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    Clinical Trial Results:
    A Multipart, Open-label Study to Evaluate the Safety and Efficacy of Ombitasvir/Paritaprevir/Ritonavir With and Without Dasabuvir Coadministered With and Without Ribavirin in Adults With Genotype 1 or 4 Chronic Hepatitis C Virus Infection and Human Immunodeficiency Virus, Type 1 Coinfection (TURQUOISE-I)

    Summary
    EudraCT number
    		 2012-005143-24
    Trial protocol
    		 GB   ES  
    Global end of trial date
    25 Oct 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2017
    First version publication date
    21 Sep 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M14-004
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01939197
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    AbbVie Deutschland GmbH & Co.KG
    Sponsor organisation address
    AbbVie House, Vanwall Business Park, Vanwall Road, Maidenhead, Berkshire, United Kingdom, SL6-4UB
    Public contact
    Rolando Viani, MD, AbbVie, rolando.viani@abbvie.com
    Scientific contact
    Rolando Viani, MD, AbbVie, rolando.viani@abbvie.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Oct 2016
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Oct 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objectives of this study were to assess the safety of ABT-450/r/ABT-267 with and without ABT-333 coadministered with and without ribavirin (RBV) for 12 and 24 weeks in hepatitis C virus (HCV) genotype (GT)1- or GT4-infected subjects with human immunodeficiency virus 1 (HIV-1) coinfection and to evaluate the percentage of subjects achieving sustained virologic response 12 (SVR12; HCV ribonucleic acid [RNA] < lower limit of quantification [LLOQ] 12 weeks following treatment). These objectives were assessed separately within each part of the study. For Part 1a, the 12- and 24-week treatment arms were assessed separately; for Part 1b, the darunavir (DRV) once and twice daily (QD/BID) arms were assessed separately and in combination; for Part 2, the GT 1-infected subjects were assessed separately from the GT 4-infected subjects, and the percentage of GT1-infected subjects achieving SVR12 was compared to a threshold based on the historical SVR12 rate of sofosbuvir (SOF) plus RBV.
    Protection of trial subjects
    Participant and/or legal guardian read and understood the information provided about the study and gave written permission.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Aug 2013
    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
    Spain: 22
    Country: Number of subjects enrolled
    United Kingdom: 30
    Country: Number of subjects enrolled
    France: 24
    Country: Number of subjects enrolled
    Germany: 29
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Canada: 17
    Country: Number of subjects enrolled
    Italy: 16
    Country: Number of subjects enrolled
    New Zealand: 6
    Country: Number of subjects enrolled
    Russian Federation: 11
    Country: Number of subjects enrolled
    United States: 142
    Worldwide total number of subjects
    318
    EEA total number of subjects
    121
    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)
    307
    From 65 to 84 years
    11
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Part 2 was not designed to test different treatments on the same subject population. Rather, the arms in Part 2 represent subpopulations with different baseline characteristics (hepatitis C virus [HCV] genotype, cirrhotic status and prior HCV therapy experience). Arms F and G were randomized to a regimen without and with RBV, respectively.

    Pre-assignment
    Screening details
    		 In Part 2, participants in Arms E, F, H, I, J all had GT1 infection and received 1 consistent treatment regimen based on label recommendations; they were therefore combined and named the "GT1 Analysis Group."

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Part 1a: Arm A
    Arm description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving atazanavir once-daily or raltegravir twice-daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    ABT-450/r/ABT-267
    Other name
    ombitasvir/paritaprevir/ritonavir, ombitasvir also known as ABT-267, paritaprevir also known as ABT-450
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-450/r/ABT-267 was taken orally as 2 tablets QD in the morning, which corresponds to a 150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    ABT-333
    Other name
    dasabuvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-333 was taken orally as 1 tablet BID, which corresponds to a 250 mg dose BID.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RBV had weight-based dosing of 1,000 or 1,200 mg total daily dose divided BID per local label. For subjects with a screening creatinine clearance (CrCl) < 50 mL/min, RBV was given as alternating daily doses of 200 mg and 400 mg.

    Arm title
    		 Part 1a: Arm B
    Arm description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks for subjects receiving atazanavir once-daily or raltegravir twice-daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    ABT-450/r/ABT-267
    Other name
    ombitasvir/paritaprevir/ritonavir, ombitasvir also known as ABT-267, paritaprevir also known as ABT-450
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-450/r/ABT-267 was taken orally as 2 tablets QD in the morning, which corresponds to a 150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    ABT-333
    Other name
    dasabuvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-333 was taken orally as 1 tablet BID, which corresponds to a 250 mg dose BID.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RBV had weight-based dosing of 1,000 or 1,200 mg total daily dose divided BID per local label. For subjects with a screening CrCl < 50 mL/min, RBV was given as alternating daily doses of 200 mg and 400 mg.

    Arm title
    		 Part 1b: Arm C
    Arm description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir once-daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    ABT-450/r/ABT-267
    Other name
    ombitasvir/paritaprevir/ritonavir, ombitasvir also known as ABT-267, paritaprevir also known as ABT-450
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-450/r/ABT-267 was taken orally as 2 tablets QD in the morning, which corresponds to a 150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    ABT-333
    Other name
    dasabuvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-333 was taken orally as 1 tablet BID, which corresponds to a 250 mg dose BID.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RBV had weight-based dosing of 1,000 or 1,200 mg total daily dose divided BID per local label. For subjects with a screening CrCl < 50 mL/min, RBV was given as alternating daily doses of 200 mg and 400 mg.

    Arm title
    		 Part 1b: Arm D
    Arm description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir twice-daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    ABT-450/r/ABT-267
    Other name
    ombitasvir/paritaprevir/ritonavir, ombitasvir also known as ABT-267, paritaprevir also known as ABT-450
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-450/r/ABT-267 was taken orally as 2 tablets QD in the morning, which corresponds to a 150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    ABT-333
    Other name
    dasabuvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-333 was taken orally as 1 tablet BID, which corresponds to a 250 mg dose BID.

    Arm title
    		 Part 2: GT1 Analysis Group
    Arm description
    		 Subjects with HCV GT1a or GT1b at screening in Arms E, F, H, I, J (no subjects enrolled in Arm H). Arm E: ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily. Arm F: ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily. Arm I: ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily. Arm J: ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    ABT-450/r/ABT-267
    Other name
    ombitasvir/paritaprevir/ritonavir, ombitasvir also known as ABT-267, paritaprevir also known as ABT-450
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-450/r/ABT-267 was taken orally as 2 tablets QD in the morning, which corresponds to a 150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    ABT-333
    Other name
    dasabuvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-333 was taken orally as 1 tablet BID, which corresponds to a 250 mg dose BID.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RBV had weight-based dosing of 1,000 or 1,200 mg total daily dose divided BID per local label. For subjects with a screening CrCl < 50 mL/min, RBV was given as alternating daily doses of 200 mg and 400 mg.

