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    Clinical Trial Results:
    Study To Evaluate Safety, Tolerability, Pharmacokinetics and Antiviral Activity of Ritonavir-Boosted DANOPREVIR in Combination With Peginterferon Alfa-2a Plus Ribavirin in Treatment-naive Patients and with addition of RO5024048 in Previous Null Responder Patients With Chronic Hepatitis C Genotype 1 or 4 and Compensated Cirrhosis.

    Summary
    EudraCT number
    		 2011-004129-28
    Trial protocol
    		 SK  
    Global end of trial date
    28 Aug 2013

    Results information
    Results version number
    		 v2(current)
    This version publication date
    09 Jul 2016
    First version publication date
    06 Aug 2015
    Other versions
    		 v1 (removed from public view)
    Version creation reason
    • Correction of full data set
    Corrections due to EudraCT system errors.

    Trial information

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    Trial identification
    Sponsor protocol code
    NP27946
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    F. Hoffmann-La Roche AG
    Sponsor organisation address
    Grenzacherstrasse 124, Basel, Switzerland, CH-4070
    Public contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.com
    Scientific contact
    Roche Trial Information Hotline, F. Hoffmann-La Roche AG, 41 616878333, global.trial_information@roche.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
    09 Sep 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the safety, tolerability, pharmacokinetics (PK) and antiviral activity of RO5190591/ritonavir (danoprevir/r) in combination with peginterferon and ribavirin in treatment-naïve genotype 1 or 4 chronic hepatitis C patients with compensated cirrhosis and danoprevir/r + RO5024048 in combination with peginterferon and ribavirin in null responder genotype 1 or 4 chronic hepatitis C patients with compensated cirrhosis.
    Protection of trial subjects
    This study was conducted in accordance with the ethical principles that have their origin in the World Medical Association (WMA) Declaration of Helsinki, adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and subsequent amendments. All patients were informed verbally and in writing regarding the objectives, procedures and risks of study participation. The patients signed the informed consent form (ICF) that contained information about the objectives of the study, about the procedures followed during the study and about the risks and restrictions of the study, with special reference to possible side effects of the medication and potential interactions. The primary investigator (PI) was responsible for the care of the patients throughout the study. If the PI was not present in the clinical site, instructions were left for the staff and a telephone number where the PI could be reached.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    21 Nov 2011
    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
    New Zealand: 9
    Country: Number of subjects enrolled
    Canada: 3
    Country: Number of subjects enrolled
    Slovakia: 4
    Country: Number of subjects enrolled
    United States: 15
    Country: Number of subjects enrolled
    Poland: 8
    Country: Number of subjects enrolled
    France: 4
    Worldwide total number of subjects
    43
    EEA total number of subjects
    16
    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)
    43
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were screened for participation in this study within 56 days before dosing. If Screening was conducted between Day -56 and Day -35, inclusive, rescreen assessments had to be completed before dosing on Day 1. Eligible patients arrived at the study unit on Day -1 for safety assessments.

    Period 1
    Period 1 title
    Treatment Period
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Treatment-naïve
    Arm description
    		 All participants received peginterferon alfa-2a (PEG-IFN) 180 micrograms (μg) subcutaneously once weekly for 24 weeks and weight-based ribavirin (RBV) 1000-1200 milligrams per day (mg/day) in two divided doses orally for 24 weeks along with DNV/r 100/100 mg twice a day (BID) orally for 24 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Danoprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received DNV 100 mg BID, every 12 hours (q12h) administered orally for 24 weeks.

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    Other name
    Norvir®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received ritonavir 100 mg BID orally for 24 weeks.

    Investigational medicinal product name
    PEG-IFN alfa 2a
    Investigational medicinal product code
    Other name
    Pegasys®
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All participants received PEG-IFN 180 μg subcutaneously once weekly.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus®, RBV
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received weight-based RBV 1000-1200 mg/day in two divided doses orally for 24 weeks.

    Arm title
    		 Cohort 2: Previous null responders
    Arm description
    		 All participants received PEG-IFN 180 μg subcutaneously once weekly and weight-based RBV 1000-1200 mg/day in two divided doses orally for 24 weeks along with RO5024048 1000 mg BID co-administered orally. Participants also received DNV/r 100/100 mg BID for 24 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Danoprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received DNV/r 100/100 mg BID q12h administered orally for 24 weeks.

    Investigational medicinal product name
    Ritonavir
    Investigational medicinal product code
    Other name
    Norvir®
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received ritonavir 100 mg BID orally for 24 weeks.

