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    Clinical Trial Results:
    A Phase II, multicentre, double-blind, randomised, placebo-controlled study of Rifaximin delayed release 400 mg tablet: clinical efficacy and safety in the prevention of post-operative endoscopic Crohn's disease recurrence

    Summary
    EudraCT number
    		 2017-002258-36
    Trial protocol
    		 DE   BE   ES   NL   IT  
    Global end of trial date
    29 Jul 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 Aug 2021
    First version publication date
    14 Aug 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    RETIPC/01/17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NA: NA
    Sponsors
    Sponsor organisation name
    Alfasigma S.p.A.
    Sponsor organisation address
    Via Ragazzi del '99, 5, Bologna, Italy, 40122
    Public contact
    Cecilia Renzulli, Alfasigma S.p.A, cecilia.renzulli@alfasigma.com
    Scientific contact
    Cecilia Renzulli, Alfasigma S.p.A, cecilia.renzulli@alfasigma.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
    25 Sep 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jul 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    29 Jul 2020
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    This study primarily aimed to demonstrate the efficacy of Rifaximin-EIR 400 mg tablet (800 mg/B.I.D., total daily dose 1600 mg) vs. Placebo in the prevention of Endoscopic Crohn’s Disease Recurrence following ileocolonic resection.
    Protection of trial subjects
    This study was conducted in compliance with the Declaration of Helsinki and the standards of Good Clinical Practice as defined in the International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) E6 (R2) “Guideline for Good Clinical Practice”.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Mar 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 5
    Country: Number of subjects enrolled
    Poland: 1
    Country: Number of subjects enrolled
    Belgium: 18
    Country: Number of subjects enrolled
    France: 12
    Country: Number of subjects enrolled
    Germany: 2
    Country: Number of subjects enrolled
    Italy: 5
    Worldwide total number of subjects
    43
    EEA total number of subjects
    43
    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)
    40
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 In total, 50 patients were screened for the study during approximately 26 months – from 17 November 2017 to 31 December 2019 in 14 out of the 25 activated study sites in 6 European countries (Belgium, France, Germany, Italy, the Netherlands, Poland).

    Pre-assignment
    Screening details
    		 In total, 50 patients were screened for the study. Eight patients (16.0%) were recorded as screening failures (SF). Among these 8 patients, 1 has been randomised in the study but has not received study drug.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Rifaximin-EIR 400 mg
    Arm description
    		 Rifaximin-EIR 400 mg film coated tablets, 2 tablets taken orally B.I.D. (1600 mg/daily)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rifaximin-EIR
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Rifaximin-EIR 400 mg film coated tablets, 2 tablets taken orally B.I.D. (1600 mg/daily) for 26 weeks

    Arm title
    		 Placebo
    Arm description
    		 Placebo matching Rifaximin-EIR 400 mg film coated tablets
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo film coated tablets: 2 tablets taken orally B.I.D. for 26 weeks

    Number of subjects in period 1
    		Rifaximin-EIR 400 mg Placebo
    Started
    21
    22
    Completed
    17
    21
    Not completed
    4
    1
         Investigator's decision
    1
    1
         Adverse event, non-fatal
    1
    -
         Exclusion Criteria
    1
    -
         Lost to follow-up
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Rifaximin-EIR 400 mg
    Reporting group description
    		 Rifaximin-EIR 400 mg film coated tablets, 2 tablets taken orally B.I.D. (1600 mg/daily)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matching Rifaximin-EIR 400 mg film coated tablets

    Reporting group values
    		 Rifaximin-EIR 400 mg Placebo Total
    Number of subjects
    		 21 22 43
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 20 20 40
        From 65-84 years
    		 1 2 3
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 9 7 16
        Male
    		 12 15 27
    Subject analysis sets

    Subject analysis set title
    Safety Analysis (SAF) Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Of all 43 patients that were randomised, 42 patients (97.7%) were included in the SAF Population: with 20 patients (95.2%) in the Rifaximin-EIR and 22 patients (100.00%) in the Placebo group. 1 out of the 43 randomised subjects was randomised to the Rifaximin-EIR group but did not receive any study drug, so the patient was recorded as Screening failure.

    Subject analysis set title
    Intention to Treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Of all 43 patients that were randomised, 42 patients (97.7%) were included in the ITT Population: with 20 patients (95.2%) in the Rifaximin-EIR and 22 patients (100.00%) in the Placebo group. 1 out of the 43 randomised subjects was randomised to the Rifaximin-EIR group but did not receive any study drug, so the patient was recorded as screening failure.

    Subject analysis set title
    Modified Intention to Treat (mITT) population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Within the ITT Population, subjects who had the endoscopic evaluation at Week 26 were included in the mITT Population

    Subject analysis set title
    Per Protocol (PP) population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Reasons for exclusion from the PP Population were the violation of inclusion/exclusion criteria, the use of prohibited medications and treatment compliance.