    Arm title
    		 Part 2: Arm G
    Arm description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    ABT-450/r/ABT-267
    Other name
    ombitasvir/paritaprevir/ritonavir, ombitasvir also known as ABT-267, paritaprevir also known as ABT-450
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-450/r/ABT-267 was taken orally as 2 tablets QD in the morning, which corresponds to a 150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD.

    Investigational medicinal product name
    ABT-333
    Investigational medicinal product code
    ABT-333
    Other name
    dasabuvir
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-333 was taken orally as 1 tablet BID, which corresponds to a 250 mg dose BID.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RBV had weight-based dosing of 1,000 or 1,200 mg total daily dose divided BID per local label. For subjects with a screening CrCl < 50 mL/min, RBV was given as alternating daily doses of 200 mg and 400 mg.

    Arm title
    		 GT4 Analysis Group
    Arm description
    		 Subjects with HCV GT4 at screening in Arms K and L (no subjects enrolled in Arm L). Arm K: ABT-450/r/ABT-267 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily, dolutegravir once-daily or twice-daily, darunavir once-daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    ABT-450/r/ABT-267
    Investigational medicinal product code
    ABT-450/r/ABT-267
    Other name
    ombitasvir/paritaprevir/ritonavir, ombitasvir also known as ABT-267, paritaprevir also known as ABT-450
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    ABT-450/r/ABT-267 was taken orally as 2 tablets QD in the morning, which corresponds to a 150 mg ABT-450/100 mg ritonavir/25 mg ABT-267 dose QD.

    Investigational medicinal product name
    ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    RBV had weight-based dosing of 1,000 or 1,200 mg total daily dose divided BID per local label. For subjects with a screening CrCl < 50 mL/min, RBV was given as alternating daily doses of 200 mg and 400 mg.

    Number of subjects in period 1
    		Part 1a: Arm A Part 1a: Arm B Part 1b: Arm C Part 1b: Arm D Part 2: GT1 Analysis Group Part 2: Arm G GT4 Analysis Group
    Started
    31
    32
    10
    12
    200
    5
    28
    Completed
    30
    31
    10
    11
    196
    4
    26
    Not completed
    1
    1
    0
    1
    4
    1
    2
         Consent withdrawn by subject
    1
    -
    -
    -
    1
    -
    -
         Lost to follow-up
    -
    1
    -
    1
    3
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Part 1a: Arm A
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving atazanavir once-daily or raltegravir twice-daily

    Reporting group title
    Part 1a: Arm B
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks for subjects receiving atazanavir once-daily or raltegravir twice-daily

    Reporting group title
    Part 1b: Arm C
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir once-daily

    Reporting group title
    Part 1b: Arm D
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir twice-daily

    Reporting group title
    Part 2: GT1 Analysis Group
    Reporting group description
    		 Subjects with HCV GT1a or GT1b at screening in Arms E, F, H, I, J (no subjects enrolled in Arm H). Arm E: ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily. Arm F: ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily. Arm I: ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily. Arm J: ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily.

    Reporting group title
    Part 2: Arm G
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily

    Reporting group title
    GT4 Analysis Group
    Reporting group description
    		 Subjects with HCV GT4 at screening in Arms K and L (no subjects enrolled in Arm L). Arm K: ABT-450/r/ABT-267 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily, dolutegravir once-daily or twice-daily, darunavir once-daily.

    Reporting group values
    		 Part 1a: Arm A Part 1a: Arm B Part 1b: Arm C Part 1b: Arm D Part 2: GT1 Analysis Group Part 2: Arm G GT4 Analysis Group Total
    Number of subjects
    		 31 32 10 12 200 5 28 318
    Age categorical
    Units: Subjects
        < 55 years
    		 23 20 5 8 145 2 24 227
        ≥ 55 years
    		 8 12 5 4 55 3 4 91
    Gender categorical
    Units: Subjects
        Female
    		 2 3 2 3 44 1 2 57
        Male
    		 29 29 8 9 156 4 26 261

    End points

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    End points reporting groups
    Reporting group title
    Part 1a: Arm A
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving atazanavir once-daily or raltegravir twice-daily

    Reporting group title
    Part 1a: Arm B
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks for subjects receiving atazanavir once-daily or raltegravir twice-daily

    Reporting group title
    Part 1b: Arm C
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir once-daily

    Reporting group title
    Part 1b: Arm D
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir twice-daily

    Reporting group title
    Part 2: GT1 Analysis Group
    Reporting group description
    		 Subjects with HCV GT1a or GT1b at screening in Arms E, F, H, I, J (no subjects enrolled in Arm H). Arm E: ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily. Arm F: ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily. Arm I: ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily. Arm J: ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily.

    Reporting group title
    Part 2: Arm G
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily

    Reporting group title
    GT4 Analysis Group
    Reporting group description
    		 Subjects with HCV GT4 at screening in Arms K and L (no subjects enrolled in Arm L). Arm K: ABT-450/r/ABT-267 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily, dolutegravir once-daily or twice-daily, darunavir once-daily.

    Subject analysis set title
    Part 1b: Total
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Arm C: ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir once-daily Arm D: ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir twice-daily

    Subject analysis set title
    Part 2: Arm F
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir oncedaily, raltegravir twice-daily

    Subject analysis set title
    Part 2: Arm K
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ABT-450/r/ABT-267 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily, dolutegravir once-daily or twice-daily, darunavir once-daily

    Subject analysis set title
    Part 2: Arm E
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir oncedaily, raltegravir twice-daily

    Subject analysis set title
    Part 2: Arm I
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily

    Subject analysis set title
    Part 2: Arm J
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily

    Primary: Percentage of Subjects in GT1 Analysis Group 1 in Part 2 Achieving SVR12

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    End point title
    		 Percentage of Subjects in GT1 Analysis Group 1 in Part 2 Achieving SVR12 [1] [2]
    End point description
    SVR12 is defined as plasma HCV RNA < LLOQ 12 weeks after the last dose of study drug without any confirmed quantifiable (≥ LLOQ) post-treatment value before or during that SVR window. The 95% confidence interval (CI) is calculated using the Wilson score method for binomial distribution. The primary efficacy endpoint was the non-inferiority of the percentage of subjects in the GT1 Analysis Group in Part 2 achieving SVR12 compared to the historical SVR12 rate for sofosbuvir plus ribavirin (a non-inferiority threshold of the lower bound of the 95% CI of 74%). Intent-to-treat (ITT) population: Part 2 randomized or enrolled participants who received at least 1 dose of study drug. Imputation applied; participants with missing HCV RNA data after imputation were counted as failures. The primary efficacy endpoint analysis was based on subjects in the GT 1 Analysis Group in Part 2 containing Arms E, F, H, I, and J.
    End point type
    Primary
    End point timeframe
    12 weeks after the last actual dose of study drug
    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: Descriptive statistics and 95% confidence interval are presented per protocol.
    [2] - 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: The endpoint is presented for GT1 Analysis Group in Part 2 subjects only per protocol.
    End point values
    		 Part 2: GT1 Analysis Group
    Number of subjects analysed
    200
    Units: percentage of subjects
        number (confidence interval 95%)
    97 (93.6 to 98.6)
    Attachments
    		 Untitled (Filename: primary endpoint stat analysis.docx)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 1a Achieving SVR12

