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    Clinical Trial Results:
    Open Label Study to Evaluate the Pharmacokinetics of Fidaxomicin in Inflammatory Bowel Disease (IBD) Subjects with Clostridium Difficile Infection (CDI)

    Summary
    EudraCT number
    2014-003002-32
    Trial protocol
    CZ   DE   AT   GR   PL  
    Global end of trial date
    24 Oct 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    28 Oct 2017
    First version publication date
    28 Oct 2017
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2819-MA-1003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02437591
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Astellas Pharma Europe Ltd.
    Sponsor organisation address
    2000 Hillswood Drive, Chertsey, United Kingdom, KT16 0RS
    Public contact
    Clinical Trial Disclosure, Astellas Pharma Europe Ltd., astellas.resultsdisclosure@astellas.com
    Scientific contact
    Clinical Trial Disclosure, Astellas Pharma Europe Ltd., astellas.resultsdisclosure@astellas.com
    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
    24 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    24 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to investigate the plasma pharmacokinetics of fidaxomicin and its primary metabolite OP-1118, in participants with inflammatory bowel disease (IBD) and clostridium difficile infection (CDI).
    Protection of trial subjects
    This clinical study was written, conducted and reported in accordance with the protocol, International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) Guidelines, and applicable local regulations, including the European Directive 2001/20/EC, on the protection of human rights, and with the ethical principles that have their origin in the Declaration of Helsinki. Astellas ensures that the use and disclosure of protected health information (PHI) obtained during a research study complies with the federal, national and/or regional legislation related to the privacy and protection of personal information.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    13 Aug 2015
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Greece: 3
    Country: Number of subjects enrolled
    France: 2
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Poland: 9
    Country: Number of subjects enrolled
    Russian Federation: 7
    Country: Number of subjects enrolled
    Austria: 1
    Country: Number of subjects enrolled
    United Kingdom: 1
    Worldwide total number of subjects
    25
    EEA total number of subjects
    18
    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)
    22
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Participants were enrolled at 28 clinical sites across 9 European countries and regions.

    Pre-assignment
    Screening details
    Male or female participants of at least 18 years of age with confirmed diagnosis or history of IBD for at least 3 months and a positive local standard CDI test for the presence of C. difficile. A CDI stool test had to be confirmed positive within 48 hours prior to enrollment.

    Period 1
    Period 1 title
    Overall Study (Treatment & Follow Up) (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    Not blinded

    Arms
    Arm title
    Fidaxomicin
    Arm description
    Participants received 200 mg of fidaxomicin from day 1 to day 10, twice daily.
    Arm type
    Experimental

    Investigational medicinal product name
    Fidaxomicin
    Investigational medicinal product code
    OPT-80, PAR-101, ASP2819
    Other name
    Dificlir TM, Dificid, Difimicin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received 200 mg of fidaxomicin orally, twice a day (every 12 hours) starting on day 1 for 10 treatment days.

    Number of subjects in period 1
    Fidaxomicin
    Started
    25
    Completed
    21
    Not completed
    4
         Consent withdrawn by subject
    3
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall Study (Treatment & Follow Up)
    Reporting group description
    Treatment Period & Follow Up Period

