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    Clinical Trial Results:
    A randomised, double-blind, double-dummy, multi-centre, comparative parallel-group study to evaluate the efficacy of oral Rifamycin SV-MMX® 400 mg b.i.d. vs. Rifamycin SV-MMX® 600 mg t.i.d. vs. placebo in the treatment of acute uncomplicated diverticulitis

    Summary
    EudraCT number
    		 2012-003300-13
    Trial protocol
    		 HU   DE   IT   RO   LT   SK   LV  
    Global end of trial date
    18 Apr 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Jan 2020
    First version publication date
    26 Jan 2020
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    RIT-4/DIV
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01847664
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Dr. Falk Pharma GmbH
    Sponsor organisation address
    Leinenweberstrasse 5, Freiburg, Germany, 79288
    Public contact
    Dept. of Clin. Res. & Development, Dr. Falk Pharma GmbH, +49 76115140, zentrale@drfalkpharma.de
    Scientific contact
    Dept. of Clin. Res. & Development, Dr. Falk Pharma GmbH, +49 76115140, zentrale@drfalkpharma.de
    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
    19 Jul 2017
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Apr 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective was to compare the efficacy of Rifamycin SV-MMX® 400 mg b.i.d. vs. Rifamycin SV-MMX® 600 mg t.i.d. vs. placebo, in patients with acute uncomplicated diverticulitis.
    Protection of trial subjects
    Close supervision of subjects by implementing interim visits every 3 days to guarantee their safety and wellbeing. Prior to recruitment of patients, all relevant documents of the clinical study were submitted and approved by the Independent Ethics Committees (IECs) responsible for the participating investigators. Written consent documents embodied the elements of informed consent as described in the Declaration of Helsinki, the ICH Guidelines for Good Clinical Practice (GCP) and were in accordance with all applicable laws and regulations. The informed consent form and patient information sheet described the planned and permitted uses, transfers and disclosures of the patient's personal data and personal health information for purposes of conducting the study. The informed consent form and the patient information sheet further explained the nature of the study, its objectives and potential risks and benefits as well as the date informed consent was given. Before being enrolled in the clinical trial, every patient was informed that participation in this trial was voluntary and that he/she could withdraw from the study at any time without giving a reason and without having to fear any loss in his/her medical care. The patient’s consent was obtained in writing before the start of the study. By signing the informed consent, the patient declared that he/she was participating voluntarily and intended to follow the study protocol instructions and the instructions of the investigator and to answer the questions asked during the course of the trial.
    Background therapy
    		 None
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    07 Jun 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy
    Long term follow-up duration
    		 1 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Romania: 13
    Country: Number of subjects enrolled
    Slovakia: 24
    Country: Number of subjects enrolled
    Germany: 78
    Country: Number of subjects enrolled
    Hungary: 42
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    Lithuania: 38
    Worldwide total number of subjects
    201
    EEA total number of subjects
    201
    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)
    142
    From 65 to 84 years
    59
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 204 patients were randomised from Germany, Hungary, Italy, Lithuania, Romania and Slovakia.

    Pre-assignment
    Screening details
    		 Patients signing the informed consent form were screened for up to 4 days to evaluate eligibility for the study. A total of 300 patients was screened for enrolment into the study. 96 patients could not be randomised.

    Period 1
    Period 1 title
    Double-blind, 10 days treatment phase (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The study was to be conducted using the double-dummy technique to guarantee the double-blinding.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rifamycin 400mg BID
    Arm description
    		 10-day treatment with Rifamycin SV-MMX® 400 mg b.i.d., 800 mg/day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rifamycin SV-MMX®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rifamycin SV-MMX® 400 mg b.i.d., 800 mg/day

    Arm title
    		 Rifamycin 600mg TID
    Arm description
    		 10-day treatment with Rifamycin SV-MMX® 600 mg t.i.d., 1800 mg/day
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rifamycin SV-MMX®
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rifamycin SV-MMX® 600 mg t.i.d., 1800 mg/day

    Arm title
    		 Placebo
    Arm description
    		 10-day treatment with Rifamycin SV-MMX® placebo tablets
    Arm type
    		 Placebo