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    End point title
    		 Percentage of Subjects in Part 1a Achieving SVR12 [3]
    End point description
    SVR12 is defined as plasma HCV RNA < LLOQ 12 weeks after the last dose of study drug without any confirmed quantifiable (≥ LLOQ) post-treatment value before or during that SVR window. The 95% CI is calculated using the Wilson score method for binomial distribution. ITT population: Part 1a randomized subjects who received at least 1 dose of study drug. Imputation applied; participants with missing HCV RNA data after imputation were counted as failures.
    End point type
    Secondary
    End point timeframe
    12 weeks after last dose of study drug
    Notes
    [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: The endpoint is presented for Part 1a subjects only per protocol.
    End point values
    		 Part 1a: Arm A Part 1a: Arm B
    Number of subjects analysed
    31
    32
    Units: percentage of subjects
        number (confidence interval 95%)
    93.5 (79.3 to 98.2)
    90.6 (75.8 to 96.8)
    Statistical analysis title
    		 Statistical Analysis 1
    Comparison groups
    Part 1a: Arm A v Part 1a: Arm B
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval

    Secondary: Percentage of Subjects in Part 1b Achieving SVR12

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    End point title
    		 Percentage of Subjects in Part 1b Achieving SVR12 [4]
    End point description
    SVR12 is defined as plasma HCV RNA < LLOQ 12 weeks after the last dose of study drug without any confirmed quantifiable (≥ LLOQ) post-treatment value before or during that SVR window. The 95% CI is calculated using the Wilson score method for binomial distribution. ITT population: Part 1b randomized subjects who received at least 1 dose of study drug. Imputation applied; subjects with missing HCV RNA data after imputation were counted as failures. The Fisher exact test was performed as prespecified on the SAP but the p-value couldn’t be calculated because SVR12 rates in both arms were 100%, hence the p-value appeared as "not available."
    End point type
    Secondary
    End point timeframe
    12 weeks after last dose of study drug
    Notes
    [4] - 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: The endpoint is presented for Part 1b subjects only per protocol.
    End point values
    		 Part 1b: Arm C Part 1b: Arm D Part 1b: Total
    Number of subjects analysed
    10
    12
    22
    Units: percentage of subjects
        number (confidence interval 95%)
    100 (72.2 to 100)
    100 (75.8 to 100)
    100 (85.1 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Arm F and Arm G of Part 2 Achieving SVR12

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    End point title
    		 Percentage of Subjects in Arm F and Arm G of Part 2 Achieving SVR12 [5]
    End point description
    SVR12 is defined as plasma HCV RNA < LLOQ 12 weeks after the last dose of study drug without any confirmed quantifiable (≥ LLOQ) post-treatment value before or during that SVR window. The 95% CI is calculated using the Wilson score method for binomial distribution. ITT population: Part 2 randomized or enrolled subjects who received at least 1 dose of study drug. Imputation applied; subjects with missing HCV RNA data after imputation were counted as failures.
    End point type
    Secondary
    End point timeframe
    12 weeks after last dose of study drug
    Notes
    [5] - 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: The endpoint is presented for Part 2 subjects only per protocol.
    End point values
    		 Part 2: Arm G Part 2: Arm F
    Number of subjects analysed
    5
    4
    Units: percentage of subjects
        number (confidence interval 95%)
    80 (37.6 to 96.4)
    75 (30.1 to 95.4)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With GT4 HCV in Part 2 Achieving SVR12, by Arm and Overall

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    End point title
    		 Percentage of Subjects With GT4 HCV in Part 2 Achieving SVR12, by Arm and Overall [6]
    End point description
    SVR12 is defined as plasma HCV RNA < LLOQ 12 weeks after the last dose of study drug without any confirmed quantifiable (≥ LLOQ) post-treatment value before or during that SVR window. The 95% CI is calculated using the Wilson score method for binomial distribution. ITT population: Part 2 randomized or enrolled subjects who received at least 1 dose of study drug. Imputation applied; subjects with missing HCV RNA data after imputation were counted as failures.
    End point type
    Secondary
    End point timeframe
    12 weeks after last dose of study drug
    Notes
    [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: The endpoint is presented for Part 2 subjects only per protocol.
    End point values
    		 GT4 Analysis Group Part 2: Arm K
    Number of subjects analysed
    28
    28
    Units: percentage of subjects
        number (confidence interval 95%)
    96.4 (82.3 to 99.4)
    96.4 (82.3 to 99.4)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 1a With On-Treatment HCV Virologic Failure During the Treatment Period

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    End point title
    		 Percentage of Subjects in Part 1a With On-Treatment HCV Virologic Failure During the Treatment Period [7]
    End point description
    Percentage of subjects with on-treatment HCV virologic failure during the treatment period for each arm in Part 1a. Virologic failure is defined as confirmed quantifiable HCV RNA among participants with previously unquantifiable HCV RNA during treatment. ITT population: Part 1a randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    up to 12 or 24 weeks, based on treatment duration
    Notes
    [7] - 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: The endpoint is presented for Part 1a subjects only per protocol.
    End point values
    		 Part 1a: Arm A Part 1a: Arm B
    Number of subjects analysed
    31
    32
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 11)
    3.1 (0.6 to 15.7)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 1b With On-Treatment HCV Virologic Failure During the Treatment Period

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    End point title
    		 Percentage of Subjects in Part 1b With On-Treatment HCV Virologic Failure During the Treatment Period [8]
    End point description
    Percentage of subjects with on-treatment HCV virologic failure during the treatment period for each arm and overall in Part 1b. Virologic failure is defined as confirmed quantifiable HCV RNA among participants with previously unquantifiable HCV RNA during treatment. ITT population: Part 1b randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    up to 12 weeks
    Notes
    [8] - 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: The endpoint is presented for Part 1b subjects only per protocol.
    End point values
    		 Part 1b: Arm C Part 1b: Arm D Part 1b: Total
    Number of subjects analysed
    10
    12
    22
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 27.8)
    0 (0 to 24.2)
    0 (0 to 14.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 2 With On-Treatment HCV Virologic Failure During the Treatment Period