    Reporting group values
    Overall Study (Treatment & Follow Up) Total
    Number of subjects
    25 25
    Age categorical
    Units: Subjects
        18 to 64
    22 22
        65 to 74
    1 1
        > 74
    2 2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.9 ± 16.5 -
    Gender categorical
    Units:
        Male
    13 13
        Female
    12 12
    Baseline CDI Severity by European Society of Clinical Microbiology and Infectious Disease Score
    Units: Subjects
        Severe
    7 7
        Non severe
    18 18
    Colonoscopy or Sigmoidoscopy
    Units: Subjects
        Pseudomembranous colitis -Yes
    2 2
        Pseudomembranous colitis -No
    23 23
    Laboratory Examinations- Marked Leucocytosis
    Units: Subjects
        Marked leucocytosis - Yes
    4 4
        Marked leucocytosis - No
    21 21
    Number of Previous CDI Episodes
    Units: Subjects
        = 0
    20 20
        = 1
    5 5
        ≥ 2
    0 0
    Use of Antibiotics for CDI Within 90 Days Prior to Enrollment
    Units: Subjects
        Yes
    5 5
        No
    20 20
    Laboratory Examinations - Marked Left Shift
    Units: Subjects
        Marked left shift – No
    24 24
        Marked left shift – Missing
    1 1
    Laboratory Examinations - Rise in Serum Creatinine
    Units: Subjects
        Rise in Serum Creatinine - No
    25 25
    Laboratory Examinations - Elevated Serum Lactate
    Units: Subjects
        Elevated Serum Lactate - No
    10 10
        Elevated Serum Lactate - Missing
    15 15
    Laboratory Examinations - Markedly Reduced Serum Albumin
    Units: Subjects
        Markedly Reduced Serum Albumin - Yes
    3 3
        Markedly Reduced Serum Albumin - No
    21 21
        Markedly Reduced Serum Albumin - Missing
    1 1
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    21.76 ± 4.87 -
    Charlson Co-Morbidity Index Score
    Units: Year
        arithmetic mean (standard deviation)
    1.3 ± 2 -
    Study Drug Average Daily Dose
    Units: Milligrams
        arithmetic mean (standard deviation)
    398.5 ± 7.27 -
    Duration of Exposure to Study Drug
    Duration of exposure to study drug was defined as (the date of last dosing) – (the date of first dosing) + 1.
    Units: Days
        arithmetic mean (standard deviation)
    10.1 ± 0.28 -
    Subject analysis sets

    Subject analysis set title
    IBD type - Crohn’s Disease
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants with Crohn’s Disease with positive CDI test for the presence of C. difficile who received 200 mg of fidaxomicin from day 1 to day 10, twice daily.

    Subject analysis set title
    IBD type - Ulcerative Colitis
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants with Ulcerative Colitis with positive CDI test for the presence of C. difficile who received 200 mg of fidaxomicin from day 1 to day 10, twice daily.

    Subject analysis sets values
    IBD type - Crohn’s Disease IBD type - Ulcerative Colitis
    Number of subjects
    14
    11
    Age categorical
    Units: Subjects
        18 to 64
    14
    8
        65 to 74
    0
    1
        > 74
    0
    2
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    35.4 ± 10.9
    43.3 ± 21.6
    Gender categorical
    Units:
        Male
    8
    5
        Female
    6
    6
    Baseline CDI Severity by European Society of Clinical Microbiology and Infectious Disease Score
    Units: Subjects
        Severe
    2
    5
        Non severe
    12
    6
    Colonoscopy or Sigmoidoscopy
    Units: Subjects
        Pseudomembranous colitis -Yes
    0
    2
        Pseudomembranous colitis -No
    14
    9
    Laboratory Examinations- Marked Leucocytosis
    Units: Subjects
        Marked leucocytosis - Yes
    2
    2
        Marked leucocytosis - No
    12
    9
    Number of Previous CDI Episodes
    Units: Subjects
        = 0
    12
    8
        = 1
    2
    3
        ≥ 2
    0
    0
    Use of Antibiotics for CDI Within 90 Days Prior to Enrollment
    Units: Subjects
        Yes
    1
    4
        No
    13
    7
    Laboratory Examinations - Marked Left Shift
    Units: Subjects
        Marked left shift – No
    14
    10
        Marked left shift – Missing
    0
    1
    Laboratory Examinations - Rise in Serum Creatinine
    Units: Subjects
        Rise in Serum Creatinine - No
    14
    11
    Laboratory Examinations - Elevated Serum Lactate
    Units: Subjects
        Elevated Serum Lactate - No
    7
    3
        Elevated Serum Lactate - Missing
    7
    8
    Laboratory Examinations - Markedly Reduced Serum Albumin
    Units: Subjects
        Markedly Reduced Serum Albumin - Yes
    1
    2
        Markedly Reduced Serum Albumin - No
    13
    8
        Markedly Reduced Serum Albumin - Missing
    0
    1
    Body Mass Index (BMI)
    Units: kg/m^2
        arithmetic mean (standard deviation)
    22.09 ± 5.88
    21.35 ± 3.39
    Charlson Co-Morbidity Index Score
    Units: Year
        arithmetic mean (standard deviation)
    0.9 ± 1.2
    1.7 ± 2.6
    Study Drug Average Daily Dose
    Units: Milligrams
        arithmetic mean (standard deviation)
    397.4 ± 9.72
    400.0 ± 0.00
    Duration of Exposure to Study Drug
    Duration of exposure to study drug was defined as (the date of last dosing) – (the date of first dosing) + 1.
    Units: Days
        arithmetic mean (standard deviation)
    10.1 ± 0.27
    10.1 ± 0.30

    End points

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    End points reporting groups
    Reporting group title
    Fidaxomicin
    Reporting group description
    Participants received 200 mg of fidaxomicin from day 1 to day 10, twice daily.

