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    Clinical Trial Results:
    Safety and tolerability of the combination of simvastatin plus rifaximin in patients with decompensated cirrhosis: a multicenter, double-blind, placebo controlled randomized clinical trial.

    Summary
    EudraCT number
    2016-004499-23
    Trial protocol
    ES   NL   GB   FR  
    Global end of trial date
    12 Mar 2018

    Results information
    Results version number
    v1(current)
    This version publication date
    22 Jul 2020
    First version publication date
    22 Jul 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    LIVERHOPE_SAFETY
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03150459
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    IDIBAPS
    Sponsor organisation address
    Rosselló, 149, Barcelona, Spain, 08036
    Public contact
    Pere Ginés, Hospital Clínic, +34 9322754001713, pgines@clinic.cat
    Scientific contact
    Pere Ginés, Hospital Clínic, +34 9322754001713, pgines@clinic.cat
    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
    02 Aug 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Mar 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    12 Mar 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the treatment-related toxicity of oral administration of simvastatin plus rifaximin in patients with decompensated cirrhosis.
    Protection of trial subjects
    Not required
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    26 Jul 2017
    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
    United Kingdom: 5
    Country: Number of subjects enrolled
    Germany: 4
    Country: Number of subjects enrolled
    Spain: 11
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Italy: 16
    Worldwide total number of subjects
    44
    EEA total number of subjects
    44
    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)
    35
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Trial subjects were recruited at 9 European European University Hospitals in Spain, Germany, UK, The Netherlands, Italy and France. Recruitment period: 28-July-2017 to 2-January-2018

    Pre-assignment
    Screening details
    Having given consent, participants will undergo screening assessments to verify their eligibility to participate in the study according the selection criteria specified in the protocol. Study population was adult patients with decompensated cirrhosis.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    It is a double-blind placebo controlled clinical trial

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo of simvastatin + Placebo of rifaximin
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo of simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets every 24 hours at night during 12 weeks

    Investigational medicinal product name
    Placebo of rifaximin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of Placebo of Rifaximin every 8 hours during 12 weeks

    Arm title
    Simvastatin 20 mg
    Arm description
    Simvastatin 20mg/day + Rifaximin 400mg/8 hours
    Arm type
    Experimental

    Investigational medicinal product name
    Simvastatin 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of simvastatin 20 mg every 24 hours at night during 12 weeks

    Investigational medicinal product name
    Placebo of simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets every 24 hours at night during 12 weeks

    Investigational medicinal product name
    Rifaximin 400 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of Rifaximin 400 mg every 8 hours during 12 weeks

    Arm title
    Simvastatin 40 mg
    Arm description
    Simvastatin 40 mg + Rifaximin 400 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Simvastatin 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of simvastatin 20 mg every 24 hours at night during 12 weeks

    Investigational medicinal product name
    Rifaximin 400 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of Rifaximin 400 mf every 8 hours during 12 weeks

    Number of subjects in period 1
    Placebo Simvastatin 20 mg Simvastatin 40 mg
    Started
    14
    14
    16
    Completed
    14
    14
    16
    Period 2
    Period 2 title
    Overall trial
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Data analyst, Carer
    Blinding implementation details
    It is a double-blind placebo controlled clinical trial

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Placebo
    Arm description
    Placebo of simvastatin + Placebo of rifaximin
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo of simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets every 24 hours at night during 12 weeks

    Investigational medicinal product name
    Placebo of rifaximin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of Placebo of Rifaximin every 8 hours during 12 weeks

    Arm title
    Simvastatin 20 mg
    Arm description
    Simvastatin 20mg/day + Rifaximin 400mg/8 hours
    Arm type
    Experimental

    Investigational medicinal product name
    Simvastatin 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of simvastatin 20 mg every 24 hours at night during 12 weeks

    Investigational medicinal product name
    Placebo of simvastatin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets every 24 hours at night during 12 weeks

    Investigational medicinal product name
    Rifaximin 400 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    One tablet of Rifaximin 400 mg every 8 hours during 12 weeks

    Arm title
    Simvastatin 40 mg
    Arm description
    Simvastatin 40 mg + Rifaximin 400 mg
    Arm type
    Experimental

    Investigational medicinal product name
    Simvastatin 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of simvastatin 20 mg every 24 hours at night during 12 weeks

    Investigational medicinal product name
    Rifaximin 400 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet of Rifaximin 400 mf every 8 hours during 12 weeks