    Subject analysis sets values
    		 Safety Analysis (SAF) Population Intention to Treat (ITT) population Modified Intention to Treat (mITT) population Per Protocol (PP) population
    Number of subjects
    42
    42
    36
    28
    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)
    39
    39
    33
    25
        From 65-84 years
    3
    3
    3
    3
        85 years and over
    0
    0
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.3 ( 13.50 )
    38.3 ( 13.50 )
    38.7 ( 14.04 )
    37.6 ( 14.8 )
    Gender categorical
    Units: Subjects
        Female
    23
    23
    20
    16
        Male
    19
    19
    16
    12

    End points

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    End points reporting groups
    Reporting group title
    Rifaximin-EIR 400 mg
    Reporting group description
    		 Rifaximin-EIR 400 mg film coated tablets, 2 tablets taken orally B.I.D. (1600 mg/daily)

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo matching Rifaximin-EIR 400 mg film coated tablets

    Subject analysis set title
    Safety Analysis (SAF) Population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Of all 43 patients that were randomised, 42 patients (97.7%) were included in the SAF Population: with 20 patients (95.2%) in the Rifaximin-EIR and 22 patients (100.00%) in the Placebo group. 1 out of the 43 randomised subjects was randomised to the Rifaximin-EIR group but did not receive any study drug, so the patient was recorded as Screening failure.

    Subject analysis set title
    Intention to Treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Of all 43 patients that were randomised, 42 patients (97.7%) were included in the ITT Population: with 20 patients (95.2%) in the Rifaximin-EIR and 22 patients (100.00%) in the Placebo group. 1 out of the 43 randomised subjects was randomised to the Rifaximin-EIR group but did not receive any study drug, so the patient was recorded as screening failure.

    Subject analysis set title
    Modified Intention to Treat (mITT) population
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    Within the ITT Population, subjects who had the endoscopic evaluation at Week 26 were included in the mITT Population

    Subject analysis set title
    Per Protocol (PP) population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Reasons for exclusion from the PP Population were the violation of inclusion/exclusion criteria, the use of prohibited medications and treatment compliance.

    Primary: Proportion of patients with Endoscopic Recurrence at Week 26

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    End point title
    		 Proportion of patients with Endoscopic Recurrence at Week 26
    End point description
    Proportion of patients with Endoscopic Recurrence at Week 26 after Randomisation, defined as Rutgeerts score ≥ i2
    End point type
    Primary
    End point timeframe
    26 weeks
    End point values
    		 Rifaximin-EIR 400 mg Placebo Intention to Treat (ITT) population
    Number of subjects analysed
    20
    22
    42
    Units: Subjects
    19
    19
    38
    Statistical analysis title
    		 Efficacy statistical analysis
    Comparison groups
    Placebo v Rifaximin-EIR 400 mg
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Fisher exact
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    28 weeks
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    Safety analysis population
    Reporting group description
    		 -

    Serious adverse events
    		 Safety analysis population
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 42 (2.38%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Safety analysis population
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 42 (85.71%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Skin papilloma
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Vascular disorders
    Hot flush
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Hypertension
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Malaise
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Pyrexia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Immune system disorders
    Seasonal allergy
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Reproductive system and breast disorders
    Galactorrhoea
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Gynaecomastia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Vulvovaginal pruritus
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Emphysema
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Rhinitis allergic
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Investigations
    Blood testosterone decreased
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Neutrophil count increased
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Red blood cell sedimentation rate increased
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    White blood cell count increased
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Animal scratch
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Muscle injury
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Lymphopenia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Neutropenia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    6
    Anal fissure
         subjects affected / exposed
    4 / 42 (9.52%)
         occurrences all number
    4
    Nausea
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    4
    Abdominal distension
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    3
    Diarrhoea
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    3
    Dyspepsia
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    2
    Haematochezia
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    2
    Proctalgia
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    2
    Anal skin tags
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Cheilosis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Gastric mucosa erythema
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Gastritis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Rectal haemorrhage
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Umbilical hernia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Infections and infestations
    Viral upper respiratory tract infection
         subjects affected / exposed
    5 / 42 (11.90%)
         occurrences all number
    5
    Gastroenteritis
         subjects affected / exposed
    4 / 42 (9.52%)
         occurrences all number
    4
    Bronchitis
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    3
    Cystitis
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    2
    Nasopharyngitis
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    2
    Ear infection
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Influenza
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Oral fungal infection
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Osteomyelitis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Otitis media
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Pneumonia
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Tinea pedis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Vulvovaginal candidiasis
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    3 / 42 (7.14%)
         occurrences all number
    3
    Hypokalaemia
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    2
    Hypophosphataemia
         subjects affected / exposed
    2 / 42 (4.76%)
         occurrences all number
    2
    Decreased appetite
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Gout
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Iron deficiency
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Malnutrition
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1
    Vitamin B12 deficiency
         subjects affected / exposed
    1 / 42 (2.38%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Sep 2017
    Amended versions of the study protocol (2.0 and 3.0) contained minor administrative updates, additions or clarifications regarding exclusion criteria and clarifications concerning schedule of assessments and secondary endpoint.
    11 Oct 2018
    Amended versions of the study protocol (2.0 and 3.0) contained minor administrative updates, additions or clarifications regarding exclusion criteria and clarifications concerning schedule of assessments and secondary endpoint.

    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 prematurely terminated due to the difficulties in patient recruitment.
    For support, Contact us.
    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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