    Investigational medicinal product name
    RO5024048
    Investigational medicinal product code
    Other name
    Mericitabine
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received RO5024048 1000 mg BID 24 weeks.

    Investigational medicinal product name
    PEG-IFN alfa 2a
    Investigational medicinal product code
    Other name
    Pegasys®
    Pharmaceutical forms
    Solution for injection/infusion
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    All participants received PEG-IFN 180 μg subcutaneously once weekly.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus®, RBV
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    All participants received weight-based RBV 1000-1200 mg/day in two divided doses orally for 24 weeks.

    Number of subjects in period 1
    		Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Started
    23
    20
    Completed
    16
    20
    Not completed
    7
    0
         Insufficient therapeutic response
    5
    -
         Consent withdrawn by subject
    1
    -
         Adverse event, non-fatal
    1
    -
    Period 2
    Period 2 title
    Follow-up Period
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cohort 1: Treatment-naïve - Follow-Up
    Arm description
    		 After Week 24 of treatment period, all study drugs were discontinued and participants who completed 24 weeks of treatment were followed at 4, 12, and 24 weeks after the last dose of all medications (corresponding to Study Weeks 28, 36, and 48).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Cohort 2: Previous null responders - Follow-Up
    Arm description
    		 After Week 24 of treatment period, all study drugs were discontinued and participants who completed 24 weeks of treatment were followed at 4, 12, and 24 weeks after the last dose of all medications (corresponding to Study Weeks 28, 36, and 48).
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2
    		Cohort 1: Treatment-naïve - Follow-Up Cohort 2: Previous null responders - Follow-Up
    Started
    16
    20
    Completed
    11
    19
    Not completed
    5
    1
         Consent withdrawn by subject
    1
    1
         Administrative reasons
    1
    -
         Lost to follow-up
    3
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cohort 1: Treatment-naïve
    Reporting group description
    		 All participants received peginterferon alfa-2a (PEG-IFN) 180 micrograms (μg) subcutaneously once weekly for 24 weeks and weight-based ribavirin (RBV) 1000-1200 milligrams per day (mg/day) in two divided doses orally for 24 weeks along with DNV/r 100/100 mg twice a day (BID) orally for 24 weeks.

    Reporting group title
    Cohort 2: Previous null responders
    Reporting group description
    		 All participants received PEG-IFN 180 μg subcutaneously once weekly and weight-based RBV 1000-1200 mg/day in two divided doses orally for 24 weeks along with RO5024048 1000 mg BID co-administered orally. Participants also received DNV/r 100/100 mg BID for 24 weeks.

    Reporting group values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders Total
    Number of subjects
    		 23 20 43
    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)
    		 55.2 ( 5.48 ) 54.1 ( 4.83 ) -
    Gender categorical
    Units: Subjects
        Female
    		 9 7 16
        Male
    		 14 13 27

    End points

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    End points reporting groups
    Reporting group title
    Cohort 1: Treatment-naïve
    Reporting group description
    		 All participants received peginterferon alfa-2a (PEG-IFN) 180 micrograms (μg) subcutaneously once weekly for 24 weeks and weight-based ribavirin (RBV) 1000-1200 milligrams per day (mg/day) in two divided doses orally for 24 weeks along with DNV/r 100/100 mg twice a day (BID) orally for 24 weeks.

    Reporting group title
    Cohort 2: Previous null responders
    Reporting group description
    		 All participants received PEG-IFN 180 μg subcutaneously once weekly and weight-based RBV 1000-1200 mg/day in two divided doses orally for 24 weeks along with RO5024048 1000 mg BID co-administered orally. Participants also received DNV/r 100/100 mg BID for 24 weeks.
    Reporting group title
    Cohort 1: Treatment-naïve - Follow-Up
    Reporting group description
    		 After Week 24 of treatment period, all study drugs were discontinued and participants who completed 24 weeks of treatment were followed at 4, 12, and 24 weeks after the last dose of all medications (corresponding to Study Weeks 28, 36, and 48).

    Reporting group title
    Cohort 2: Previous null responders - Follow-Up
    Reporting group description
    		 After Week 24 of treatment period, all study drugs were discontinued and participants who completed 24 weeks of treatment were followed at 4, 12, and 24 weeks after the last dose of all medications (corresponding to Study Weeks 28, 36, and 48).

