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    Clinical Trial Results:
    Phase II clinical trial for the evaluation of different regimens of benznidazole as a treatment for Chagas disease in chronic phase in adult patients. Berenice project.

    Summary
    EudraCT number
    		 2016-003789-21
    Trial protocol
    		 ES  
    Global end of trial date
    21 Sep 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    MULTBENZ
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Fundació Hospital Universitari Vall d´Hebron - Institut de Recerca (VHIR)
    Sponsor organisation address
    Passeig Vall Hebron 119-129, Barcelona, Spain, 08035
    Public contact
    Israel Molina Romero, Fundación Hospital Universitari Vall d'Hebron - Institut de Recerca, 34 932746080, aro@vhir.org
    Scientific contact
    Israel Molina Romero, Fundación Hospital Universitari Vall d'Hebron - Institut de Recerca, 34 932746080, aro@vhir.org
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    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
    13 Jul 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Sep 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Sep 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the efficacy of different benznidazole regimens using the proportion of patients with sustained load suppression parasitic measured with PCR in peripheral blood during the first 12 months follow-up after the start treatment, in patients equal to or older than 18 years with Chagas disease in chronic phase both in its form indeterminate as in organic (digestive o cardiac)
    Protection of trial subjects
    There is no need to have special measurements to protect patients in this assay, since no pain or stress is expected
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2017
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Brazil: 60
    Country: Number of subjects enrolled
    Argentina: 60
    Country: Number of subjects enrolled
    Colombia: 58
    Country: Number of subjects enrolled
    Spain: 60
    Worldwide total number of subjects
    238
    EEA total number of subjects
    60
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    200
    From 65 to 84 years
    38
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 -

    Pre-assignment period milestones
    Number of subjects started
    		 238
    Number of subjects completed
    		 238

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rama B300/60
    Arm description
    		 Benznidazole 150 mg is administered every 12 hours for 60 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Benznidazole 150mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Benznidazole 150 mg is administered every 12 hours for 60 days.

    Arm title
    		 B150/60
    Arm description
    		 Benznidazole 150mg is administered every 24 hours for 60 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benznidazole 150mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Benznidazole 150mg is administered every 24 hours for 60 days.

    Arm title
    		 B400/15
    Arm description
    		 Benznidazole 200 mg is administered every 12 hours for 15 days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Benznidazole 200mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Benznidazole 200 mg is administered every 12 hours for 15 days.

    Number of subjects in period 1
    		Rama B300/60 B150/60 B400/15
    Started
    79
    80
    79
    Completed
    54
    62
    62
    Not completed
    25
    18
    17
         Physician decision
    -
    9
    7
         Lost to follow-up
    12
    9
    10
         Lack of efficacy
    13
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rama B300/60
    Reporting group description
    		 Benznidazole 150 mg is administered every 12 hours for 60 days.

    Reporting group title
    B150/60
    Reporting group description
    		 Benznidazole 150mg is administered every 24 hours for 60 days.

    Reporting group title
    B400/15
    Reporting group description
    		 Benznidazole 200 mg is administered every 12 hours for 15 days.

    Reporting group values
    		 Rama B300/60 B150/60 B400/15 Total
    Number of subjects
    		 79 80 79 238
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 66 67 67 200
        From 65-84 years
    		 13 13 12 38
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 44.6 ± 16.2 47.6 ± 11.2 46.9 ± 13 -
    Gender categorical
    Units: Subjects
        Female
    		 53 48 45 146
        Male
    		 26 32 34 92

    End points

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    End points reporting groups
    Reporting group title
    Rama B300/60
    Reporting group description
    		 Benznidazole 150 mg is administered every 12 hours for 60 days.

    Reporting group title
    B150/60
    Reporting group description
    		 Benznidazole 150mg is administered every 24 hours for 60 days.

    Reporting group title
    B400/15
    Reporting group description
    		 Benznidazole 200 mg is administered every 12 hours for 15 days.

    Subject analysis set title
    Overall study
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All the patients who started the treatment are included

    Primary: To assess the efficacy of different benznidazole regimens using the patients with sustained load suppression parasitic measured with PCR in peripheral blood during the first 12 months follow-up after the start treatment

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    End point title
    		 To assess the efficacy of different benznidazole regimens using the patients with sustained load suppression parasitic measured with PCR in peripheral blood during the first 12 months follow-up after the start treatment
    End point description
    End point type
    Primary
    End point timeframe
    R300/60 and R150/60 at 60 days after introduction of IMP R400/15 at 15 days after introduction of IMP
    End point values
    		 Rama B300/60 B150/60 B400/15
    Number of subjects analysed
    79
    80
    79
    Units: Percentage
        number (not applicable)
    54
    62
    67
    Statistical analysis title
    		 Treatment
    Comparison groups
    Rama B300/60 v B150/60 v B400/15
    Number of subjects included in analysis
    238
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.3631
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    End of study
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    25
    Reporting groups
    Reporting group title
    All groups
    Reporting group description
    		 -

    Serious adverse events
    		 All groups
    Total subjects affected by serious adverse events
         subjects affected / exposed
    8 / 228 (3.51%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Supraventricular tachyarrhythmia
         subjects affected / exposed
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Acute myocardial infarction
         subjects affected / exposed
    1 / 228 (0.44%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Neutropenia
         subjects affected / exposed
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Rash and fever
         subjects affected / exposed
    2 / 228 (0.88%)
         occurrences causally related to treatment / all
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 All groups
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    177 / 228 (77.63%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    52 / 228 (22.81%)
         occurrences all number
    52
    Dysgeusia
         subjects affected / exposed
    13 / 228 (5.70%)
         occurrences all number
    13
    Paresthesia
         subjects affected / exposed
    10 / 228 (4.39%)
         occurrences all number
    10
    Dizziness
         subjects affected / exposed
    8 / 228 (3.51%)
         occurrences all number
    8
    Blood and lymphatic system disorders
    leucopenia
         subjects affected / exposed
    12 / 228 (5.26%)
         occurrences all number
    12
    Social circumstances
    Anxiety
         subjects affected / exposed
    5 / 228 (2.19%)
         occurrences all number
    5
    Insomnia
         subjects affected / exposed
    36 / 228 (15.79%)
         occurrences all number
    36
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    59 / 228 (25.88%)
         occurrences all number
    59
    Epigastric discomfort
         subjects affected / exposed
    55 / 228 (24.12%)
         occurrences all number
    55
    Diffuse abdominal pain
         subjects affected / exposed
    31 / 228 (13.60%)
         occurrences all number
    31
    Diarrhoea
         subjects affected / exposed
    15 / 228 (6.58%)
         occurrences all number
    15
    Transaminases increased
         subjects affected / exposed
    100 / 228 (43.86%)
         occurrences all number
    100
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    61 / 228 (26.75%)
         occurrences all number
    61
    Rash
         subjects affected / exposed
    81 / 228 (35.53%)
         occurrences all number
    81
    Urticaria
         subjects affected / exposed
    14 / 228 (6.14%)
         occurrences all number
    14
    Facial oedema
         subjects affected / exposed
    5 / 228 (2.19%)
         occurrences all number
    5
    Musculoskeletal and connective tissue disorders
    Musculoskeletal disorder
         subjects affected / exposed
    59 / 228 (25.88%)
         occurrences all number
    59

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    25 Aug 2016
    Due to the fact that recruitment is lower than expected, it was decided to include a new center in Spain (Ramon y Cajal Hospital).

    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.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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