    Subject analysis set title
    IBD type - Crohn’s Disease
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants with Crohn’s Disease with positive CDI test for the presence of C. difficile who received 200 mg of fidaxomicin from day 1 to day 10, twice daily.

    Subject analysis set title
    IBD type - Ulcerative Colitis
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    Participants with Ulcerative Colitis with positive CDI test for the presence of C. difficile who received 200 mg of fidaxomicin from day 1 to day 10, twice daily.

    Primary: Maximum Plasma Concentration (Cmax) for Fidaxomicin

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    End point title
    Maximum Plasma Concentration (Cmax) for Fidaxomicin [1]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients), which consisted of all participants from the subset of the safety analysis set (SAF). The safety analysis set (SAF) consisted of all participants who received at least 1 dose of study drug. The PKAS population contained at least 1 blood plasma measurement of fidaxomicin and its metabolite OP-1118, regardless of whether the value of the measurement was above or below lower limit of quantification and whether the participant had a full pharmacokinetic sampling profile or a limited pharmacokinetic sampling profile. For participants with limited PK sampling, Cmax on Days 5 and 10 was estimated by value from scheduled time window for tmax (2 hours ± 30 minutes). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 1, Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [1] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 [N=23]
    14.61 ± 16.10
        Day 5 [N=23]
    20.33 ± 31.80
        Day 10
    16.25 ± 15.06
        Maximum Across Days
    22.57 ± 30.42
    No statistical analyses for this end point

    Primary: Maximum Plasma Concentration (Cmax) for OP-1118

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    End point title
    Maximum Plasma Concentration (Cmax) for OP-1118 [2]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). For participants with limited PK sampling, Cmax on Days 5 and 10 was estimated by value from scheduled time window for tmax (2 hours ± 30 minutes). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 1, Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 [N=23]
    45.26 ± 67.48
        Day 5 [N=23]
    70.28 ± 116.7
        Day 10
    53.10 ± 43.54
        Maximum Across Days
    78.50 ± 111.58
    No statistical analyses for this end point

    Primary: Area Under the Curve from 0 to 12 hrs (AUC12) for Fidaxomicin

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    End point title
    Area Under the Curve from 0 to 12 hrs (AUC12) for Fidaxomicin [3]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax).
    End point type
    Primary
    End point timeframe
    Day 1 (Predose to 12 hours postdose)
    Notes
    [3] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    14
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 1
    77.70 ± 79.77
    No statistical analyses for this end point

    Primary: Area Under the Curve from 0 to 12 hrs (AUC12) for OP-1118

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    End point title
    Area Under the Curve from 0 to 12 hrs (AUC12) for OP-1118 [4]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax).
    End point type
    Primary
    End point timeframe
    Day 1 (Predose to 12 hours postdose)
    Notes
    [4] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    13
    Units: h*ng/mL
        arithmetic mean (standard deviation)
    283.5 ± 400.8
    No statistical analyses for this end point

    Primary: Time of Maximum Concentration (tmax) for Fidaxomicin

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    End point title
    Time of Maximum Concentration (tmax) for Fidaxomicin [5]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 1, Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [5] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: hours
    median (full range (min-max))
        Day 1 [N=23]
    1.500 (0.450 to 11.5)
        Day 5 [N=13]
    1.033 (0.500 to 3.00)
        Day 10 [N=14]
    1.750 (0.00 to 5.35)
    No statistical analyses for this end point

    Primary: Time of Maximum Concentration (tmax) for OP-1118

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    End point title
    Time of Maximum Concentration (tmax) for OP-1118 [6]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 1, Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [6] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: hours
    median (full range (min-max))
        Day 1 [N=23]
    1.500 (0.450 to 11.5)
        Day 5 [N=13]
    1.033 (0.500 to 5.00)
        Day 10 [N=14]
    2.042 (0.00 to 5.35)
    No statistical analyses for this end point