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    End point title
    		 Percentage of Subjects in Part 2 With On-Treatment HCV Virologic Failure During the Treatment Period [9]
    End point description
    Percentage of subjects with on-treatment HCV virologic failure during the treatment period for arms in Part 2. Virologic failure is defined as confirmed quantifiable HCV RNA among participants with previously unquantifiable HCV RNA during treatment. ITT population: Part 2 randomized or enrolled subjects in the GT1 analysis group (and its composing arms) and GT4 analysis group who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    up to 12 or 24 weeks, based on treatment duration
    Notes
    [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: The endpoint is presented for Part 2 subjects only per protocol.
    End point values
    		 Part 2: GT1 Analysis Group GT4 Analysis Group Part 2: Arm F Part 2: Arm K Part 2: Arm E Part 2: Arm I Part 2: Arm J
    Number of subjects analysed
    200
    28
    4
    28
    42
    135
    19
    Units: percentage of subjects
        number (confidence interval 95%)
    0.5 (0.1 to 2.8)
    0 (0 to 12.1)
    25 (4.6 to 69.9)
    0 (0 to 12.1)
    0 (0 to 8.4)
    0 (0 to 2.8)
    0 (0 to 16.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 1a With Relapse12

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    End point title
    		 Percentage of Subjects in Part 1a With Relapse12 [10]
    End point description
    Percentage of subjects who experienced Relapse12 among participants who completed treatment with HCV RNA < LLOQ at final treatment visit and had at least one post-treatment HCV RNA value. Relapse12 is defined as confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after last actual dose of study drug (up to and including the SVR12 assessment time point) for a participant with HCV RNA < LLOQ at final treatment visit who completed treatment and had post-treatment data. Completion of treatment is defined as study drug duration ≥ 77 days for Arm C and Arm D. The 95% CI is calculated using Wilson score method for the binomial distribution. ITT population: all Part 1a randomized subjects who received at least 1 dose of study drug and who completed treatment with HCV RNA < LLOQ at final treatment visit and had at least one post-treatment HCV RNA value.
    End point type
    Secondary
    End point timeframe
    up to 12 or 24 weeks, based on treatment duration
    Notes
    [10] - 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: The endpoint is presented for Part 1a subjects only per protocol.
    End point values
    		 Part 1a: Arm A Part 1a: Arm B
    Number of subjects analysed
    30
    31
    Units: percentage of subjects
        number (confidence interval 95%)
    3.3 (0.6 to 16.7)
    0 (0 to 11)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 1b With Relapse12 for Each Arm and Overall

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    End point title
    		 Percentage of Subjects in Part 1b With Relapse12 for Each Arm and Overall [11]
    End point description
    Percentage of subjects who experienced Relapse12 among participants who completed treatment with HCV RNA < LLOQ at final treatment visit and had at least one post-treatment HCV RNA value. Relapse12 is defined as confirmed HCV RNA ≥ LLOQ between end of treatment and 12 weeks after last actual dose of study drug (up to and including the SVR12 assessment time point) for a subject with HCV RNA < LLOQ at final treatment visit who completed treatment and had post-treatment data. Completion of treatment is defined as study drug duration ≥ 77 days for Arm C and Arm D. The 95% CI is calculated using Wilson score method for the binomial distribution. ITT population: all Part 1b randomized subjects who received at least 1 dose of study drug and who completed treatment with HCV RNA < LLOQ at final treatment visit and had at least one post-treatment HCV RNA value.
    End point type
    Secondary
    End point timeframe
    up to 12 or 24 weeks, based on treatment duration
    Notes
    [11] - 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: The endpoint is presented for Part 1b subjects only per protocol.
    End point values
    		 Part 1b: Arm C Part 1b: Arm D Part 1b: Total
    Number of subjects analysed
    10
    12
    22
    Units: percentage of subjects
        number (confidence interval 95%)
    0 (0 to 27.8)
    0 (0 to 24.2)
    0 (0 to 14.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 2 With Relapse12

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    End point title
    		 Percentage of Subjects in Part 2 With Relapse12 [12]
    End point description
    Percentage of subjects who experienced Relapse12 among those who completed treatment with HCV RNA <LLOQ at final treatment visit and had ≥1 post-treatment HCV RNA value. Relapse12=confirmed HCV RNA ≥LLOQ between end of treatment and 12 weeks after last actual dose of study drug (up to and including the SVR12 window) for a subject with HCV RNA <LLOQ at final treatment visit who completed treatment and had post-treatment data, excluding reinfection. Completion of treatment=study drug duration ≥77 days for subjects who received 12 weeks of treatment and ≥154 days for subjects who received 24 weeks of treatment. HCV reinfection=confirmed HCV RNA ≥LLOQ after end of treatment in a subject who had HCV RNA <LLOQ at final treatment visit, along with the post-treatment detection of a different HCV genotype, subtype, or clade compared with baseline, as determined by phylogenetic analysis. The 95% CI is calculated using Wilson score method for the binomial distribution. ITT population.
    End point type
    Secondary
    End point timeframe
    up to 12 or 24 weeks based on treatment duration
    Notes
    [12] - 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: The endpoint is presented for Part 2 subjects only per protocol.
    End point values
    		 Part 2: GT1 Analysis Group GT4 Analysis Group Part 2: Arm F Part 2: Arm K Part 2: Arm E Part 2: Arm I Part 2: Arm J
    Number of subjects analysed
    192 [13]
    27 [14]
    3 [15]
    27 [16]
    42 [17]
    131 [18]
    16 [19]
    Units: percentage of subjects
        number (confidence interval 95%)
    0.5 (0.1 to 2.9)
    0 (0 to 12.5)
    0 (0 to 56.1)
    0 (0 to 12.5)
    0 (0 to 8.4)
    0.8 (0.1 to 4.2)
    0 (0 to 19.4)
    Notes
    [13] - completed treatment w/ HCV RNA <LLOQ at final treatment visit & had ≥1 post-treatment HCV RNA value
    [14] - completed treatment w/ HCV RNA <LLOQ at final treatment visit & had ≥1 post-treatment HCV RNA value
    [15] - completed treatment w/ HCV RNA <LLOQ at final treatment visit & had ≥1 post-treatment HCV RNA value
    [16] - completed treatment w/ HCV RNA <LLOQ at final treatment visit & had ≥1 post-treatment HCV RNA value
    [17] - completed treatment w/ HCV RNA <LLOQ at final treatment visit & had ≥1 post-treatment HCV RNA value
    [18] - completed treatment w/ HCV RNA <LLOQ at final treatment visit & had ≥1 post-treatment HCV RNA value
    [19] - completed treatment w/ HCV RNA <LLOQ at final treatment visit & had ≥1 post-treatment HCV RNA value
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 1a With Plasma HIV-1 RNA Suppression at End of Treatment and 12 Weeks Post-Treatment