    Investigational medicinal product name
    Rifamycin SV-MMX® Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo

    Number of subjects in period 1
    		Rifamycin 400mg BID Rifamycin 600mg TID Placebo
    Started
    82
    79
    40
    Completed
    70
    70
    35
    Not completed
    12
    9
    5
         Adverse event, non-fatal
    2
    3
    1
         Lack of patient's cooperation
    5
    -
    3
         Non-eligibility detected after randomisation
    1
    4
    1
         Lack of efficacy
    4
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rifamycin 400mg BID
    Reporting group description
    		 10-day treatment with Rifamycin SV-MMX® 400 mg b.i.d., 800 mg/day

    Reporting group title
    Rifamycin 600mg TID
    Reporting group description
    		 10-day treatment with Rifamycin SV-MMX® 600 mg t.i.d., 1800 mg/day

    Reporting group title
    Placebo
    Reporting group description
    		 10-day treatment with Rifamycin SV-MMX® placebo tablets

    Reporting group values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Total
    Number of subjects
    		 82 79 40 201
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 53 60 29 142
        From 65-84 years
    		 29 19 11 59
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.7 ± 10.67 58.4 ± 11.13 56.8 ± 13.8 -
    Gender categorical
    Units: Subjects
        Female
    		 44 49 27 120
        Male
    		 38 30 13 81
    Signs of inflammation of colonic wall
    Units: Subjects
        No
    		 1 1 0 2
        Yes
    		 81 78 40 199
    Presence of complications (US/CT) findings
    Units: Subjects
        No
    		 82 79 40 201
        Yes
    		 0 0 0 0
    Worst left lower quadrant pain over the last 24 hours (0-10cm VAS)
    Intensity of left lower quadrant pain was assessed by a 0 to 10cm visual analogue scale (VAS). Higher values indicate more pain.
    Units: cm
        arithmetic mean (standard deviation)
    		 5.91 ± 2.095 5.36 ± 2.142 5.46 ± 2.193 -
    C-reactive protein (CRP) at baseline [mg/l]
    Units: mg/l
        median (full range (min-max))
    		 36.75 (2.1 to 195.0) 19.0 (1.2 to 180) 31.5 (1.0 to 207) -
    Subject analysis sets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) includes all randomised patients who received at least one dose of IMP.

    Subject analysis sets values
    		 Full analysis set
    Number of subjects
    201
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    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)
    142
        From 65-84 years
    59
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.6 ± 11.52
    Gender categorical
    Units: Subjects
        Female
    120
        Male
    81
    Signs of inflammation of colonic wall
    Units: Subjects
        No
    2
        Yes
    199
    Presence of complications (US/CT) findings
    Units: Subjects
        No
    201
        Yes
    0
    Worst left lower quadrant pain over the last 24 hours (0-10cm VAS)
    Intensity of left lower quadrant pain was assessed by a 0 to 10cm visual analogue scale (VAS). Higher values indicate more pain.
    Units: cm
        arithmetic mean (standard deviation)
    5.6 ± 2.137
    C-reactive protein (CRP) at baseline [mg/l]
    Units: mg/l
        median (full range (min-max))
    29.9 (1.0 to 207.0)

    End points

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    End points reporting groups
    Reporting group title
    Rifamycin 400mg BID
    Reporting group description
    		 10-day treatment with Rifamycin SV-MMX® 400 mg b.i.d., 800 mg/day

    Reporting group title
    Rifamycin 600mg TID
    Reporting group description
    		 10-day treatment with Rifamycin SV-MMX® 600 mg t.i.d., 1800 mg/day

    Reporting group title
    Placebo
    Reporting group description
    		 10-day treatment with Rifamycin SV-MMX® placebo tablets

    Subject analysis set title
    Full analysis set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    The full analysis set (FAS) includes all randomised patients who received at least one dose of IMP.