    Primary: Metabolite-to-Parent Ratio (MPR) for OP-1118

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    End point title
    Metabolite-to-Parent Ratio (MPR) for OP-1118 [7]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 1, Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [7] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: Ratio
    arithmetic mean (standard deviation)
        Day 1 [N=10]
    2.912 ± 0.8492
        Day 5 [N=10]
    3.883 ± 1.127
        Day 10 [N=11]
    3.471 ± 0.9172
    No statistical analyses for this end point

    Primary: Area Under the Concentration Time Curve From the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) for Fidaxomicin

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    End point title
    Area Under the Concentration Time Curve From the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) for Fidaxomicin [8]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [8] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 5 [N=11]
    155.6 ± 150.9
        Day 10 [N=11]
    129.1 ± 115.0
    No statistical analyses for this end point

    Primary: Area Under the Concentration Time Curve From the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) for OP-1118

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    End point title
    Area Under the Concentration Time Curve From the Time of Dosing to the Start of the Next Dosing Interval (AUCtau) for OP-1118 [9]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [9] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: h*ng/mL
    arithmetic mean (standard deviation)
        Day 5 [N=10]
    668.7 ± 726.0
        Day 10 [N=10]
    389.1 ± 364.7
    No statistical analyses for this end point

    Primary: Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) for Fidaxomicin

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    End point title
    Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) for Fidaxomicin [10]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [10] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 5 [N=23]
    6.183 ± 6.521
        Day 10 [N=22]
    4.414 ± 3.173
    No statistical analyses for this end point

    Primary: Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) for OP-1118

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    End point title
    Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) for OP-1118 [11]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [11] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 5 [N=23]
    22.08 ± 22.21
        Day 10 [N=23]
    18.24 ± 15.63
    No statistical analyses for this end point

    Primary: Apparent Total Systemic Clearance After Single or Multiple Extra-Vascular Dosing (CL/F) for Fidaxomicin

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    End point title
    Apparent Total Systemic Clearance After Single or Multiple Extra-Vascular Dosing (CL/F) for Fidaxomicin [12]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 1, Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [12] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: L/h
    arithmetic mean (standard deviation)
        Day 1 [N=14]
    2460 ± 1458
        Day 5 [N=11]
    2306 ± 1556
        Day 10 [N=11]
    3228 ± 3037
    No statistical analyses for this end point

    Primary: Apparent Total Systemic Clearance After Single or Multiple Extra-Vascular Dosing (CL/F) for OP-1118

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    End point title
    Apparent Total Systemic Clearance After Single or Multiple Extra-Vascular Dosing (CL/F) for OP-1118 [13]
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). N represents number of participants with the available data.
    End point type
    Primary
    End point timeframe
    Day 1, Day 5 and Day 10 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose)
    Notes
    [13] - 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: Statistical analysis for this endpoint was not completed.
    End point values
    Fidaxomicin
    Number of subjects analysed
    24
    Units: L/h
    arithmetic mean (standard deviation)
        Day 1 [N=13]
    1293 ± 1311
        Day 5 [N=10]
    630.1 ± 541.0
        Day 10 [N=12]
    1083 ± 1072
    No statistical analyses for this end point

    Secondary: Stool Concentrations of Fidaxomicin Throughout Fidaxomicin Treatment on Day 1, Day 5, Day 10 and at Any Unscheduled Failure Visit

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    End point title
    Stool Concentrations of Fidaxomicin Throughout Fidaxomicin Treatment on Day 1, Day 5, Day 10 and at Any Unscheduled Failure Visit
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Concentrations below the limit of quantification (10 ng/mL of diluted fecal homogenate or about 2 mcg/g fecal concentrations) were set to zero. Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). Day 1 as per protocol data excludes fecal samples taken less than 12-hours after the first dose. N represents number of participants with the available data.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 5 and Day 10
    End point values
    IBD type - Crohn’s Disease IBD type - Ulcerative Colitis
    Number of subjects analysed
    14
    10
    Units: mcg/g
    arithmetic mean (standard deviation)
        Day 1 As Per Protocol [N=5;2]
    348.80 ± 341.17
    196.90 ± 253.29
        Day 1 [N=10;7]
    174.40 ± 292.45
    94.11 ± 158.07
        Day 5 [N=12;9]
    840.50 ± 397.55
    628.79 ± 418.57
        Day 10 [N=13;9]
    894.23 ± 687.71
    772.71 ± 520.85
    No statistical analyses for this end point

