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    Clinical Trial Results:
    Safety and Efficacy of Rifaximin Delayed Release 400 mg Tablets in Patients with Moderate-to-Severe Papulopustular Rosacea and Positive Lactulose Breath Test. A Multicenter Double-Blind, Placebo-Controlled Randomized Clinical Trial.

    Summary
    EudraCT number
    		 2017-003722-33
    Trial protocol
    		 IT   DE  
    Global end of trial date
    21 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Aug 2023
    First version publication date
    04 Aug 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    REROS/001/17
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Alfasigma
    Sponsor organisation address
    Via Ragazzi del '99 5, Bologna, Italy,
    Public contact
    Nicola Gargano, Alfasigma, nicola.gargano@alfasigma.com
    Scientific contact
    Nicola Gargano, Alfasigma, nicola.gargano@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
    29 Sep 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    21 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the safety and efficacy of oral Rifaximin-EIR (rifaximin delayed release) versus placebo in adults with moderate-to-severe papulopustular rosacea (a.k.a. subtype II).
    Protection of trial subjects
    Before initiating the trial, the Sponsor and the Investigators/institutions obtained written and dated approval/favourable opinion from the IRB/IEC for the trial protocol, written informed consent and assent forms and any other written/oral information provided to the subjects. The Sponsor provided the IRB/IEC with a current copy of the Investigator's Brochure and any updated copy prepared during the trial, when requested. The Sponsor and the Investigators/institutions obtained approval/favourable opinion from the IRB/IEC for change(s) to any aspect of the trial, such as modification(s) of the protocol, written informed consent form (ICF), written information provided to subjects. The Sponsor had to promptly report any new information that could affect the safety of the subjects or the conduct of the trial to both the IRB/IEC and the Regulatory Authorities, if applicable. This study was conducted in compliance with the study protocol, the recommendations on biomedical research on human subjects of the Declaration of Helsinki, ICH GCP E6 (R2) Guidelines, and all applicable national laws and regulations. Agreement to adhere to the protocol was indicated by Investigators signing and returning the protocol signature page. Subject identities were kept confidential by assigning each subject a unique identifier consisting of a subject-specific numeric code, which was used throughout the study instead of the subject’s name.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Jun 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
    Germany: 103
    Country: Number of subjects enrolled
    Italy: 42
    Country: Number of subjects enrolled
    Russian Federation: 87
    Country: Number of subjects enrolled
    Ukraine: 11
    Worldwide total number of subjects
    243
    EEA total number of subjects
    145
    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)
    229
    From 65 to 84 years
    14
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were planned to be competitively enrolled at approximately 50 study sites in Italy, Germany, Russia and Ukraine.

    Pre-assignment
    Screening details
    		 A total of 661 subjects provided written informed consent to participate in this study. Two hundred and forty-three subjects completed screening successfully and 418 were screening failures.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 2 rifaximin-EIR 400 mg tablets BID for 10 days and 2 tablets of placebo BID for the following 20 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rifaximin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets BID (10 days)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets BID (20 days)

    Arm title
    		 Arm B
    Arm description
    		 1 rifaximin-EIR 400 mg tablet and 1 placebo tablet BID for 30 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rifaximin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablets BID (30 days)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablets BID (30 days)

    Arm title
    		 Arm C
    Arm description
    		 1 rifaximin-EIR 400 mg tablet and 1 placebo tablet BID for 10 days and 2 tablets of placebo BID for the following 20 days
    Arm type
    		 Experimental

    Investigational medicinal product name
    Rifaximin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet BID (10 days)

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet BID (10 days) and 2 tablets BID (20 days)

    Arm title
    		 Arm D
    Arm description
    		 2 tablets of placebo BID for 30 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    2 tablets BID (30 days)