    Primary: Rate of patients with treatment success at the day 10 visit (Primary Endpoint, Stage 1= Primary Analysis)

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    End point title
    		 Rate of patients with treatment success at the day 10 visit (Primary Endpoint, Stage 1= Primary Analysis)
    End point description
    Denominator: all patients in the analysis set. Treatment success was ‘Yes’, if all of the following were fulfilled: • Absence of fever (i.e., body temperature < 38°C) at the visit, • Adequate relief of left lower quadrant pain defined as worst intensity during the last 24 h (visual analogue scale on day of visit) of < 4, • Within the last 48 h, no intake of pain medication except for chronic low dose acetylsalicylic acid ≤ 100 mg/d for reasons other than pain, • Leucocytes ≤ ULN at the visit, • CRP ≤ ULN or at least 50% improvement compared to baseline at the visit, • No complications of acute diverticulitis, No need for extra antimicrobial treatment due to acute diverticulitis, No need for surgical intervention of acute diverticulitis, No hospitalisation due to acute diverticulitis up to the visit. Treatment success was ‘No’, if at least one of the above criteria was violated, and for patients withdrawn due to lack of efficacy.
    End point type
    Primary
    End point timeframe
    Visit Day 10
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    74 [1]
    74 [2]
    37 [3]
    185 [4]
    Units: Subjects
        Not assessable
    4
    10
    8
    22
        No
    22
    26
    11
    59
        Yes
    48
    38
    18
    104
    Notes
    [1] - Stage 1 Results = Patients included in interim analysis
    [2] - Stage 1 Results = Patients included in interim analysis
    [3] - Stage 1 Results = Patients included in interim analysis
    [4] - Stage 1 Results = Patients included in interim analysis
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Statistical analysis description
    Rifamycin 600mg TID versus Placebo Rifamycin 600mg TID versus Placebo was first to be tested according to the hierarchically ordered hypotheses. Rifamycin 400mg BID versus Placebo was only to be tested if Rifamycin 600mg TID was statistically significantly superior to Placebo. Unadjusted one-sided p-values were to be compared with the one-sided Stage 1 alpha of 0.0021. The overall adjusted p-value adjusts for the adaptive design and considers the hierarchy of the hypotheses.
    Comparison groups
    Rifamycin 600mg TID v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.562 [6]
    Method
    		 Normal approximation test for rates
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.027
    Confidence interval
         level
    		 99.58%
         sides
    2-sided
         lower limit
    		 -0.2611
         upper limit
    		 0.3151
    Notes
    [5] - Not assessable results were set to 'No' in this analysis.
    [6] - Overall adjusted one-sided p-value calculated using ADDPLAN® Version 6.1.1 (licensed by ADDPLAN, Inc., an ICON Clinical Research, LLC company). Unadjusted p-value: 0.3942
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Statistical analysis description
    Rifamycin 400mg BID versus Placebo Rifamycin 600mg TID versus Placebo was first to be tested according to the hierarchically ordered hypotheses. Rifamycin 400mg BID versus Placebo was not to be tested as Rifamycin 600mg TID was not statistically significantly superior to Placebo. The unadjusted one-sided p-value was exploratively compared with the one-sided Stage 1 alpha of 0.0021. The overall adjusted p-value adjusts for the adaptive design and considers the hierarchy of the hypotheses.
    Comparison groups
    Rifamycin 400mg BID v Placebo
    Number of subjects included in analysis
    111
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.562 [8]
    Method
    		 Normal approximation test for rates
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.1622
    Confidence interval
         level
    		 99.58%
         sides
    2-sided
         lower limit
    		 -0.1217
         upper limit
    		 0.446
    Notes
    [7] - Not assessable results were set to 'No' in this analysis.
    [8] - Overall adjusted one-sided p-value calculated using ADDPLAN® Version 6.1.1 (licensed by ADDPLAN, Inc., an ICON Clinical Research, LLC company). Unadjusted p-value: 0.0505

    Primary: Rate of patients with treatment success at the day 10 visit (Primary Endpoint, Stage 1 and Overrun)

