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    Clinical Trial Results:
    Achieving appropriate exposuRe to RIBAvirin after a dose advise based on an abbreviated AUC of a first dose of ribavirin (ARRIBA)

    Summary
    EudraCT number
    		 2010-020371-22
    Trial protocol
    		 NL   DE  
    Global end of trial date
    08 Jan 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    21 Sep 2019
    Other versions
    Summary report(s)
    		 ARRIBA paper

    Trial information

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    Trial identification
    Sponsor protocol code
    UMCN-AKF 10.04
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboudumc
    Sponsor organisation address
    Geert Grooteplein Zuid 10, Nijmegen, Netherlands,
    Public contact
    Prof. David Burger, Radboudumc, david.burger@radboudumc.nl
    Scientific contact
    Prof. David Burger, Radboudumc, david.burger@radboudumc.nl
    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
    17 Sep 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jan 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate if adequate exposure to ribavirin can be achieved after a dose adjustment based on the AUC0-4h from a first dose of ribavirin.
    Protection of trial subjects
    We inlcuded patients who had been treated with RBV (and PEG-IFN) before. These patients had already been exposed to RBV during several weeks or months as part of their HCV treatment. In this study they would receive two extra doses of RBV which is negligible when compared to the number of doses they have received before, and thus, no additional harm was expected. We included only patients who had received at least 4 weeks of RBV which was equal to at least 56 doses, and they received 2 additional doses. Still we can evaluate the effectiveness of our intervention as these patients do not need chronic treatment with RBV and two single doses can be given.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 Oct 2010
    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: 19
    Country: Number of subjects enrolled
    Germany: 10
    Worldwide total number of subjects
    29
    EEA total number of subjects
    29
    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)
    26
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruited at: Radboud university medical center, Nijmegen, and Erasmus University Medical Center, Rotterdam, both in the Netherlands, and at University Hospital Bonn, Bonn, Germany.

    Pre-assignment
    Screening details
    		 HCV-treatment experienced patients were selected who were at least 18 years at screening, had tolerated ribavirin in the past and who were either cured or not yet eligible for subsequent HCV treatment.

    Pre-assignment period milestones
    Number of subjects started
    		 29
    Number of subjects completed
    		 26

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Physician decision: 3
    Period 1
    Period 1 title
    treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 RBV dose 1
    Arm description
    		 -
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Ribavirine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1 of the study, participants received a single dose of ribavirin based on their body weight: <75kg: 400mg ribavirin (2 tablets of 200mg Copegus®, Roche, the Netherlands), ≥75kg: 600mg ribavirin (3 tablets of 200mg Copegus®, Roche, the Netherlands). Medication was taken at the study centre with a standardized breakfast (2 pieces of brown bread, one slice of cheese and one slice of meat, one cup of custard, and one cup of water (200mL)).

    Number of subjects in period 1 [1]
    		RBV dose 1
    Started
    26
    Completed
    26
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Baseline period was done after screening period, therefore screening failures were not included in the baseline period.
    Period 2
    Period 2 title
    RBV dose 2
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 RBV dose 2
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ribavirine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    IF ribavirin AUC0-4h on day 1 was adequate, i.e. ≥1.755mg.h/L, subjects received the same dose on day 29. If exposure to ribavirin was too low, i.e. an AUC0-4h <1.755mg.h/L, an adjusted dose of ribavirin was administered on day 29, based on a predefined algorithm.

    Number of subjects in period 2
    		RBV dose 2
    Started
    26
    Completed
    26

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    treatment
    Reporting group description
    		 -

    Reporting group values
    		 treatment Total
    Number of subjects
    		 26 26
    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
        median (full range (min-max))
    		 50 (20 to 70) -
    Gender categorical
    Units: Subjects
        Female
    		 9 9
        Male
    		 17 17
    Subject analysis sets

    Subject analysis set title
    ARRIBA
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects eligible for inclusion

    Subject analysis sets values
    		 ARRIBA
    Number of subjects
    26
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        median (full range (min-max))
    50 (20 to 70)
    Gender categorical
    Units: Subjects
        Female
    9
        Male
    17

    End points

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    End points reporting groups
    Reporting group title
    RBV dose 1
    Reporting group description
    		 -
    Reporting group title
    RBV dose 2
    Reporting group description
    		 -

    Subject analysis set title
    ARRIBA
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects eligible for inclusion

    Primary: adequate exposure

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    End point title
    		 adequate exposure [1]
    End point description
    End point type
    Primary
    End point timeframe
    Entire study
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No formal satistical analyses were done
    End point values
    		 ARRIBA
    Number of subjects analysed
    Units: %
        % of paitents achieved adeuqate AUC0-4
    62
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Entire study
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 no
    Dictionary version
    1
    Reporting groups
    Reporting group title
    ARRIBA group
    Reporting group description
    		 -

    Serious adverse events
    		 ARRIBA group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 26 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ARRIBA group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 26 (23.08%)
    Nervous system disorders
    headache
         subjects affected / exposed
    4 / 26 (15.38%)
         occurrences all number
    4
    Infections and infestations
    common cold
         subjects affected / exposed
    2 / 26 (7.69%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    17 Aug 2011
    amendment 1
    27 Mar 2013
    amendment 2

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    08 Jan 2014
    After 50% of the patients to be included an interim analysis was done according to the protocol. Based on the stopping criteria as defined in the study protocol the results of the interim analysis propose to continue with the study. However, for a number of reasons were of the opinion that it was better not to continue with ARRIBA These reasons are: -the target AUC0-4h was based on dual combination therapy of RBV + PegIFN;this no longer applied in 2014 - although the intervention in ARRIBA was effective in some patients, the increase in RBV exposure was not linear, so probably the dosing algorithm is not optimal - there is a higher need to evaluate the role of RBV PK as part of DAA combinations, and possibly another target for AUC0-4h is needed, for instance when combined with Sofosbuvir in GT 3.
    -

    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/25599333
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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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