    Number of subjects in period 2
    Placebo Simvastatin 20 mg Simvastatin 40 mg
    Started
    14
    14
    16
    Completed
    12
    12
    5
    Not completed
    2
    2
    11
         Liver transplantation
    -
    1
    -
         Adverse event, non-fatal
    1
    -
    5
         Prematurely discontinuation (DSMB recommendation)
    -
    -
    1
         Consent withdrawn by subject
    1
    1
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo of simvastatin + Placebo of rifaximin

    Reporting group title
    Simvastatin 20 mg
    Reporting group description
    Simvastatin 20mg/day + Rifaximin 400mg/8 hours

    Reporting group title
    Simvastatin 40 mg
    Reporting group description
    Simvastatin 40 mg + Rifaximin 400 mg

    Reporting group values
    Placebo Simvastatin 20 mg Simvastatin 40 mg Total
    Number of subjects
    14 14 16 44
    Age categorical
    median age 18-64
    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)
    10 14 11 35
        From 65-84 years
    4 0 5 9
        85 years and over
    0 0 0 0
    Age continuous
    55.89 (11.58)
    Units: years
        median (standard deviation)
    59 ± 12 49 ± 11 60 ± 12 -
    Gender categorical
    Units: Subjects
        Female
    5 3 4 12
        Male
    9 11 12 32
    Etiology of cirrhosis
    Units: Subjects
        Alcohol
    9 9 9 27
        Others
    5 5 7 17
    CHild Pugh class
    Units: Subjects
        Child B
    10 10 12 32
        CHild C
    4 4 4 12
    MELD score
    Units: no
        arithmetic mean (standard deviation)
    13 ± 3 14 ± 3 14 ± 3 -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    Placebo of simvastatin + Placebo of rifaximin

    Reporting group title
    Simvastatin 20 mg
    Reporting group description
    Simvastatin 20mg/day + Rifaximin 400mg/8 hours

    Reporting group title
    Simvastatin 40 mg
    Reporting group description
    Simvastatin 40 mg + Rifaximin 400 mg
    Reporting group title
    Placebo
    Reporting group description
    Placebo of simvastatin + Placebo of rifaximin

    Reporting group title
    Simvastatin 20 mg
    Reporting group description
    Simvastatin 20mg/day + Rifaximin 400mg/8 hours

    Reporting group title
    Simvastatin 40 mg
    Reporting group description
    Simvastatin 40 mg + Rifaximin 400 mg

    Primary: Liver toxicity

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    End point title
    Liver toxicity
    End point description
    (1) liver toxicity assessed by the development of liver injury defined as 3-fold increase in serum transaminases to a final value at least 3 times the upper normal limit, or 2-fold increase in serum levels of alkaline phosphatase with respect to baseline value to a final value at least 2 times the upper normal limit
    End point type
    Primary
    End point timeframe
    12 weeks of treatment period
    End point values
    Placebo Simvastatin 20 mg Simvastatin 40 mg
    Number of subjects analysed
    14
    14
    16
    Units: IU/L
    14
    14
    16
    Statistical analysis title
    primary endpoint liver toxicity
    Comparison groups
    Simvastatin 20 mg v Placebo v Simvastatin 40 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    50
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    5
         upper limit
    95

    Primary: Muscle toxicity

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    End point title
    Muscle toxicity
    End point description
    2) muscle toxicity, defined as 5-fold increase in creatinine kinase (CK) levels during treatment.
    End point type
    Primary
    End point timeframe
    12 weeks treatment period
    End point values
    Placebo Simvastatin 20 mg Simvastatin 40 mg
    Number of subjects analysed
    14
    14
    16
    Units: IU/l
    14
    14
    16
    Statistical analysis title
    primary endpoint muscle toxicity
    Comparison groups
    Placebo v Simvastatin 20 mg v Simvastatin 40 mg
    Number of subjects included in analysis
    44
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    P-value
    < 0.05
    Method
    Mixed models analysis
    Parameter type
    Mean difference (final values)
    Point estimate
    50
    Confidence interval
         level
    90%
         sides
    2-sided
         lower limit
    5
         upper limit
    95

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    12 weeks
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    -