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    End point title
    		 Rate of patients with treatment success at the day 10 visit (Primary Endpoint, Stage 1 and Overrun)
    End point description
    Denominator: all patients in the analysis set. Treatment success was ‘Yes’, if all of the following were fulfilled: • Absence of fever (i.e., body temperature < 38°C) at the visit, • Adequate relief of left lower quadrant pain defined as worst intensity during the last 24 h (visual analogue scale on day of visit) of < 4, • Within the last 48 h, no intake of pain medication except for chronic low dose acetylsalicylic acid ≤ 100 mg/d for reasons other than pain, • Leucocytes ≤ ULN at the visit, • CRP ≤ ULN or at least 50% improvement compared to baseline at the visit, • No complications of acute diverticulitis, No need for extra antimicrobial treatment due to acute diverticulitis, No need for surgical intervention of acute diverticulitis, No hospitalisation due to acute diverticulitis up to the visit. Treatment success was ‘No’, if at least one of the above criteria was violated, and for patients withdrawn due to lack of efficacy.
    End point type
    Primary
    End point timeframe
    Visit Day 10
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    82
    79
    40
    201
    Units: Subjects
        Not asessable
    5
    10
    9
    24
        No
    26
    30
    12
    68
        Yes
    51
    39
    19
    109
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Statistical analysis description
    Rifamycin 600mg TID versus Placebo Rifamycin 600mg TID versus Placebo was first to be tested according to the hierarchically ordered hypotheses. Rifamycin 400mg BID versus Placebo was only to be tested if Rifamycin 600mg TID was statistically significantly superior to Placebo. Unadjusted one-sided p-values were to be compared with the one-sided Stage 1 alpha of 0.0021. The overall adjusted p-value adjusts for the adaptive design and considers the hierarchy of the hypotheses.
    Comparison groups
    Rifamycin 600mg TID v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.5882 [10]
    Method
    		 Normal approximation test for rates
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.0187
    Confidence interval
         level
    		 99.58%
         sides
    2-sided
         lower limit
    		 -0.2589
         upper limit
    		 0.2962
    Notes
    [9] - Not assessable results were set to 'No' in this analysis.
    [10] - Overall adjusted one-sided p-value calculated using ADDPLAN® Version 6.1.1 (licensed by ADDPLAN, Inc., an ICON Clinical Research, LLC company). Unadjusted p-value: 0.4237
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Statistical analysis description
    Rifamycin 400mg BID versus Placebo Rifamycin 600mg TID versus Placebo was first to be tested according to the hierarchically ordered hypotheses. Rifamycin 400mg BID versus Placebo was not to be tested as Rifamycin 600mg TID was not statistically significantly superior to Placebo. The unadjusted one-sided p-value was exploratively compared with the one-sided Stage 1 alpha of 0.0021. The overall adjusted p-value adjusts for the adaptive design and considers the hierarchy of the hypotheses.
    Comparison groups
    Placebo v Rifamycin 400mg BID
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.5882 [12]
    Method
    		 Normal approximation test for rates
    Parameter type
    		 Risk difference (RD)
    Point estimate
    0.147
    Confidence interval
         level
    		 99.58%
         sides
    2-sided
         lower limit
    		 -0.1262
         upper limit
    		 0.4201
    Notes
    [11] - Not assessable results were set to 'No' in this analysis.
    [12] - Overall adjusted one-sided p-value calculated using ADDPLAN® Version 6.1.1 (licensed by ADDPLAN, Inc., an ICON Clinical Research, LLC company). Unadjusted p-value: 0.0617
    Statistical analysis title
    		 Rifamycin 600mg TID versus Rifamycin 400mg BID
    Statistical analysis description
    Exploratory comparison of Rifamycin 600mg TID versus Rifamycin 400mg BID
    Comparison groups
    Rifamycin 400mg BID v Rifamycin 600mg TID
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [13]
    P-value
    		 = 0.1012 [14]
    Method
    		 Normal approximation test for rates
    Parameter type
    		 Risk difference (RD)
    Point estimate
    -0.1283
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2805
         upper limit
    		 0.0239
    Notes
    [13] - Not assessable results were set to 'No' in this analysis.
    [14] - Two-sided unadjusted p-value