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    End point title
    		 Percentage of Subjects in Part 1a With Plasma HIV-1 RNA Suppression at End of Treatment and 12 Weeks Post-Treatment [20]
    End point description
    HIV virologic success was defined as HIV-1 RNA suppression (HIV-1 RNA value < 40 copies/mL). ITT population: Part 1a randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment: HIV Week 12 window for 12-weeks of treatment (Treatment Day 71 - 98) or HIV Week 24 window (Treatment Day 155 - 182) for 24-weeks of treatment. Post-Treatment Week 12 (PTW12): HIV PTW12 window (Post-Treatment Day 57 - 126)
    Notes
    [20] - 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: The endpoint is presented for Part 1a subjects only per protocol.
    End point values
    		 Part 1a: Arm A Part 1a: Arm B
    Number of subjects analysed
    31
    32
    Units: percentage of subjects
    number (confidence interval 95%)
        End of Treatment
    93.5 (79.3 to 98.2)
    90.6 (75.8 to 96.8)
        Post-Treatment Week 12
    96.8 (83.8 to 99.4)
    93.8 (79.9 to 98.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 1b With Plasma HIV-1 RNA Suppression at End of Treatment and 12 Weeks Post-Treatment

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    End point title
    		 Percentage of Subjects in Part 1b With Plasma HIV-1 RNA Suppression at End of Treatment and 12 Weeks Post-Treatment [21]
    End point description
    HIV virologic success was defined as HIV-1 RNA suppression (HIV-1 RNA value < 40 copies/mL). ITT population: Part 1b randomized subjects who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment: HIV Week 12 window (Treatment Day 78 - 98). PTW12: HIV PTW12 window (Post-Treatment Day 57 - 126)
    Notes
    [21] - 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: The endpoint is presented for Part 1b subjects only per protocol.
    End point values
    		 Part 1b: Arm C Part 1b: Arm D Part 1b: Total
    Number of subjects analysed
    10
    12
    22
    Units: percentage of subjects
    number (confidence interval 95%)
        End of Treatment
    100 (72.2 to 100)
    83.3 (55.2 to 95.3)
    90.9 (72.2 to 97.5)
        Post-Treatment Week 12
    100 (72.2 to 100)
    75 (46.8 to 91.1)
    86.4 (66.7 to 95.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects in Part 2 With Plasma HIV-1 RNA Suppression at End of Treatment and 12 Weeks Post-Treatment

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    End point title
    		 Percentage of Subjects in Part 2 With Plasma HIV-1 RNA Suppression at End of Treatment and 12 Weeks Post-Treatment [22]
    End point description
    HIV virologic success was defined as HIV-1 RNA suppression (HIV-1 RNA value < 40 copies/mL). ITT population: Part 2 randomized or enrolled subjects in the GT1 analysis group (and its composing arms) and GT4 analysis group who received at least 1 dose of study drug.
    End point type
    Secondary
    End point timeframe
    End of treatment: HIV Week 12 window for 12-weeks of treatment (Treatment Day 71 - 98) or HIV Week 24 window (Treatment Day 155 - 182) for 24-weeks of treatment. PTW12: HIV PTW12 window (Post-Treatment Day 57 - 126)
    Notes
    [22] - 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: The endpoint is presented for Part 2 subjects only per protocol.
    End point values
    		 Part 2: GT1 Analysis Group GT4 Analysis Group Part 2: Arm F Part 2: Arm K Part 2: Arm E Part 2: Arm I Part 2: Arm J
    Number of subjects analysed
    200
    28
    4
    28
    42
    135
    19
    Units: percentage of subjects
    number (confidence interval 95%)
        End of Treatment
    89 (83.9 to 92.6)
    85.7 (68.5 to 94.3)
    100 (51 to 100)
    85.7 (68.5 to 94.3)
    90.5 (77.9 to 96.2)
    89.6 (83.3 to 93.7)
    78.9 (56.7 to 91.5)
        Post-Treatment Week 12
    93 (88.6 to 95.8)
    92.9 (77.4 to 98)
    100 (51 to 100)
    92.9 (77.4 to 98)
    97.6 (87.7 to 99.6)
    91.9 (86 to 95.4)
    89.5 (68.6 to 97.1)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Protocol-related treatment-emergent adverse events (TEAEs) were collected from the first dose of study drug through end of treatment Week 12 and Week 24; serious TEAEs were collected from the first dose of study drug until post-treatment Day 30.
    Adverse event reporting additional description
    A protocol-related event is defined as any event with onset or worsening reported by a participant from the first dose of study drug until 30 days have elapsed following discontinuation of study drug administration. Events were collected whether elicited or spontaneously reported by the subject.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Part 1a: Arm A
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving atazanavir once-daily or raltegravir twice-daily

    Reporting group title
    Part 1a: Arm B
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks for subjects receiving atazanavir once-daily or raltegravir twice-daily

    Reporting group title
    Part 1b: Arm C
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir once-daily

    Reporting group title
    Part 1b: Arm D
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving darunavir twice-daily

    Reporting group title
    Part 2: Arm E
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir oncedaily, raltegravir twice-daily

    Reporting group title
    Part 2: Arm F
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 for 12 weeks for subjects receiving any of the following: atazanavir oncedaily, raltegravir twice-daily

    Reporting group title
    Part 2: Arm G
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily

    Reporting group title
    Part 2: Arm I
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily

    Reporting group title
    Part 2: Arm J
    Reporting group description
    		 ABT-450/r/ABT-267 and ABT-333 coadministered with RBV for 24 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily

    Reporting group title
    Part 2: Arm K
    Reporting group description
    		 ABT-450/r/ABT-267 coadministered with RBV for 12 weeks for subjects receiving any of the following: atazanavir once-daily, raltegravir twice-daily, dolutegravir once-daily or twice-daily, darunavir once-daily