    Secondary: Stool Concentrations of Metabolite OP-1118 Throughout Fidaxomicin Treatment on Day 1, Day 5, Day 10 and at Any Unscheduled Failure Visit

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    End point title
    Stool Concentrations of Metabolite OP-1118 Throughout Fidaxomicin Treatment on Day 1, Day 5, Day 10 and at Any Unscheduled Failure Visit
    End point description
    The analysis population was the pharmacokinetic analysis set (PKAS All Patients). Concentrations below the limit of quantification (10 ng/mL of diluted fecal homogenate or about 2 mcg/g fecal concentrations) were set to zero. Sampling for participants with reduced PK profile was completed on Day 1 (Predose, 0.5, 1, 1.5, 2, 3, 4, 5 and 10 hours postdose) and Day 5 & 10 (Predose and tmax). Day 1 as per protocol data excludes fecal samples taken less than 12-hours after the first dose. N represents number of participants with the available data.
    End point type
    Secondary
    End point timeframe
    Day 1, Day 5 and Day 10
    End point values
    IBD type - Crohn’s Disease IBD type - Ulcerative Colitis
    Number of subjects analysed
    14
    10
    Units: mcg/g
    arithmetic mean (standard deviation)
        Day 1 As Per Protocol [N=5;2]
    143.54 ± 134.04
    85.00 ± 120.21
        Day 1 [N=10;7]
    71.77 ± 117.08
    40.86 ± 71.50
        Day 5 [N=12;9]
    618.08 ± 492.88
    331.51 ± 234.82
        Day 10 [N=13;9]
    496.29 ± 558.32
    424.58 ± 241.24
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Clinical Response of CDI at Day 12 Test of Cure (TOC) after End of Treatment (EoT)

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    End point title
    Percentage of Participants with Clinical Response of CDI at Day 12 Test of Cure (TOC) after End of Treatment (EoT)
    End point description
    The analysis population was the modified full analysis set (mFAS), which consisted of all participants with confirmed CDI who received at least 1 dose of study treatment and had a valid assessment of TOC. The CDI clinical response (ToC) was based on the European Society of Clinical Microbiology and Infectious Diseases (ESCMID) criteria. Treatment response was present when either stool frequency decreased or stool consistency improved and parameters of disease severity (clinical, laboratory, radiological) improved and there were no new signs of severe disease developed. In all other cases, treatment was considered a failure. Treatment response was observed daily and evaluated after at least three days, assuming that the participant was not worsening on treatment.
    End point type
    Secondary
    End point timeframe
    Day 12 (48-72 hours after EoT)
    End point values
    Fidaxomicin IBD type - Crohn’s Disease IBD type - Ulcerative Colitis
    Number of subjects analysed
    25
    14
    11
    Units: Percentage of Participants
        number (confidence interval 95%)
    80.0 (60.9 to 91.1)
    64.3 (38.8 to 83.7)
    100.0 (74.1 to 100.0)
    No statistical analyses for this end point

    Secondary: Health Economic and Resource Variables by CDI Response at ToC on Day 12 – Overall Length of Hospital Stay

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    End point title
    Health Economic and Resource Variables by CDI Response at ToC on Day 12 – Overall Length of Hospital Stay
    End point description
    The analysis population was modified full analysis set (mFAS). Health economic and resource variables were stratified by clinical response of CDI at ToC on day 12 (yes/no/total). Responders/nonresponders were participants assessed as cured/not cured for clinical response for CDI at day 12. N represents number of participants with the available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 180
    End point values
    Fidaxomicin
    Number of subjects analysed
    25
    Units: Days
    arithmetic mean (standard deviation)
        Overall Length of Hospital Stay Responder [N=17]
    34.8 ± 41.6
        Overall Length of Hospital Stay Nonresponder [N=4]
    21.5 ± 13.2
        Overall Length of Hospital Stay Total [N=21]
    32.2 ± 37.9
    No statistical analyses for this end point

    Secondary: Health Economic and Resource Variables by CDI Response at ToC on Day 12 – Length of Stay on Isolated Ward