    Primary: Rate of patients with treatment success at the day 10 visit (sensitivity analysis using LOCF, Stage 1 and Overrun)

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    End point title
    		 Rate of patients with treatment success at the day 10 visit (sensitivity analysis using LOCF, Stage 1 and Overrun)
    End point description
    Denominator: all patients in the analysis set. Sensitivity analysis for primary endpoint using last observation carried forward (LOCF).
    End point type
    Primary
    End point timeframe
    Visit Day 10 (LOCF)
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    82
    79
    40
    201
    Units: Subjects
        Not assessable
    2
    1
    2
    5
        No
    26
    32
    12
    70
        Yes
    54
    46
    26
    126
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Statistical analysis description
    Rifamycin 600mg TID versus Placebo Rifamycin 600mg TID versus Placebo was first to be tested according to the hierarchically ordered hypotheses. Rifamycin 400mg BID versus Placebo was only to be tested if Rifamycin 600mg TID was statistically significantly superior to Placebo. Unadjusted one-sided p-values were to be compared with the one-sided Stage 1 alpha of 0.0021.
    Comparison groups
    Rifamycin 600mg TID v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.7624 [16]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [15] - Not assessable results were set to 'No' in this analysis.
    [16] - Unadjusted one-sided p-value.
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Statistical analysis description
    Rifamycin 400mg BID versus Placebo Rifamycin 600mg TID versus Placebo was first to be tested according to the hierarchically ordered hypotheses. Rifamycin 400mg BID versus Placebo was only to be tested if Rifamycin 600mg TID was statistically significantly superior to Placebo. Unadjusted one-sided p-values were to be compared with the one-sided Stage 1 alpha of 0.0021.
    Comparison groups
    Placebo v Rifamycin 400mg BID
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [17]
    P-value
    		 = 0.4629 [18]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [17] - Not assessable results were set to 'No' in this analysis.
    [18] - Unadjusted one-sided p-value.
    Statistical analysis title
    		 Rifamycin 600mg TID versus Rifamycin 400mg BID
    Statistical analysis description
    Exploratory comparison of Rifamycin 600mg BID versus Rifamycin 400mg BID
    Comparison groups
    Rifamycin 400mg BID v Rifamycin 600mg TID
    Number of subjects included in analysis
    161
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [19]
    P-value
    		 = 0.3187 [20]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [19] - Not assessable results were set to 'No' in this analysis.
    [20] - Two-sided unadjusted p-value.

    Primary: Rate of patients with treatment success at the day 10 visit (sensitivity analysis based on patients with assessable treatment success at the day 10 visit, Stage 1 and Overrun)

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    End point title
    		 Rate of patients with treatment success at the day 10 visit (sensitivity analysis based on patients with assessable treatment success at the day 10 visit, Stage 1 and Overrun)
    End point description
    Denominator: Patients with assessable treatment success at the day 10 visit. Sensitivity analysis for primary endpoint, excluding patients with not assessable treatment success at visit Day 10.
    End point type
    Primary
    End point timeframe
    Visit Day 10
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    77 [21]
    69 [22]
    31 [23]
    177 [24]
    Units: Subjects
        No
    26
    30
    12
    68
        Yes
    51
    39
    19
    109
    Notes
    [21] - Patients with assessable treatment success at the day 10 visit
    [22] - Patients with assessable treatment success at the day 10 visit
    [23] - Patients with assessable treatment success at the day 10 visit
    [24] - Patients with assessable treatment success at the day 10 visit
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Statistical analysis description
    Rifamycin 600mg TID versus Placebo Rifamycin 600mg TID versus Placebo was first to be tested according to the hierarchically ordered hypotheses. Rifamycin 400mg BID versus Placebo was only to be tested if Rifamycin 600mg TID was statistically significantly superior to Placebo. Unadjusted one-sided p-values were to be compared with the one-sided Stage 1 alpha of 0.0021.
    Comparison groups
    Rifamycin 600mg TID v Placebo
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [25]
    P-value
    		 = 0.6725 [26]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [25] - Not assessable results were excluded from this analysis.
    [26] - Unadjusted one-sided p-value.
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Statistical analysis description
    Rifamycin 400mg BID versus Placebo Rifamycin 600mg TID versus Placebo was first to be tested according to the hierarchically ordered hypotheses. Rifamycin 400mg BID versus Placebo was only to be tested if Rifamycin 600mg TID was statistically significantly superior to Placebo. Unadjusted one-sided p-values were to be compared with the one-sided Stage 1 alpha of 0.0021.
    Comparison groups
    Placebo v Rifamycin 400mg BID
    Number of subjects included in analysis
    108
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [27]
    P-value
    		 = 0.3132 [28]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [27] - Not assessable results were excluded from this analysis.
    [28] - Unadjusted one-sided p-value.
    Statistical analysis title
    		 Rifamycin 600mg TID versus Rifamycin 400mg BID
    Statistical analysis description
    Exploratory comparison of Rifamycin 600mg BID versus Rifamycin 400mg BID
    Comparison groups
    Rifamycin 400mg BID v Rifamycin 600mg TID
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [29]
    P-value
    		 = 0.2283 [30]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [29] - Not assessable results were excluded from this analysis.
    [30] - Two-sided unadjusted p-value.