    Subject analysis set title
    Pharmacokinetic Analysis Population- Cohort 1 treatment-naïve
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK Analysis Population comprised all patients who received at least one dose of study medication and for whom at least one post-baseline PK measurement was performed.

    Subject analysis set title
    Pharmacokinetic Analysis Population- Cohort 2 previous null-re
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The PK Analysis Population comprised all patients who received at least one dose of study medication and for whom at least one post-baseline PK measurement was performed.

    Primary: Maximum Plasma Concentration (Cmax) and Plasma Concentration at 12 Hours Post-dose (C12h) for Danoprevir (DNV) and Ritonavir

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    End point title
    		 Maximum Plasma Concentration (Cmax) and Plasma Concentration at 12 Hours Post-dose (C12h) for Danoprevir (DNV) and Ritonavir [1]
    End point description
    Plasma concentrations for DNV and ritonavir were measured by specific and validated liquid chromatography tandem mass spectrometry (LC-MS/MS) methods. Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Days 1 and 14
    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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    23
    20
    Units: ng/mL
    arithmetic mean (standard deviation)
        DNV-Cmax Day 1 (n=23,20)
    381 ( 394 )
    437 ( 339 )
        DNV-Cmax Day 14 (n=22,20)
    333 ( 346 )
    355 ( 310 )
        DNV-C12h Day 1 (n=23,20)
    8.49 ( 14 )
    11 ( 20.3 )
        DNV-C12h Day 14 (n=22,20)
    7.97 ( 24.2 )
    3.97 ( 6.42 )
        Ritonavir-Cmax Day 1 (n=23,20)
    744 ( 400 )
    739 ( 401 )
        Ritonavir-Cmax Day 14 (n=22,20)
    1614 ( 587 )
    1449 ( 745 )
        Ritonavir-C12h Day 1 (n=23,20)
    209 ( 185 )
    201 ( 92.4 )
        Ritonavir-C12h Day 14 (n=22,20)
    391 ( 22.4 )
    369 ( 158 )
    No statistical analyses for this end point

    Primary: Cmax and C12h for RO4995855 and RO5012433

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    End point title
    		 Cmax and C12h for RO4995855 and RO5012433 [2] [3]
    End point description
    Plasma concentrations for RO4995855 (parent of pro-drug RO5024048) and RO5012433 (the metabolite of RO4995855) were measured by specific and validated LC-MS/MS methods. Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Days 1 and 14
    Notes
    [2] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: RO5024048 was not administered to Cohort 1 participants. Therefore, calculating AUC of RO4995855 and RO5012433 (metabolites of RO5024048) was not feasible in these participants.
    End point values
    		 Cohort 2: Previous null responders
    Number of subjects analysed
    20
    Units: ng/mL
    arithmetic mean (standard deviation)
        RO4995855-Cmax Day 1
    7171 ( 2157 )
        RO4995855-Cmax Day 14
    9096 ( 2041 )
        RO4995855-C12h Day 1
    1680 ( 703 )
        RO4995855-C12h Day 14
    2106 ( 693 )
        RO5012433 Cmax Day 1
    407 ( 188 )
        RO5012433 Cmax Day 14
    827 ( 310 )
        RO5012433 C12h Day 1
    242 ( 105 )
        RO5012433 C12h Day 14
    532 ( 262 )
    No statistical analyses for this end point

    Primary: Area Under the Curve (AUC) for DNV and Ritonavir

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    End point title
    		 Area Under the Curve (AUC) for DNV and Ritonavir [4]
    End point description
    AUC is the area under the curve (mathematically known as integral) in a plot of concentration of drug in blood plasma against time. Typically, the area is computed starting at the time the drug is administered and ending when the concentration in plasma is negligible. Here the drug concentration is measured at certain discrete points in time and the trapezoidal rule is used to estimate AUC. Blood samples for DNV and ritonavir were collected at the following times: Days 1 and 14 (serial PK): Predose (within 60 min), 0.5, 1 ,2, 3, 4, 6, 8, 12, and 24 hours post morning dose. AUC 0-12 denotes Area Under the Concentration Curve from 0 to 12 hours and AUC tau is the AUC from 0 hours to the time of next dosing measured as hours times nanograms per milliliter (hr*ng/mL)
    End point type
    Primary
    End point timeframe
    Days 1 and 14
    Notes
    [4] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    23
    20
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        DNV-AUC(0-12h) Day 1 (n=23,20)
    957 ( 807 )
    1181 ( 863 )
        DNV-AUC(0-tau) Day 14 (n=22,20)
    926 ( 1227 )
    1078 ( 1144 )
        Ritonavir-AUC(0-12h) Day 1 (n=23,20)
    4288 ( 2323 )
    3956 ( 1817 )
        Ritonavir-AUC(0-tau) Day 14 (n=22,20)
    9574 ( 3672 )
    8566 ( 3723 )
    No statistical analyses for this end point