    Reporting group title
    Simvastatina 20
    Reporting group description
    -

    Reporting group title
    Simnvastatina 40
    Reporting group description
    -

    Serious adverse events
    Placebo Simvastatina 20 Simnvastatina 40
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 14 (28.57%)
    3 / 14 (21.43%)
    9 / 16 (56.25%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Hepatitis toxic
         subjects affected / exposed
    4 / 14 (28.57%)
    3 / 14 (21.43%)
    9 / 16 (56.25%)
         occurrences causally related to treatment / all
    1 / 6
    0 / 3
    4 / 11
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Peritonitis bacterial
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hepatic encephalopathy
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Fistula
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Muscle spasms
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    2 / 16 (12.50%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Placebo Simvastatina 20 Simnvastatina 40
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 14 (78.57%)
    10 / 14 (71.43%)
    15 / 16 (93.75%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    1 / 16 (6.25%)
         occurrences all number
    0
    2
    1
    Chest pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Influenza like illness
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    2
    Malaise
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    1 / 16 (6.25%)
         occurrences all number
    0
    1
    1
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hepatitis toxic
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 14 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    1
    2
    0
    Weight increased
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Paracentesis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    Dyspnoea
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Viral upper respiratory tract infection
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    2 / 14 (14.29%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    2
    0
    0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Encephalopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Headache
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Abdominal distension
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Abdominal pain
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Ascites
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    3
    3
    0
    Constipation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Diarrhoea
         subjects affected / exposed
    1 / 14 (7.14%)
    2 / 14 (14.29%)
    3 / 16 (18.75%)
         occurrences all number
    1
    2
    3
    Dyspepsia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Rectal haemorrhage
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Vomiting
         subjects affected / exposed
    0 / 14 (0.00%)
    2 / 14 (14.29%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Renal and urinary disorders
    Polyuria
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Acute kidney injury
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    2 / 16 (12.50%)
         occurrences all number
    1
    1
    2
    Hepatobiliary disorders
    Ascites
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    3
    Hepatic encephalopathy
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    1 / 16 (6.25%)
         occurrences all number
    4
    1
    1
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Pruritus
         subjects affected / exposed
    4 / 14 (28.57%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    4
    1
    0
    Musculoskeletal and connective tissue disorders
    Fistula
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Muscle spasms
         subjects affected / exposed
    2 / 14 (14.29%)
    1 / 14 (7.14%)
    1 / 16 (6.25%)
         occurrences all number
    3
    1
    1
    Myalgia
         subjects affected / exposed
    0 / 14 (0.00%)
    3 / 14 (21.43%)
    2 / 16 (12.50%)
         occurrences all number
    0
    3
    2
    Myopathy
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Myositis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Rhabdomyolysis
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    2 / 16 (12.50%)
         occurrences all number
    0
    0
    2
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Hyponatraemia
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    1
    1
    0
    Infections and infestations
    Furuncle
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 14 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    Pneumonia
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Urinary tract infection
         subjects affected / exposed
    3 / 14 (21.43%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    4
    0
    1
    Escherichia urinary tract infection
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 14 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    1
    Enterocolitis infectious
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 14 (7.14%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    20 Mar 2017
    The objective of the amendment is the correction of some errors detected related to the amount of blood and urine required during the follow-up of the study and their timepoints.
    23 Oct 2017
    The aim of the substantial amendment was the introduction of the following modifications: 1. Addition of the definition of women of child-bearing potential. 2. Addition of a urine pregnancy test at baseline. 3. Addition of a telephone contact visit 4 weeks after study completion. 4. Addition of cyclosporine and simeprevir as nonpermitted medication. 5. Correction of the group to which clarithromycin and telithromycin belong. 6. Removal week 2 visit as a timepoint for secondary endpoints 2, 3, 4 and 5 and as a timepoint for collecting samples for storage at the biobank. 7. Replacement of the principal investigator in Bologna University Hospital.

    Interruptions (globally)

    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Mar 2018
    On 13th February 2018, the DSMB concluded during its regular meeting to recommend stopping one of the arms of the LIVERHOPE SAFETY study because of safety concerns. The decision to stop one of the arms of the trial was made because the data indicated that there was a higher prevalence of early study discontinuation (either because of adverse events or patient decision) in this group as compared with the other two groups. After extensive discussion within the executive committee of the LIVERHOPE SAFETY study and the Principal Investigators from the partner centers involved, the 16th February 2018 it was agreed unanimously to support this recommendation. This implied to stop therapy in those patients that were still active, but only in this specific treatment arm. In the other two arms, there were no safety concerns during the trial until that moment. Patients remaining active in the other two arms continued in the study until the end of the 12 week treatment period, the end of study according to the protocol. Only one patient was on treatment with the affected study arm and discontinued the study treatment the 16th February 2018. The blindness was maintained. The affected treatment arm has been identified at the time of the analysis of the results. The study arm concerned was Simvastatin 40mg + Rifaximin 400mg.
    -

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/31607677
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