    Secondary: Rate of patients with treatment success at visit Day 3

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    End point title
    		 Rate of patients with treatment success at visit Day 3
    End point description
    Denominator: all patients in the analysis set. For definition of treatment success see description of primary endpoint.
    End point type
    Secondary
    End point timeframe
    Visit Day 3
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    82
    79
    40
    201
    Units: Subjects
        Not assessable
    4
    2
    6
    12
        No
    51
    57
    20
    128
        Yes
    27
    20
    14
    61
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Comparison groups
    Rifamycin 600mg TID v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [31]
    P-value
    		 = 0.2693 [32]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [31] - Not assessable results were set to 'No' in this analysis.
    [32] - Exploratory unadjusted two-sided p-value.
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Comparison groups
    Placebo v Rifamycin 400mg BID
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [33]
    P-value
    		 = 0.82 [34]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [33] - Not assessable results were set to 'No' in this analysis.
    [34] - Exploratory unadjusted two-sided p-value.

    Secondary: Rate of patients with treatment success at visit Day 7

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    End point title
    		 Rate of patients with treatment success at visit Day 7
    End point description
    Denominator: all patients in the analysis set. For definition of treatment success see description of primary endpoint.
    End point type
    Secondary
    End point timeframe
    Visit Day 7
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    82
    79
    40
    201
    Units: Subjects
        Not assessable
    7
    3
    6
    16
        No
    30
    36
    13
    79
        Yes
    45
    40
    21
    106
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Comparison groups
    Rifamycin 600mg TID v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [35]
    P-value
    		 = 0.8474 [36]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [35] - Not assessable results were set to 'No' in this analysis.
    [36] - Exploratory unadjusted two-sided p-value.
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Comparison groups
    Placebo v Rifamycin 400mg BID
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [37]
    P-value
    		 = 0.8046 [38]
    Method
    		 Normal approximation test for rates
    Confidence interval
    Notes
    [37] - Not assessable results were set to 'No' in this analysis.
    [38] - Exploratory unadjusted two-sided p-value.

    Secondary: Rate of patients with complete treatment success at visit Day 3

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    End point title
    		 Rate of patients with complete treatment success at visit Day 3
    End point description
    Complete treatment success is the same as treatment success, except that the criterion ‘CRP ≤ ULN or at least 50% improvement compared to baseline at the visit’ is ‘CRP ≤ ULN at the visit‘.
    End point type
    Secondary
    End point timeframe
    Visit Day 3
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    82
    79
    40
    201
    Units: Subjects
        Not assessable
    1
    2
    3
    6
        No
    72
    67
    37
    176
        Yes
    9
    10
    0
    19
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Comparison groups
    Placebo v Rifamycin 600mg TID
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [39]
    P-value
    		 = 0.016 [40]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [39] - Not assessable results were set to 'No' in this analysis.
    [40] - Exploratory unadjusted two-sided p-value.
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Comparison groups
    Placebo v Rifamycin 400mg BID
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [41]
    P-value
    		 = 0.0296 [42]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [41] - Not assessable results were set to 'No' in this analysis.
    [42] - Exploratory unadjusted two-sided p-value.