    Primary: AUC for RO4995855 and RO5012433

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    End point title
    		 AUC for RO4995855 and RO5012433 [5] [6]
    End point description
    AUC is the area under the curve (mathematically known as integral) in a plot of concentration of drug in blood plasma against time. Typically, the area is computed starting at the time the drug is administered and ending when the concentration in plasma is negligible. Here the drug concentration is measured at certain discrete points in time and the trapezoidal rule is used to estimate AUC. Blood samples were collected at the following times: Days 1 and 14 (serial PK): Predose (within 60 min), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours post morning dose. RO4995855 is the parent of RO5024048 and RO5012433 is the metabolite of RO4995855.
    End point type
    Primary
    End point timeframe
    Days 1 and 14
    Notes
    [5] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: RO5024048 was not administered to Cohort 1 participants. Therefore, calculating concentrations of RO4995855 and RO5012433 (metabolites of RO5024048) was not feasible in these participants.
    End point values
    		 Cohort 2: Previous null responders
    Number of subjects analysed
    20
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        RO4995855-AUC(0-12h) Day 1
    45233 ( 14020 )
        RO4995855-AUC(0-tau) Day 14
    60733 ( 14468 )
        RO5012433-AUC(0-12h) Day 1
    3262 ( 1457 )
        RO5012433-AUC(0-tau) Day 14
    7944 ( 2972 )
    No statistical analyses for this end point

    Primary: Time to Attain Maximum Plasma Concentration (Tmax) for DNV and Ritonavir

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    End point title
    		 Time to Attain Maximum Plasma Concentration (Tmax) for DNV and Ritonavir [7]
    End point description
    Tmax is defined as the time in hours to attain maximum concentration of the specific drug. Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Days 1 and 14
    Notes
    [7] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    23
    20
    Units: hours
    median (full range (min-max))
        DNV Day 1 (n=23,20)
    2 (0.483 to 4.08)
    2 (0.483 to 4.03)
        DNV Day 14 (n=22,20)
    2.58 (0.483 to 4.07)
    2 (0.5 to 4)
        Ritonavir Day 1 (n=23,20)
    3.9 (1 to 6)
    4 (0.483 to 6)
        Ritonavir Day 14 (n=22,20)
    3.03 (1 to 4.17)
    4 (0 to 8)
    No statistical analyses for this end point

    Primary: Tmax for RO4995855 and RO5012433

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    End point title
    		 Tmax for RO4995855 and RO5012433 [8] [9]
    End point description
    Tmax is defined as the time in hours to attain maximum plasma concentration of the specified metabolite. Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Days 1 and 14
    Notes
    [8] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: RO5024048 was not administered to Cohort 1 participants. Therefore, calculating AUC of RO4995855 and RO5012433 (metabolites of RO5024048) was not feasible in these participants.
    End point values
    		 Cohort 2: Previous null responders
    Number of subjects analysed
    20
    Units: hours
    median (full range (min-max))
        RO4995855 Day 1
    3 (1 to 6)
        RO4995855 Day 14
    3 (1.02 to 4.02)
        RO5012433 Day 1
    4.99 (3 to 11.9)
        RO5012433 Day 14
    4 (1.02 to 12)
    No statistical analyses for this end point

    Primary: Apparent Volume of Distribution at Steady State After Non-intravenous Administration

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    End point title
    		 Apparent Volume of Distribution at Steady State After Non-intravenous Administration [10]
    End point description
    The volume of distribution (VD), also known as apparent volume of distribution, is a pharmacological, theoretical volume that the total amount of administered drug would have to occupy (if it were uniformly distributed), to provide the same concentration as it currently is in blood plasma. Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Day 14
    Notes
    [10] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    21
    20
    Units: litre(s)
    arithmetic mean (standard deviation)
        DNV (n=21,20)
    517 ( 456 )
    536 ( 506 )
        Ritonavir (n=20,15)
    78.8 ( 38 )
    113 ( 66 )
    No statistical analyses for this end point