    Serious adverse events
    		 Part 1a: Arm A Part 1a: Arm B Part 1b: Arm C Part 1b: Arm D Part 2: Arm E Part 2: Arm F Part 2: Arm G Part 2: Arm I Part 2: Arm J Part 2: Arm K
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    6 / 135 (4.44%)
    2 / 19 (10.53%)
    1 / 28 (3.57%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Injury, poisoning and procedural complications
    OVERDOSE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    HYPERTENSIVE CRISIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    ANGINA UNSTABLE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    PERICARDITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    COLITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    RECTAL PERFORATION
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    DEPRESSION
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    DRUG DEPENDENCE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    URETEROLITHIASIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    APPENDICITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    INFLUENZA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    DEHYDRATION
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 3%
    Non-serious adverse events
    		 Part 1a: Arm A Part 1a: Arm B Part 1b: Arm C Part 1b: Arm D Part 2: Arm E Part 2: Arm F Part 2: Arm G Part 2: Arm I Part 2: Arm J Part 2: Arm K
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    28 / 31 (90.32%)
    28 / 32 (87.50%)
    10 / 10 (100.00%)
    10 / 12 (83.33%)
    26 / 42 (61.90%)
    3 / 4 (75.00%)
    4 / 5 (80.00%)
    112 / 135 (82.96%)
    18 / 19 (94.74%)
    24 / 28 (85.71%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    ANOGENITAL WARTS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    SKIN PAPILLOMA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    Vascular disorders
    DIASTOLIC HYPOTENSION
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    HAEMATOMA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    HOT FLUSH
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    HYPERTENSION
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    4 / 135 (2.96%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    1
    0
    1
    1
    0
    4
    0
    0
    ORTHOSTATIC HYPOTENSION
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    THROMBOPHLEBITIS SUPERFICIAL
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    ASTHENIA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    13 / 135 (9.63%)
    2 / 19 (10.53%)
    3 / 28 (10.71%)
         occurrences all number
    0
    0
    0
    1
    1
    1
    0
    14
    2
    3
    CHEST DISCOMFORT
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    2
    0
    1
    CHEST PAIN
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    1
    0
    0
    0
    0
    1
    0
    0
    CHILLS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    EARLY SATIETY
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    FATIGUE
         subjects affected / exposed
    18 / 31 (58.06%)
    12 / 32 (37.50%)
    5 / 10 (50.00%)
    4 / 12 (33.33%)
    2 / 42 (4.76%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    40 / 135 (29.63%)
    6 / 19 (31.58%)
    5 / 28 (17.86%)
         occurrences all number
    20
    17
    5
    5
    2
    0
    0
    42
    8
    6
    FEELING ABNORMAL
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    0
    0
    FEELING JITTERY
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    1
    INFLUENZA LIKE ILLNESS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    1
    0
    OEDEMA PERIPHERAL
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    0
    1
    0
    0
    PAIN
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    4 / 135 (2.96%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    1
    4
    0
    0
    PERIPHERAL SWELLING
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    PYREXIA
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    1 / 19 (5.26%)
    2 / 28 (7.14%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    2
    1
    2
    TEMPERATURE INTOLERANCE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    TENDERNESS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    VESSEL PUNCTURE SITE BRUISE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    Immune system disorders
    SEASONAL ALLERGY
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    Social circumstances
    MENOPAUSE
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Reproductive system and breast disorders
    BREAST MASS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    ERECTILE DYSFUNCTION
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    GENITAL RASH
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    BRONCHOSPASM
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    COUGH
         subjects affected / exposed
    2 / 31 (6.45%)
    5 / 32 (15.63%)
    2 / 10 (20.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    7 / 135 (5.19%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    2
    6
    3
    0
    1
    0
    0
    8
    1
    1
    DYSPNOEA
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    8 / 135 (5.93%)
    2 / 19 (10.53%)
    2 / 28 (7.14%)
         occurrences all number
    1
    2
    0
    0
    0
    0
    0
    9
    2
    2
    DYSPNOEA EXERTIONAL
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    6 / 135 (4.44%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    6
    1
    1
    EPISTAXIS
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    1
    0
    0
    NASAL CONGESTION
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    2
    1
    1
    0
    0
    0
    0
    1
    1
    0
    NASAL DRYNESS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    OROPHARYNGEAL PAIN
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    2 / 42 (4.76%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    0
    2
    0
    0
    3
    0
    0
    RESPIRATORY TRACT CONGESTION
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    RHINORRHOEA
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    4
    0
    0
    0
    1
    0
    0
    3
    0
    0
    UPPER-AIRWAY COUGH SYNDROME
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Psychiatric disorders
    ABNORMAL DREAMS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    3
    0
    0
    AFFECT LABILITY
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 135 (2.96%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    4
    2
    0
    AGITATION
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    ANXIETY
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    11 / 135 (8.15%)
    1 / 19 (5.26%)
    2 / 28 (7.14%)
         occurrences all number
    0
    4
    0
    0
    0
    0
    0
    11
    1
    2
    CONFUSIONAL STATE
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    DEPRESSED MOOD
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    4 / 135 (2.96%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    4
    0
    0
    DEPRESSION
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 32 (9.38%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    0
    3
    1
    1
    0
    0
    0
    3
    1
    1
    INSOMNIA
         subjects affected / exposed
    5 / 31 (16.13%)
    7 / 32 (21.88%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    3 / 42 (7.14%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    25 / 135 (18.52%)
    2 / 19 (10.53%)
    2 / 28 (7.14%)
         occurrences all number
    6
    11
    1
    0
    3
    0
    1
    26
    2
    2
    IRRITABILITY
         subjects affected / exposed
    3 / 31 (9.68%)
    3 / 32 (9.38%)
    3 / 10 (30.00%)
    2 / 12 (16.67%)
    0 / 42 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    7 / 135 (5.19%)
    2 / 19 (10.53%)
    1 / 28 (3.57%)
         occurrences all number
    3
    4
    3
    2
    0
    1
    0
    7
    2
    1
    LIBIDO INCREASED
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    MIDDLE INSOMNIA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    NERVOUSNESS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    NIGHTMARE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    RESTLESSNESS
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    SLEEP DISORDER
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    2
    0
    0
    STRESS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    WITHDRAWAL SYNDROME
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    1
    Investigations
    ASPARTATE AMINOTRANSFERASE INCREASED
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    BLOOD BILIRUBIN INCREASED
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    1
    0
    4
    0
    0
    BLOOD CREATINE PHOSPHOKINASE INCREASED
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    0
    1
    BLOOD PHOSPHORUS DECREASED
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    BLOOD POTASSIUM INCREASED
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    CREATININE RENAL CLEARANCE DECREASED
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    1
    0
    HAEMOGLOBIN DECREASED
         subjects affected / exposed
    3 / 31 (9.68%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    4 / 12 (33.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    13 / 135 (9.63%)
    6 / 19 (31.58%)
    4 / 28 (14.29%)
         occurrences all number
    3
    0
    1
    4
    0
    0
    0
    15
    6
    4
    WEIGHT DECREASED
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    0
    1
    1
    0
    0
    0
    1
    0
    WEIGHT INCREASED
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    Injury, poisoning and procedural complications