    Secondary: Rate of patients with complete treatment success at visit Day 7

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    End point title
    		 Rate of patients with complete treatment success at visit Day 7
    End point description
    Complete treatment success is the same as treatment success, except that the criterion ‘CRP ≤ ULN or at least 50% improvement compared to baseline at the visit’ is ‘CRP ≤ ULN at the visit‘.
    End point type
    Secondary
    End point timeframe
    Visit Day 7
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    82
    79
    40
    201
    Units: Subjects
        Not assessable
    4
    3
    5
    12
        No
    46
    46
    24
    116
        Yes
    32
    30
    11
    73
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Comparison groups
    Rifamycin 600mg TID v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [43]
    P-value
    		 = 0.3098 [44]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [43] - Not assessable results were set to 'No' in this analysis.
    [44] - Exploratory unadjusted two-sided p-value.
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Comparison groups
    Placebo v Rifamycin 400mg BID
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [45]
    P-value
    		 = 0.2325 [46]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [45] - Not assessable results were set to 'No' in this analysis.
    [46] - Exploratory unadjusted two-sided p-value.

    Secondary: Rate of patients with complete treatment success at visit Day 10

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    End point title
    		 Rate of patients with complete treatment success at visit Day 10
    End point description
    Complete treatment success is the same as treatment success, except that the criterion ‘CRP ≤ ULN or at least 50% improvement compared to baseline at the visit’ is ‘CRP ≤ ULN at the visit‘.
    End point type
    Secondary
    End point timeframe
    Visit Day 10
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    82
    79
    40
    201
    Units: Subjects
        Not assessable
    5
    7
    8
    20
        No
    35
    39
    16
    90
        Yes
    42
    33
    16
    91
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Comparison groups
    Rifamycin 600mg TID v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [47]
    P-value
    		 = 1 [48]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [47] - Not assessable results were set to 'No' in this analysis.
    [48] - Exploratory unadjusted two-sided p-value.
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Comparison groups
    Placebo v Rifamycin 400mg BID
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [49]
    P-value
    		 = 0.2549 [50]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [49] - Not assessable results were set to 'No' in this analysis.
    [50] - Exploratory unadjusted two-sided p-value.

    Secondary: Rate of patients with complete treatment success at visit Day 10 (LOCF)

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    End point title
    		 Rate of patients with complete treatment success at visit Day 10 (LOCF)
    End point description
    Complete treatment success is the same as treatment success, except that the criterion ‘CRP ≤ ULN or at least 50% improvement compared to baseline at the visit’ is ‘CRP ≤ ULN at the visit‘.
    End point type
    Secondary
    End point timeframe
    Visit Day 10 (LOCF): Visit Day 10 analysis using last observation carried forward (LOCF).
    End point values
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo Full analysis set
    Number of subjects analysed
    82
    79
    40
    201
    Units: Subjects
        Not assessable
    1
    1
    2
    4
        No
    37
    41
    17
    95
        Yes
    44
    37
    21
    102
    Statistical analysis title
    		 Rifamycin 600mg TID versus Placebo
    Comparison groups
    Rifamycin 600mg TID v Placebo
    Number of subjects included in analysis
    119
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [51]
    P-value
    		 = 0.5677 [52]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [51] - Not assessable results were set to 'No' in this analysis.
    [52] - Exploratory unadjusted two-sided p-value.
    Statistical analysis title
    		 Rifamycin 400mg BID versus Placebo
    Comparison groups
    Placebo v Rifamycin 400mg BID
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [53]
    P-value
    		 = 1 [54]
    Method
    		 Fisher exact
    Confidence interval
    Notes
    [53] - Not assessable results were set to 'No' in this analysis.
    [54] - Exploratory unadjusted two-sided p-value.