    Primary: Apparent Total Oral Clearance at Steady State

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    End point title
    		 Apparent Total Oral Clearance at Steady State [11]
    End point description
    The apparent total oral clearance at Steady State 1 is the volume of plasma cleared of the drug per unit time and is measured in liters per hour (L/hr). Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Day 14
    Notes
    [11] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    21
    20
    Units: L/hr
    arithmetic mean (standard deviation)
        DNV (n=21,20)
    215 ( 202 )
    223 ( 202 )
        Ritonavir (n= 21,16)
    12.1 ( 5.28 )
    13.6 ( 5.21 )
    No statistical analyses for this end point

    Primary: Terminal Elimination Half Life (t1/2)for DNV and Ritonavir

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    End point title
    		 Terminal Elimination Half Life (t1/2)for DNV and Ritonavir [12]
    End point description
    t1/2 is the time required for the concentration of the drug to reach half of its original value. Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Days 1 and 14
    Notes
    [12] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    22
    20
    Units: hours
    arithmetic mean (standard deviation)
        DNV Day 1 (n=22,20)
    2.05 ( 0.572 )
    2.01 ( 0.858 )
        DNV Day 14 (n=21,20)
    1.83 ( 0.746 )
    1.57 ( 0.328 )
        Ritonavir Day 1(n=19,12)
    5.17 ( 2.05 )
    5.7 ( 2.04 )
        Ritonavir Day 14 (n=20,15)
    4.51 ( 1.01 )
    5.28 ( 1.48 )
    No statistical analyses for this end point

    Primary: t1/2 for RO4995855 and RO5012433

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    End point title
    		 t1/2 for RO4995855 and RO5012433 [13] [14]
    End point description
    t1/2 is the time required for the concentration of the drug to reach half of its original value. Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Days 1 and 14
    Notes
    [13] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: RO5024048 was not administered to Cohort 1 participants. Therefore, calculating AUC of RO4995855 and RO5012433 (metabolites of RO5024048) was not feasible in these participants.
    End point values
    		 Cohort 2: Previous null responders
    Number of subjects analysed
    20
    Units: hours
    arithmetic mean (standard deviation)
        RO4995855 Day 1 (n=18)
    4.14 ( 0.52 )
        RO4995855 Day 14 (n=20)
    4.52 ( 1.34 )
        RO5012433 Day 1 (n=9)
    8.74 ( 3.48 )
        RO5012433 Day 14 (n=13)
    11.2 ( 3.31 )
    No statistical analyses for this end point

    Primary: Accumulation Ratio (AR) for DNV and Ritonavir

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    End point title
    		 Accumulation Ratio (AR) for DNV and Ritonavir [15]
    End point description
    Accumulation ratio was calculated as the ratio of AUC(0-tau, Day 14)/AUC(0-12h, Day 1). Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Day 14
    Notes
    [15] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    22
    20
    Units: ratio
    arithmetic mean (standard deviation)
        DNV
    0.91 ( 0.4 )
    0.84 ( 0.38 )
        Ritonavir
    2.47 ( 0.94 )
    2.25 ( 0.59 )
    No statistical analyses for this end point

    Primary: AR for RO4995855 and RO5012433

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    End point title
    		 AR for RO4995855 and RO5012433 [16] [17]
    End point description
    AR was calculated as the ratio of AUC(0-tau, Day 14)/AUC(0-12h, Day 1). Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Day 14
    Notes
    [16] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: RO5024048 was not administered to Cohort 1 participants. Therefore, calculating AUC of RO4995855 and RO5012433 (metabolites of RO5024048) was not feasible in these participants.
    End point values
    		 Cohort 2: Previous null responders
    Number of subjects analysed
    20
    Units: ratio
    arithmetic mean (standard deviation)
        RO4995855
    1.42 ( 0.45 )
        RO5012433
    2.61 ( 0.78 )
    No statistical analyses for this end point

    Primary: Trough concentrations for PEG-IFN

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    End point title
    		 Trough concentrations for PEG-IFN [18]
    End point description
    The trough levels is the lowest concentration reached by the drug before the next dose is administered, as determined by therapeutic drug monitoring. The concentrations were measured as picograms per milliliter (pg/mL). Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Predose Days 1, 8 and 15
    Notes
    [18] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    23
    20
    Units: pg/mL
    arithmetic mean (standard deviation)
        Day 1 predose (n=23,20)
    0 ( 0 )
    0 ( 0 )
        Day 8 predose (n=22,20)
    5750.2 ( 3672.05 )
    4267.8 ( 3231.44 )
        Day 15 predose (n=20,20)
    7662.5 ( 3840.98 )
    6506 ( 5529.46 )
    No statistical analyses for this end point