    Number of subjects in period 1
    		Arm A Arm B Arm C Arm D
    Started
    60
    61
    60
    62
    Completed
    55
    54
    52
    55
    Not completed
    5
    7
    8
    7
         Consent withdrawn by subject
    2
    3
    5
    4
         Adverse event, non-fatal
    1
    -
    2
    -
         other
    1
    1
    1
    -
         Lost to follow-up
    1
    3
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 2 rifaximin-EIR 400 mg tablets BID for 10 days and 2 tablets of placebo BID for the following 20 days

    Reporting group title
    Arm B
    Reporting group description
    		 1 rifaximin-EIR 400 mg tablet and 1 placebo tablet BID for 30 days

    Reporting group title
    Arm C
    Reporting group description
    		 1 rifaximin-EIR 400 mg tablet and 1 placebo tablet BID for 10 days and 2 tablets of placebo BID for the following 20 days

    Reporting group title
    Arm D
    Reporting group description
    		 2 tablets of placebo BID for 30 days.

    Reporting group values
    		 Arm A Arm B Arm C Arm D Total
    Number of subjects
    		 60 61 60 62 243
    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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.2 ( 11.46 ) 44.6 ( 11.75 ) 43.8 ( 11.09 ) 43.6 ( 11.16 ) -
    Gender categorical
    Units: Subjects
        Female
    		 45 45 45 39 174
        Male
    		 15 16 15 23 69

    End points

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    End points reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 2 rifaximin-EIR 400 mg tablets BID for 10 days and 2 tablets of placebo BID for the following 20 days

    Reporting group title
    Arm B
    Reporting group description
    		 1 rifaximin-EIR 400 mg tablet and 1 placebo tablet BID for 30 days

    Reporting group title
    Arm C
    Reporting group description
    		 1 rifaximin-EIR 400 mg tablet and 1 placebo tablet BID for 10 days and 2 tablets of placebo BID for the following 20 days

    Reporting group title
    Arm D
    Reporting group description
    		 2 tablets of placebo BID for 30 days.

    Primary: Mean change in number of rosacea inflammatory lesions

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    End point title
    		 Mean change in number of rosacea inflammatory lesions
    End point description
    Co-primary endpoint: Mean change from Baseline/Randomization in number of rosacea inflammatory lesions at Day 30
    End point type
    Primary
    End point timeframe
    30 days
    End point values
    		 Arm A Arm B Arm C Arm D
    Number of subjects analysed
    60
    61
    60
    62
    Units: change
        arithmetic mean (standard deviation)
    -8.4 ( 12.71 )
    -6.7 ( 13.92 )
    -12.3 ( 17.07 )
    -8.6 ( 13.13 )
    Statistical analysis title
    		 1st co-primary endpoint (A vs D)
    Comparison groups
    Arm A v Arm D
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 1st co-primary endpoint (B vs D)
    Comparison groups
    Arm B v Arm D
    Number of subjects included in analysis
    123
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 1st co-primary endpoint (C vs D)
    Comparison groups
    Arm C v Arm D
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANCOVA
    Confidence interval

    Primary: Treatment success

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    End point title
    		 Treatment success
    End point description
    Co-primary endpoint: Percent of participants showing treatment success (IGA score) at Day 30
    End point type
    Primary
    End point timeframe
    30 days
    End point values
    		 Arm A Arm B Arm C Arm D
    Number of subjects analysed
    60
    61
    60
    62
    Units: percent
        number (not applicable)
    11.7
    11.5
    8.3
    14.5
    Statistical analysis title
    		 2nd co-primary endpoint
    Comparison groups
    Arm A v Arm B v Arm C v Arm D
    Number of subjects included in analysis
    243
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Cochran-Mantel-Haenszel
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    60 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Arm A SAF
    Reporting group description
    		 All randomized subjects are included in the Safe Analysis Set (SAF). Subjects affected by non-serious adverse events: number of subjects with at least 1 most common Treatment Emergent Adverse Event (TEAE), i.e. at least 2% in any treatment group, is reported.