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Double-blind, 10 days treatment phase
    Adverse event reporting additional description
    Treatment emergent adverse events are presented for the safety analysis set, which includes all randomised patients who received at least one dose of IMP and have at least one follow-up value for the safety variables to be analysed (n=199).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Rifamycin 400mg BID
    Reporting group description
    		 10-day treatment with Rifamycin SV-MMX® 400 mg b.i.d., 800 mg/day

    Reporting group title
    Rifamycin 600mg TID
    Reporting group description
    		 10-day treatment with Rifamycin SV-MMX® 600 mg t.i.d., 1800 mg/day

    Reporting group title
    Placebo
    Reporting group description
    		 10-day treatment with Rifamycin SV-MMX® placebo tablets

    Serious adverse events
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
    0 / 40 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Infections and infestations
    Diverticulitis
         subjects affected / exposed
    1 / 81 (1.23%)
    1 / 78 (1.28%)
    0 / 40 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1.5%
    Non-serious adverse events
    		 Rifamycin 400mg BID Rifamycin 600mg TID Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 81 (32.10%)
    28 / 78 (35.90%)
    10 / 40 (25.00%)
    Injury, poisoning and procedural complications
    Muscle strain
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Vascular disorders
    Hypertension
         subjects affected / exposed
    4 / 81 (4.94%)
    1 / 78 (1.28%)
    1 / 40 (2.50%)
         occurrences all number
    4
    1
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    8 / 81 (9.88%)
    4 / 78 (5.13%)
    1 / 40 (2.50%)
         occurrences all number
    8
    4
    1
    General disorders and administration site conditions
    Facial pain
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    1 / 81 (1.23%)
    3 / 78 (3.85%)
    0 / 40 (0.00%)
         occurrences all number
    1
    3
    0
    Abdominal pain
         subjects affected / exposed
    4 / 81 (4.94%)
    2 / 78 (2.56%)
    2 / 40 (5.00%)
         occurrences all number
    4
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    1
    Colitis
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    4 / 81 (4.94%)
    2 / 78 (2.56%)
    0 / 40 (0.00%)
         occurrences all number
    4
    2
    0
    Dry mouth
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Nausea
         subjects affected / exposed
    3 / 81 (3.70%)
    2 / 78 (2.56%)
    2 / 40 (5.00%)
         occurrences all number
    3
    2
    2
    Vomiting
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 78 (1.28%)
    0 / 40 (0.00%)
         occurrences all number
    2
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 78 (1.28%)
    0 / 40 (0.00%)
         occurrences all number
    2
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 81 (2.47%)
    1 / 78 (1.28%)
    0 / 40 (0.00%)
         occurrences all number
    2
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Back pain
         subjects affected / exposed
    0 / 81 (0.00%)
    2 / 78 (2.56%)
    0 / 40 (0.00%)
         occurrences all number
    0
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 81 (0.00%)
    1 / 78 (1.28%)
    1 / 40 (2.50%)
         occurrences all number
    0
    1
    1
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 81 (0.00%)
    3 / 78 (3.85%)
    0 / 40 (0.00%)
         occurrences all number
    0
    3
    0
    Diverticulitis
         subjects affected / exposed
    1 / 81 (1.23%)
    2 / 78 (2.56%)
    0 / 40 (0.00%)
         occurrences all number
    1
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 81 (1.23%)
    0 / 78 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    0 / 81 (0.00%)
    0 / 78 (0.00%)
    1 / 40 (2.50%)
         occurrences all number
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Dec 2013
    This amendment was primarily required to take into account the new information of the latest Investigator’s Brochure (IB) for Rifamycin SV-MMX®. Additionally, the Federal Institute for Drugs and Medical Devices (BfArM) in Germany wished, during the approval process, to include a second ultrasonography or computed tomography after treatment end. Finally, some further changes were introduced to the protocol (e.g. inclusion criteria, concomitant medication etc.).
    04 May 2015
    This amendment was primarily required to take into account the new information of the latest Investigator’s Brochure (IB) for Rifamycin SV-MMX®. In addition, some administrative amendments were introduced to the protocol to verbalize more detailed guidance as per the current status quo.

    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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