    Primary: Trough Concentrations of RBV

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    End point title
    		 Trough Concentrations of RBV [19]
    End point description
    The trough levels is the lowest concentration reached by the drug before the next dose is administered, as determined by therapeutic drug monitoring. The concentrations were measured as nanograms per milliliter (ng/mL). Blood samples were collected at the following times: Days 1 and 14 (serial PK): Pre-dose (within 60 minutes), 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours (Day 2 and Day 15, respectively) post morning dose.
    End point type
    Primary
    End point timeframe
    Predose Days 1, 8 and 15
    Notes
    [19] - 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: As a Phase II study, there was no hypothesis testing, but descriptive statistical analyses were performed according to the protocol.
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    23
    20
    Units: ng/mL
    arithmetic mean (standard deviation)
        Day 1 predose (n=23,20)
    0 ( 0 )
    2.97 ( 13.282 )
        Day 8 predose (n=22,20)
    1469.1 ( 346.491 )
    1598.3 ( 801.375 )
        Day 15 predose (n=19,20)
    1848.4 ( 546.293 )
    1850.8 ( 607.411 )
    No statistical analyses for this end point

    Secondary: Changes From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels

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    End point title
    		 Changes From Baseline in Hepatitis C Virus Ribonucleic Acid (HCV RNA) Levels
    End point description
    HCV RNA antiviral activity was summarized by cohort in the Efficacy Population. Efficacy Population comprised all patients who received at least one dose of study medication, and for whom at least one post-baseline efficacy measurement was performed. Summary statistics for changes from baseline HCV RNA levels throughout the study were provided. Before calculating the change from baseline in HCV RNA levels, the levels were log transformed (base 10) measured as International Units per milliliter (IU/mL). If at a particular visit the HCV RNA level was unquantifiable or undetectable, the level was imputed as 24.99 before being log transformed.
    End point type
    Secondary
    End point timeframe
    Day 14, Weeks 4, 12, and 24
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    23
    20
    Units: IU/mL
    arithmetic mean (standard deviation)
        Baseline(n=23,20)
    6.5 ( 0.62 )
    6.4 ( 0.34 )
        Change from Baseline at Day 14 predose
    -4.6 ( 0.71 )
    -5 ( 0.39 )
        Change from Baseline at Week 4 predose
    -4.7 ( 1.04 )
    -5 ( 0.34 )
        Change from Baseline at Week 12 predose
    -4.8 ( 0.73 )
    -5 ( 0.34 )
        Change from Baseline at Week 24 predose
    -5 ( 0.69 )
    -5 ( 0.34 )
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Virological Response

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    End point title
    		 Percentage of Participants with Virological Response
    End point description
    Virological response is defined as HCV RNA under the lower limit of quantification; less than (<) 25 IU/mL. a : HCV RNA samples were obtained before administration of any of the study drugs RVR: participants with response at Week 4 and cEVR: participants with response at Week 12.
    End point type
    Secondary
    End point timeframe
    Days 8 and 14 and Weeks 4, 12, and 24
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    23
    20
    Units: Percentage of participants
    number (confidence interval 95%)
        Day 8 pre-dose (a){n=23,20}
    26.1 (12.5 to 46.5)
    35 (18.1 to 56.7)
        Day 14 pre-dose {n=23,20}
    43.5 (25.6 to 63.2)
    85 (64 to 94.8)
        Week 4 pre-dose (RVR){n=23,20}
    73.9 (53.5 to 87.5)
    100 (83.9 to 100)
        Week 12 pre-dose (cEVR){n=23,20}
    73.9 (53.5 to 87.5)
    100 (83.9 to 100)
        Week 24 pre-dose {n=23,20}
    65.2 (44.9 to 81.2)
    100 (83.9 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with Virological Response at End of Treatment (EOT) and Sustained Virological Response (SVR)