    ANIMAL BITE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    2 / 42 (4.76%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    0
    0
    0
    0
    ANKLE FRACTURE
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    ARTHROPOD BITE
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    1
    0
    0
    0
    0
    0
    0
    CONTUSION
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    1
    0
    0
    0
    1
    0
    0
    EXCORIATION
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    FALL
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    LIGAMENT SPRAIN
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    0
    1
    MENISCUS INJURY
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    MUSCLE STRAIN
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    1
    0
    0
    0
    0
    0
    0
    0
    SKIN ABRASION
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Cardiac disorders
    TACHYCARDIA
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    VENTRICULAR EXTRASYSTOLES
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    Nervous system disorders
    DISTURBANCE IN ATTENTION
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    1
    0
    DIZZINESS
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    10 / 135 (7.41%)
    2 / 19 (10.53%)
    1 / 28 (3.57%)
         occurrences all number
    0
    2
    1
    1
    0
    0
    0
    11
    2
    1
    DIZZINESS EXERTIONAL
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    DYSGEUSIA
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    2
    0
    0
    HEADACHE
         subjects affected / exposed
    6 / 31 (19.35%)
    4 / 32 (12.50%)
    2 / 10 (20.00%)
    1 / 12 (8.33%)
    2 / 42 (4.76%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    22 / 135 (16.30%)
    4 / 19 (21.05%)
    5 / 28 (17.86%)
         occurrences all number
    6
    4
    2
    1
    2
    0
    1
    27
    4
    5
    HYPOAESTHESIA
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    LETHARGY
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    2 / 42 (4.76%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    3
    0
    0
    1
    0
    0
    MEMORY IMPAIRMENT
         subjects affected / exposed
    0 / 31 (0.00%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    3
    0
    1
    1
    0
    0
    0
    0
    0
    NEURALGIA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    NEUROPATHY PERIPHERAL
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    0
    0
    0
    PARAESTHESIA
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    2
    1
    0
    PRESYNCOPE
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    SCIATICA
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    SINUS HEADACHE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    0
    0
    0
    0
    SOMNOLENCE
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    SYNCOPE
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    2
    0
    0
    Blood and lymphatic system disorders
    ANAEMIA
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 32 (9.38%)
    1 / 10 (10.00%)
    2 / 12 (16.67%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    6 / 135 (4.44%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    1
    3
    1
    2
    0
    0
    1
    7
    1
    0
    LYMPHADENOPATHY
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    0
    2
    0
    0
    Ear and labyrinth disorders
    VERTIGO
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    Eye disorders
    BLEPHAROSPASM
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    DRY EYE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    EYE DISCHARGE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    EYE PRURITUS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    EYELID HAEMATOMA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    EYELID PTOSIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    MYDRIASIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    OCULAR DISCOMFORT
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    OCULAR HYPERAEMIA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    1
    0
    0
    OCULAR ICTERUS
         subjects affected / exposed
    5 / 31 (16.13%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    5
    1
    0
    0
    0
    0
    0
    3
    0
    0
    Gastrointestinal disorders
    ABDOMINAL DISCOMFORT
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    0
    1
    0
    ABDOMINAL DISTENSION
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    3
    1
    1
    ABDOMINAL PAIN
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    2 / 42 (4.76%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    3 / 135 (2.22%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    3
    1
    1
    ABDOMINAL PAIN UPPER
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    2 / 42 (4.76%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    5 / 135 (3.70%)
    0 / 19 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    1
    0
    0
    0
    2
    1
    0
    6
    0
    3
    APHTHOUS ULCER
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    2
    0
    0
    BARRETT'S OESOPHAGUS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    CONSTIPATION
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    7 / 135 (5.19%)
    2 / 19 (10.53%)
    2 / 28 (7.14%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    7
    2
    2
    DIARRHOEA
         subjects affected / exposed
    1 / 31 (3.23%)
    4 / 32 (12.50%)
    1 / 10 (10.00%)
    2 / 12 (16.67%)
    4 / 42 (9.52%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    26 / 135 (19.26%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    1
    4
    1
    2
    4
    1
    0
    35
    1
    3
    DIVERTICULUM
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    DRY MOUTH
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    0
    1
    0
    2
    DYSPEPSIA
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    10 / 135 (7.41%)
    0 / 19 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    1
    3
    0
    1
    1
    0
    0
    11
    0
    3
    DYSPHAGIA
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    FAECES PALE
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    0
    0
    0
    FAECES SOFT
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    FLATULENCE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    3
    0
    1
    GASTRITIS
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    GASTROINTESTINAL SOUNDS ABNORMAL
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    GASTROOESOPHAGEAL REFLUX DISEASE
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    2 / 135 (1.48%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    2
    1
    0
    0
    0
    0
    1
    2
    1
    0
    GINGIVAL BLEEDING
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    HAEMORRHOIDAL HAEMORRHAGE
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    MOUTH ULCERATION
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    NAUSEA
         subjects affected / exposed
    5 / 31 (16.13%)
    6 / 32 (18.75%)
    2 / 10 (20.00%)
    2 / 12 (16.67%)
    3 / 42 (7.14%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    34 / 135 (25.19%)
    4 / 19 (21.05%)
    5 / 28 (17.86%)
         occurrences all number
    5
    8
    3
    2
    3
    1
    0
    41
    4
    5
    ORAL PAIN
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    STOMATITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    TOOTHACHE
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    VOMITING
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    11 / 135 (8.15%)
    1 / 19 (5.26%)
    3 / 28 (10.71%)
         occurrences all number
    3
    7
    0
    1
    1
    0
    0
    19
    1
    3
    Hepatobiliary disorders
    GALLBLADDER POLYP
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    HYPERBILIRUBINAEMIA
         subjects affected / exposed
    4 / 31 (12.90%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 135 (2.96%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    4
    1
    0
    0
    3
    0
    0
    9
    1
    0
    JAUNDICE
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    7 / 135 (5.19%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    3
    0
    0
    0
    0
    1
    0
    7
    0
    1
    Skin and subcutaneous tissue disorders
    COLD SWEAT
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    DERMATITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    1
    0
    DRUG ERUPTION
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    1
    0
    0
    0
    0
    0
    1
    0
    0
    DRY SKIN
         subjects affected / exposed
    1 / 31 (3.23%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 135 (2.96%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    1
    0
    1
    0
    0
    0
    4
    0
    1
    ECZEMA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 135 (2.96%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    4
    0
    1
    ERYTHEMA
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    1
    HYPERHIDROSIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    1
    PRURITUS
         subjects affected / exposed
    6 / 31 (19.35%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    18 / 135 (13.33%)
    2 / 19 (10.53%)
    1 / 28 (3.57%)
         occurrences all number
    6
    2
    0
    1
    1
    2
    0
    20
    2
    1
    PRURITUS GENERALISED
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    0
    0
    1
    0
    RASH
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    6 / 135 (4.44%)
    2 / 19 (10.53%)
    1 / 28 (3.57%)
         occurrences all number