    Reporting group title
    Arm B SAF
    Reporting group description
    		 All randomized subjects are included in the Safe Analysis Set (SAF). Subjects affected by non-serious adverse events: number of subjects with at least 1 most common Treatment Emergent Adverse Event (TEAE), i.e. at least 2% in any treatment group, is reported. Of note, the treatment kit of Group C was wrongly dispensed to 1 subject randomized to Group B; therefore, the subject is included in Group C of the SAF for the analysis.

    Reporting group title
    Arm C SAF
    Reporting group description
    		 All randomized subjects are included in the Safe Analysis Set (SAF). Subjects affected by non-serious adverse events: number of subjects with at least 1 most common Treatment Emergent Adverse Event (TEAE), i.e. at least 2% in any treatment group, is reported. Of note, the treatment kit of Group C was wrongly dispensed to 1 subject randomized to Group B; therefore, the subject is included in Group C of the SAF for the analysis.

    Reporting group title
    Arm D SAF
    Reporting group description
    		 All randomized subjects are included in the Safe Analysis Set (SAF). Subjects affected by non-serious adverse events: number of subjects with at least 1 most common Treatment Emergent Adverse Event (TEAE), i.e. at least 2% in any treatment group, is reported.

    Serious adverse events
    		 Arm A SAF Arm B SAF Arm C SAF Arm D SAF
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    1 / 62 (1.61%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Gastrointestinal disorders
    Gastrointestinal motility disorder
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronavirus infection
         subjects affected / exposed
    1 / 60 (1.67%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Arm A SAF Arm B SAF Arm C SAF Arm D SAF
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 60 (26.67%)
    14 / 60 (23.33%)
    8 / 61 (13.11%)
    11 / 62 (17.74%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    3 / 60 (5.00%)
    2 / 60 (3.33%)
    3 / 61 (4.92%)
    3 / 62 (4.84%)
         occurrences all number
    3
    2
    3
    3
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    1
    0
    0
    pyrexia
         subjects affected / exposed
    2 / 60 (3.33%)
    1 / 60 (1.67%)
    0 / 61 (0.00%)
    1 / 62 (1.61%)
         occurrences all number
    2
    1
    0
    1
    Vaccination site pain
         subjects affected / exposed
    0 / 60 (0.00%)
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 60 (3.33%)
    1 / 61 (1.64%)
    0 / 62 (0.00%)
         occurrences all number
    1
    2
    1
    0
    Nausea
         subjects affected / exposed
    0 / 60 (0.00%)
    1 / 60 (1.67%)
    1 / 61 (1.64%)
    2 / 62 (3.23%)
         occurrences all number
    0
    2
    2
    2
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 60 (3.33%)
    0 / 60 (0.00%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Rosacea
         subjects affected / exposed
    0 / 60 (0.00%)
    0 / 60 (0.00%)
    1 / 61 (1.64%)
    2 / 62 (3.23%)
         occurrences all number
    0
    0
    1
    2
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    5 / 60 (8.33%)
    3 / 60 (5.00%)
    2 / 61 (3.28%)
    3 / 62 (4.84%)
         occurrences all number
    5
    4
    2
    4
    Conjunctivitis
         subjects affected / exposed
    1 / 60 (1.67%)
    2 / 60 (3.33%)
    0 / 61 (0.00%)
    0 / 62 (0.00%)
         occurrences all number
    1
    2
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Feb 2019
    The protocol was first amended (version 2.0) mainly to improve inclusion/exclusion criteria and statistical analysis.
    04 Dec 2019
    The version 2.0 of protocol was amended into version 3.0 to report administrative changes, to update the number of enrolling sites, to better define concomitant medications and helicobacter pylori infection assessment, to add the English version of some of the Protocol Appendices and to amend the “Subject screening and enrolment log”.
    06 Apr 2021
    The version 3.0 of protocol was amended into version 4.0 to to revise some inclusion criteria and to include further stratification analyses.

    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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