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    End point title
    		 Percentage of Participants with Virological Response at End of Treatment (EOT) and Sustained Virological Response (SVR)
    End point description
    SVR4/12/24 is defined as sustained virological response at 4, 12, and 24 weeks after the last study drug administration. EOT = End of Treatment response; SVR4 = Sustained Virological Response 4 weeks after the last study drug administration; SVR12 = Sustained Virological Response 12 weeks after the last study drug administration; SVR24 = Sustained Virological Response 24 weeks after the last study drug administration.
    End point type
    Secondary
    End point timeframe
    EOT, SVR 4, 12, and 24
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    23
    20
    Units: Percentage of participants
    number (confidence interval 95%)
        EOT
    69.6 (49.1 to 84.4)
    100 (83.9 to 100)
        SVR4
    47.8 (29.2 to 67)
    75 (53.1 to 88.8)
        SVR12
    39.1 (22.2 to 59.2)
    65 (43.3 to 81.9)
        SVR24
    39.1 (22.2 to 59.2)
    65 (43.3 to 81.9)
    No statistical analyses for this end point

    Secondary: Percentage of Participants with EOT Response and Relapse at 4, 12, and 24 Weeks Follow-Up

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    End point title
    		 Percentage of Participants with EOT Response and Relapse at 4, 12, and 24 Weeks Follow-Up
    End point description
    Participants who had an EOT virological response and did not have an HCV RNA assessment during follow-up were excluded; these participants were not considered as having relapsed. Participants who achieved a virological response at the end of the follow-up period but had no HCV RNA assessment at the end of the actual treatment period were also considered EOT virological responders. Relapse = number of participants who achieved a response at EOT but had a detectable HCV RNA at the last assessment post-treatment divided by the number of participants with a virological response at the end of treatment who had at least one HCV RNA assessment post-treatment.
    End point type
    Secondary
    End point timeframe
    EOT and 4, 12, and 24 weeks of treatment free follow-up
    End point values
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Number of subjects analysed
    23
    20
    Units: Percentage of participants
    number (confidence interval 95%)
        EOT (n=23,20)
    69.6 (49.1 to 84.4)
    100 (83.9 to 100)
        Relapse at Week 4 (n=15,20)
    26.7 (10.9 to 52)
    25 (11.2 to 46.9)
        Relapse at Week 12 (n=15,20)
    40 (19.8 to 64.3)
    35 (18.1 to 56.7)
        Relapse at Week 24 (n= 15,20
    40 (19.8 to 64.3)
    35 (18.1 to 56.7)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were continuously monitored daily starting after the time of informed consent through the final follow-up visit up to 24 weeks after EOT.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    Cohort 1: Treatment-naïve
    Reporting group description
    		 All patients received PEG-IFN 180 μg subcutaneously once weekly and weight-based RBV 1000-1200 mg/day in two divided doses orally for 24 weeks along with DNV/r 100/100 mg BID orally for 24 weeks.

    Reporting group title
    Cohort 2: Previous null responders
    Reporting group description
    		 All patients received PEG-IFN 180 μg subcutaneously once weekly and weight-based RBV 1000-1200 mg/day in two divided doses orally for 24 weeks along with RO5024048 1000 mg BID co-administered orally.