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    End point title
    Health Economic and Resource Variables by CDI Response at ToC on Day 12 – Length of Stay on Isolated Ward
    End point description
    The analysis population was modified full analysis set (mFAS). Health economic and resource variables were stratified by clinical response of CDI at ToC on day 12 (yes/no/total). Responders/nonresponders were participants assessed as cured/not cured for clinical response for CDI at day 12. N represents number of participants with the available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 180
    End point values
    Fidaxomicin
    Number of subjects analysed
    25
    Units: Days
    arithmetic mean (standard deviation)
        Isolated Ward Responder [N=3]
    19.3 ± 8.4
        Isolated Ward Nonresponder [N=1]
    3 ± 0
        Isolated Ward Total [N=4]
    15.3 ± 10.7
    No statistical analyses for this end point

    Secondary: Health Economic and Resource Variables by CDI Response at ToC on Day 12 – Length of Hospital Stay With Reason CDI Recurrence

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    End point title
    Health Economic and Resource Variables by CDI Response at ToC on Day 12 – Length of Hospital Stay With Reason CDI Recurrence
    End point description
    The analysis population was modified full analysis set (mFAS). Health economic and resource variables were stratified by clinical response of CDI at ToC on day 12 (yes/no/total). Responders/nonresponders were participants assessed as cured/not cured for clinical response for CDI at day 12. N represents number of participants with the available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 180
    End point values
    Fidaxomicin
    Number of subjects analysed
    25
    Units: Days
    arithmetic mean (standard deviation)
        CDI Recurrence Responder [N=2]
    6 ± 0
        CDI Recurrence Nonresponder [N=0]
    0 ± 0
        CDI Recurrence Total [N=2]
    6 ± 0
    No statistical analyses for this end point

    Secondary: Health Economic and Resource Variables by CDI Response at ToC on Day 12 – Hospital Admissions

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    End point title
    Health Economic and Resource Variables by CDI Response at ToC on Day 12 – Hospital Admissions
    End point description
    The analysis population was modified full analysis set (mFAS). Health economic and resource variables were stratified by clinical response of CDI at ToC on day 12 (yes/no/total). Responders/nonresponders were participants assessed as cured/not cured for clinical response for CDI at day 12. N represents number of participants with the available data.
    End point type
    Secondary
    End point timeframe
    Day 1 to Day 180
    End point values
    Fidaxomicin
    Number of subjects analysed
    25
    Units: Participants
    arithmetic mean (standard deviation)
        Hospital Admissions Responder [N=17]
    2.3 ± 1.8
        Hospital Admissions Nonresponder [N=4]
    2.5 ± 1.3
        Hospital Admissions Total [N=21]
    2.3 ± 1.7
    No statistical analyses for this end point

    Secondary: Health-Related Quality of Life (HRQoL) as Measured by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) Score

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    End point title
    Health-Related Quality of Life (HRQoL) as Measured by the Short Inflammatory Bowel Disease Questionnaire (SIBDQ) Score
    End point description
    The HRQoL total score results are based on the SIBDQ that consisted of 10 items covering 4 dimensions and 7 levels: Bowel dimension, Systemic dimension, Emotional dimension and the Social dimension. The Short IBDQ questionnaire consisted of 10 questions, each was graded on a scale from 1 (worst case) to 7. All scores were averaged by dividing each score by its number of items so that all score ranges are from 1 to 7, with one being poor and 7 optimum health related quality of life. The analysis population was the modified full analysis set (mFAS). N represents number of participants with the available data.
    End point type
    Secondary
    End point timeframe
    Day 10, Day 26, Day 40,Day 90 and Day 180 (EOS)
    End point values
    Fidaxomicin
    Number of subjects analysed
    25
    Units: Units on a Scale
    arithmetic mean (standard deviation)
        SIBDQ: total score Day 10 [N=24]
    3.68 ± 1.08
        SIBDQ: total score Day 26 [N=24]
    4.28 ± 1.16
        SIBDQ: total score Day 40 [N=23]
    4.64 ± 1.06
        SIBDQ: total score Day 90 [N=23]
    4.87 ± 1.21
        SIBDQ: total score Day 180 [N=20]
    4.98 ± 1.32
    No statistical analyses for this end point

    Secondary: Number of Participants with Treatment-Emergent Adverse Events (TEAEs) up to 30 days after End of Treatment (EOT)

