urticaria
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pelvic inflammatory disease
         subjects affected / exposed
    0 / 111 (0.00%)
    1 / 219 (0.46%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear infection
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 111 (0.90%)
    0 / 219 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Nifurtimox 30 days Nifurtimox 60 days
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    44 / 111 (39.64%)
    98 / 219 (44.75%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 111 (14.41%)
    28 / 219 (12.79%)
         occurrences all number
    22
    41
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 111 (2.70%)
    16 / 219 (7.31%)
         occurrences all number
    3
    17
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    7 / 111 (6.31%)
    15 / 219 (6.85%)
         occurrences all number
    9
    23
    Abdominal pain upper
         subjects affected / exposed
    4 / 111 (3.60%)
    14 / 219 (6.39%)
         occurrences all number
    5
    19
    Diarrhoea
         subjects affected / exposed
    6 / 111 (5.41%)
    10 / 219 (4.57%)
         occurrences all number
    7
    10
    Nausea
         subjects affected / exposed
    14 / 111 (12.61%)
    18 / 219 (8.22%)
         occurrences all number
    15
    23
    Vomiting
         subjects affected / exposed
    9 / 111 (8.11%)
    32 / 219 (14.61%)
         occurrences all number
    10
    56
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 111 (5.41%)
    14 / 219 (6.39%)
         occurrences all number
    6
    17
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    8 / 111 (7.21%)
    23 / 219 (10.50%)
         occurrences all number
    8
    24

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Apr 2015
    - Text added to indicate that ECGs will be obtained at the time PK samples are collected when nifurtimox has reached Cmax or peak steady-state concentrations (i.e., at the 2 – 4 hour time point). - Clarification of study objectives and efficacy variables regarding sero-reduction and sero-conversion; change in tests required for confirmation of Chagas’ disease (recombinant ELISA and total purified antigen ELISA). - Baseline specimens for serological tests to be collected for diagnosis, and frozen as a subject control. - Change in urine color to be reinforced to subjects at the visits where study drug is dispensed. - Information about laboratory procedures, assay variability and cutoffs, and facilities to be used for all assays was added. - A safety and compliance questionnaire/script (Phone Contact Form) for use by site staff when conducting the telephone assessments was added. - For standardization of adverse event reporting, the terms “mild”, “moderate”, and “severe” were defined within the protocol. - A telephone assessment at Day 14 was added. - Measurement of ECGs will be optional assessments for subjects < 5 years of age, and required for subjects 5 years of age and older. - A neurological examination to be performed at the time of each physical examination in the study was added. - Detailed procedures regarding follow-up on all subjects who prematurely discontinue study drug was added. - Monitoring of treatment compliance was included in the Visit 6 (Day 30) study assessments to be conducted via telephone; this is reflected in the Phone Contact Form. - A Phone Contact Form was developed and added as an appendix to the protocol. - A Subject Diary was developed and added as an appendix to the protocol.
    19 Oct 2015
    - To address FDA comments regarding handling of the analyses of data for the primary efficacy endpoint. - To provide textual clarifications resulting from comments received from Ethics Committees and ex-US Health Authorities. - Overall editorial corrections and clarifications.
    07 Apr 2016
    - To delete a phrase “and ECG abnormalities” which was added in error to amendment 2.
    15 Nov 2016
    - To implement a PK subject diary which will allow PK subjects to record the meals consumed with study drug administration. - Clarifying editorial changes were made
    12 Oct 2017
    - To introduce an additional test (Immunofluorescent antibody, IFA), which would validate the current ELISA test results, as requested by FDA. This test will be carried out at Visit 1 and Visit 11 using random back-up samples from the study subjects.
    20 Dec 2017
    - To replace the immunofluorescent antibody (IFA) test introduced via Amendment 5 by the indirect hemagglutination assay (IHA). - Use of another serological test such as IFA or IHA was requested by FDA to validate the current ELISA test results. This test will be carried out at Visit 1 and Visit 11 using random back-up samples from the study subjects.
    11 May 2018
    - To satisfy FDA’s request to “further describe and verify the clinical benefit of nifurtimox” according to the FDA meeting minutes of the Type C meeting in August 2017 by following the subjects in Study 16027 for a reasonable amount of time to demonstrate reversion of serology to negative. - Changes include extending the current Study 16027 with the long-term follow-up (LTFU), and detailed study design and procedures for this LTFU considering FDA’s recommendations to the detailed study concept for the LTFU received in March 2018.
    23 Jul 2019
    To incorporate feedback received from study site personnel at the investigator meeting for part 2 of the study in APR 2019. None of the changes implemented in this amendment impact the benefit-risk evaluation of the study.
    18 Oct 2019
    - To incorporate feedback received from the FDA on 19 SEP 2019. It will allow subjects who were randomized and received at least one dose of their assigned nifurtimox treatment regimen and who are otherwise eligible to participate in the long-term follow-up portion of the study (Part 2, CHICO SECURE), regardless of subsequent treatment for Chagas’ disease. None of the changes implemented in this amendment impact the benefit-risk evaluation of the study.
    03 Nov 2020
    - To incorporate feedback received from the FDA on 10 JUL 2020. The Agency requested inclusion of non-conventional ELISA in Part 2 (CHICO SECURE) of the study and that antibody titers by serial dilution be obtained for all available serum samples. None of the changes implemented in this amendment impacted the benefit-risk evaluation of the study.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Abnormal findings on neurological examination by physical examination after Screening will be documented as AEs.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/33412557
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