    Serious adverse events
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 20 (5.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    Blood and lymphatic system disorders
    Pancytopenia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Hemobilia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    1 / 23 (4.35%)
    0 / 20 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Corneal infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cohort 1: Treatment-naïve Cohort 2: Previous null responders
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 23 (95.65%)
    20 / 20 (100.00%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Orthostatic hypotension
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    8 / 23 (34.78%)
    4 / 20 (20.00%)
         occurrences all number
    8
    4
    Influenza like illness
         subjects affected / exposed
    4 / 23 (17.39%)
    5 / 20 (25.00%)
         occurrences all number
    4
    10
    Irritability
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 20 (20.00%)
         occurrences all number
    3
    4
    Asthenia
         subjects affected / exposed
    4 / 23 (17.39%)
    1 / 20 (5.00%)
         occurrences all number
    4
    1
    Injection site erythema
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    Pyrexia
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    Chills
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Injection site haemorrhage
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Injection site bruising
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Oedema peripheral
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Pelvic pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Vaginal discharge
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    5 / 23 (21.74%)
    1 / 20 (5.00%)
         occurrences all number
    5
    1
    Dyspnoea
         subjects affected / exposed
    0 / 23 (0.00%)
    4 / 20 (20.00%)
         occurrences all number
    0
    4
    Oropharyngeal pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Rhinorrhoea
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Oropharyngeal discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    3 / 23 (13.04%)
    2 / 20 (10.00%)
         occurrences all number
    3
    2
    Depression
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Anxiety
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Confusional state
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Mood altered
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Investigations
    Weight decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Haemoglobin decreased
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Injury, poisoning and procedural complications
    Laceration
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Post-traumatic pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tooth fracture
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 23 (17.39%)
    7 / 20 (35.00%)
         occurrences all number
    4
    16
    Dizziness
         subjects affected / exposed
    3 / 23 (13.04%)
    3 / 20 (15.00%)
         occurrences all number
    3
    4
    Syncope
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 20 (5.00%)
         occurrences all number
    3
    1
    Amnesia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Disturbance in attention
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Dysgeusia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Hypoaesthesia
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Mental impairment
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Sciatica
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Tension headache
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    8 / 23 (34.78%)
    6 / 20 (30.00%)
         occurrences all number
    11
    7
    Neutropenia
         subjects affected / exposed
    7 / 23 (30.43%)
    6 / 20 (30.00%)
         occurrences all number
    9
    10
    Thrombocytopenia
         subjects affected / exposed
    3 / 23 (13.04%)
    6 / 20 (30.00%)
         occurrences all number
    3
    6
    Haemolytic Anaemia
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Ear and labyrinth disorders
    Deafness bilateral
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Eye disorders
    Vision blurred
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Conjunctivitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Eye pruritus
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    5
    Visual impairment
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    7 / 23 (30.43%)
    6 / 20 (30.00%)
         occurrences all number
    9
    6
    Nausea
         subjects affected / exposed
    6 / 23 (26.09%)
    1 / 20 (5.00%)
         occurrences all number
    8
    2
    Constipation
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Vomiting
         subjects affected / exposed
    3 / 23 (13.04%)
    1 / 20 (5.00%)
         occurrences all number
    4
    1
    Dyspepsia
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Abdominal pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Abdominal distension
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Aphthous stomatitis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Epigastric discomfort
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Irritable bowel syndrome
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    4 / 23 (17.39%)
    4 / 20 (20.00%)
         occurrences all number
    4
    5
    Pruritus
         subjects affected / exposed
    2 / 23 (8.70%)
    3 / 20 (15.00%)
         occurrences all number
    2
    3
    Alopecia
         subjects affected / exposed
    4 / 23 (17.39%)
    0 / 20 (0.00%)
         occurrences all number
    4
    0
    Dry skin
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Eczema
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Petechiae
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Urticaria
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    3 / 23 (13.04%)
    4 / 20 (20.00%)
         occurrences all number
    3
    9
    Back pain
         subjects affected / exposed
    2 / 23 (8.70%)
    4 / 20 (20.00%)
         occurrences all number
    2
    5
    Arthralgia
         subjects affected / exposed
    2 / 23 (8.70%)
    2 / 20 (10.00%)
         occurrences all number
    2
    2
    Muscle spasms
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    2
    Pain in extremity
         subjects affected / exposed
    3 / 23 (13.04%)
    0 / 20 (0.00%)
         occurrences all number
    4
    0
    Musculoskeletal pain
         subjects affected / exposed
    2 / 23 (8.70%)
    0 / 20 (0.00%)
         occurrences all number
    2
    0
    Musculoskeletal chest pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Neck pain
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Infections and infestations
    Lower respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    3 / 20 (15.00%)
         occurrences all number
    0
    3
    Bronchitis
         subjects affected / exposed
    2 / 23 (8.70%)
    1 / 20 (5.00%)
         occurrences all number
    2
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 23 (0.00%)
    2 / 20 (10.00%)
         occurrences all number
    0
    4
    Ear infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    2
    Fungal skin infection
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Gastroenteritis
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Influenza
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    3
    Otitis media
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    3 / 23 (13.04%)
    3 / 20 (15.00%)
         occurrences all number
    3
    3
    Dehydration
         subjects affected / exposed
    0 / 23 (0.00%)
    1 / 20 (5.00%)
         occurrences all number
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    22 Feb 2012
    This amendment included changes in Sponsor's name and address, sample size, sample collection times and data summarizing methods. Study committee and data monitoring committee were included. Study drug references were corrected to accurately reflect the information in clinical study protocol. The collection and reporting time for unrelated SAEs following the last dose of study treatment was updated. Patient safety data on ongoing studies was updated.
    01 Oct 2012
    This amendment included changes according to which pregnancy and drug testing did not need to be performed on Day 13 or Day 14. Text was added to clarify that sites should use their own Electrocardiogram (ECG) readout/printouts. The electronic Case Report Form (eCRF) was updated. Serial and Trough Pharmacokinetic (PK) sampling times were amended. SAE and pregnancy reporting timeframe was changed.

    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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