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    End point title
    Number of Participants with Treatment-Emergent Adverse Events (TEAEs) up to 30 days after End of Treatment (EOT)
    End point description
    A TEAE was defined as an AE starting, or an existing condition that worsened, after first drug intake and until 30 days after the EoT visit on day 10. The analysis population was safety analysis set (SAF) and it consisted of all participants who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    From first dose of study drug up to 30 days after the EOT visit (Day 10)
    End point values
    Fidaxomicin
    Number of subjects analysed
    25
    Units: Participants
        TEAE
    15
        Drug-related TEAE
    10
        Serious TEAE
    6
        Drug-related serious TEAEs
    2
        TEAEs leading to death
    0
        Drug-related TEAE leading to death
    0
        TEAE leading to withdrawal of treatment
    0
        Drug-related TEAEs leading to withdrawal of treat
    0
        Death
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study drug up to 7 days after EOS (up to 187)
    Adverse event reporting additional description
    An adverse events (AE) was defined as any untoward medical occurrence in a participants administered a study drug or who had undergone study procedures and did not necessarily have a causal relationship with this treatment. All participants remained in the study until end of study (EoS) visit 8 (day 180) for safety assessments.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Fidaxomicin
    Reporting group description
    Participants received 200 mg of fidaxomicin orally, twice a day (every 12 hours) on day 1 for 10 treatment days.

    Serious adverse events
    Fidaxomicin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 25 (24.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Hypoxia
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Colitis ulcerative
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Crohn's disease
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulcer
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Clostridial infection
         subjects affected / exposed
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Fidaxomicin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 25 (40.00%)
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    3
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    3 / 25 (12.00%)
         occurrences all number
    3
    Flatulence
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    3
    Inflammatory bowel disease
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 25 (8.00%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Aug 2015
    -The phase of study was amended from phase 4 to phase 3b/4. As fidaxomicin was not an approved drug within the Russian Federation, this study was to be regarded as a phase 3b study. -To maximize the probability of enrolling the required number of participants within the stipulated enrollment period, 3 sites in the Russian Federation were added to the study. -The time point changed from 12 to 10 hours postdose of fidaxomicin and acceptable time window (changed from within 24 hours of first dose to not earlier than 12 hours) for the last pharmacokinetic sampling was updated to introduce some flexibility to assist the logistical challenges faced by the clinical sites. -In the protocol text it was clarified when to take stool samples. -In the protocol text it was clarified that the review of pharmacokinetic data was ongoing throughout the study. -In the protocol text it was clarified that the enrollment was interrupted after the first 3 patients. -Definitions of activity of IBD were updated in the inclusion criteria. New recommendations for ‘active IBD’ have been discussed among authorities and IBD specialists and will assist with the analyses of efficacy, as discussed with the protocol Steering Committee. -As some medication on the list had to be used in case of failure and/or recurrence of CDI, the protocol terminology was amended from ‘prohibited medication’ to ‘medication to be avoided’. -Independent’ was added in the text before Data Monitoring Committee (DMC), to clarify that the external DMC was independent. -The information regarding the stool sample taken for enrollment was updated. As it could take time to retrieve the results from CDI testing, the wording in the text was changed to ‘the time of confirmation of CDI diagnosis’ rather than ‘the time of sample taken’ so participantscould be enrolled within 48 hours after receiving the diagnosis of CDI.
    19 Aug 2015
    -In the protocol text it was clarified when screening samples for safety laboratory assessment were to be taken. -The SmPC was added as reference safety information for AEs for countries where fidaxomicin was an approved drug. -For the AEs of special interest, the ranges for hepatic laboratory abnormalities were updated as clarified by the global pharmacovigilance department. -The information regarding the collection of treatment-emergent adverse events (TEAEs) was updated. As this study was continuous for a long period after the stop of study drug, a distinction was made between ‘TEAEs’ and ‘other AEs’. -As endoscopic findings were not part of the Mayo Score, the information regarding endoscopic findings was removed and the summary of score was updated. -The CDI clinical assessment and severity score was deleted from visit 4. This assessment could not be performed as this visit was conducted over the telephone. -To improve the evaluation of outcomes of IBD during the study, definitions were added for the response and flare of both ‘ulcerative colitis’ and ‘Crohn’s disease’. -As requested by the IEC in the UK, the number of mucosal samples taken during the study was maximized to 4. -Contact details of sponsor’s personnel were updated to reflect the change of role of the medical expert and changes to European and regional study management.

    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.
    The study was on hold after first 3 participants PK results were examined to ensure maximum plasma concentrations were not high and to minimize the safety risks.The Microbiological Response endpoint data was not available, it will be reported later.
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