    1
    2
    0
    1
    0
    0
    0
    7
    2
    1
    RASH MACULAR
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    RASH PAPULAR
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    0
    1
    RASH PRURITIC
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    1
    1
    0
    RASH VESICULAR
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    SKIN EXFOLIATION
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    SKIN FISSURES
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    SKIN LESION
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    Renal and urinary disorders
    CHROMATURIA
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    NEPHROLITHIASIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    PROTEINURIA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    Endocrine disorders
    HYPOGONADISM MALE
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    ARTHRALGIA
         subjects affected / exposed
    2 / 31 (6.45%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    3 / 42 (7.14%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    5 / 135 (3.70%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    2
    1
    3
    0
    3
    1
    0
    5
    0
    1
    ARTHRITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    BACK PAIN
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 32 (9.38%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    2 / 42 (4.76%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    6 / 135 (4.44%)
    3 / 19 (15.79%)
    1 / 28 (3.57%)
         occurrences all number
    1
    3
    0
    1
    2
    0
    0
    6
    3
    1
    COSTOCHONDRITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    FLANK PAIN
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    1
    0
    1
    JOINT STIFFNESS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    JOINT SWELLING
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    0
    0
    0
    1
    MUSCLE FATIGUE
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    MUSCLE SPASMS
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    1
    1
    MUSCLE TIGHTNESS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    1 / 19 (5.26%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    1
    0
    MYALGIA
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    4 / 135 (2.96%)
    0 / 19 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    0
    1
    0
    0
    0
    0
    5
    0
    2
    NECK PAIN
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    2
    PAIN IN EXTREMITY
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    1 / 19 (5.26%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    1
    0
    2
    0
    0
    1
    1
    2
    PERIARTHRITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    RHABDOMYOLYSIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    TENDONITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    1
    0
    0
    Infections and infestations
    ACUTE SINUSITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    1
    0
    0
    0
    0
    0
    0
    0
    BRONCHITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    3 / 10 (30.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    6 / 135 (4.44%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    3
    0
    1
    1
    0
    6
    0
    1
    CELLULITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    CHLAMYDIAL INFECTION
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    EAR INFECTION
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    1
    ERYSIPELAS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    GASTROENTERITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    2
    1
    1
    GASTROENTERITIS VIRAL
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    0
    0
    GINGIVITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    0
    0
    0
    HERPES ZOSTER
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    1
    0
    0
    0
    1
    0
    0
    HERPES ZOSTER DISSEMINATED
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    0
    0
    0
    HERPES ZOSTER OTICUS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    INFLUENZA
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    5 / 135 (3.70%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    5
    0
    0
    NASOPHARYNGITIS
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    12 / 135 (8.89%)
    4 / 19 (21.05%)
    4 / 28 (14.29%)
         occurrences all number
    1
    0
    0
    1
    1
    0
    0
    17
    7
    4
    ORAL HERPES
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    5
    0
    2
    PARONYCHIA
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    PERTUSSIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    PYELONEPHRITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 4 (25.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    0
    1
    0
    0
    PYURIA
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    0
    0
    0
    0
    RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    1
    0
    0
    2
    0
    0
    RHINITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    2
    0
    2
    SECONDARY SYPHILIS
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 32 (6.25%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    0
    0
    0
    0
    SINUSITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    2 / 135 (1.48%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    2
    0
    1
    STAPHYLOCOCCAL INFECTION
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0
    TINEA VERSICOLOUR
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    0
    0
    0
    1
    TONSILLITIS
         subjects affected / exposed
    0 / 31 (0.00%)
    1 / 32 (3.13%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    0
    1
    0
    0
    TOOTH ABSCESS
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    1
    0
    0
    UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    4 / 31 (12.90%)
    5 / 32 (15.63%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    3 / 42 (7.14%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    12 / 135 (8.89%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    4
    5
    1
    0
    4
    0
    0
    12
    1
    1
    URINARY TRACT INFECTION
         subjects affected / exposed
    2 / 31 (6.45%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 4 (25.00%)
    1 / 5 (20.00%)
    6 / 135 (4.44%)
    2 / 19 (10.53%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    1
    0
    0
    2
    1
    6
    2
    0
    VIRAL UPPER RESPIRATORY TRACT INFECTION
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    1 / 135 (0.74%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    0
    1
    0
    0
    Metabolism and nutrition disorders
    DECREASED APPETITE
         subjects affected / exposed
    1 / 31 (3.23%)
    2 / 32 (6.25%)
    1 / 10 (10.00%)
    2 / 12 (16.67%)
    3 / 42 (7.14%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    3 / 135 (2.22%)
    1 / 19 (5.26%)
    1 / 28 (3.57%)
         occurrences all number
    1
    2
    1
    2
    3
    0
    1
    3
    1
    1
    GOUT
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    0
    0
    0
    0
    HYPOKALAEMIA
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    1 / 5 (20.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    2
    0
    0
    1
    0
    0
    3
    0
    0
    0
    HYPOPHOSPHATAEMIA
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 32 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 4 (0.00%)
    0 / 5 (0.00%)
    0 / 135 (0.00%)
    0 / 19 (0.00%)
    0 / 28 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    0
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 May 2014
    - Added dolutegravir (DTG) as a qualifying HIV-1 antiretroviral (ARV) for HCV/HIV-1 coinfected subjects and included updates related to the addition of this HIV-1 protease inhibitor throughout the protocol. - Updated the list of exclusionary laboratory parameters that were not eligible to be rescreened and updated the list of eligibility criteria that did not need to be repeated upon rescreening. - Updated the inclusion/exclusion criteria including eligible screening laboratory results. - Specified that female subjects of childbearing potential should have used contraception to prevent pregnancy starting with Study Day 1 and for 7 months after stopping study drugs or as directed by local RBV label per inclusion criterion (No. 3). - Updated the definition of pegylated interferon/ribavirin (pegIFN/RBV)-experienced subjects in the inclusion criteria (No. 5) and throughout the protocol. - Removed inclusion criterion requiring confirmation of a past positive result for anti-HIV antibody (HIV Ab) of HIV-1 infection. - Removed inclusion criterion for subjects who had confirmation of a plasma HIV-1 RNA > LLOQ at least twice prior to screening and inclusion criterion for confirmation of their CD4+ count or CD4+% prior to screening. - Clarified process for confirming the presence or absence of cirrhosis. - Allowed the use of hormonal contraceptives during study drug administration based on results of drug-drug interaction (DDI) studies. - Updated "Failure to Maintain HIV Virologic Suppression" section. - Updated Treatments Administered and Selection and Timing of Dose for Each Subject for atazanavir. - Updated Toxicity Management for consistency with other AbbVie HCV Phase 3 studies. - Added Collection of data regarding known HIV opportunistic infections.
    17 Jul 2014
    - Clarified the minimum and maximum number of subjects with no HIV-1 protease inhibitor (PI) exposure other than DRV allowed to enroll in Part 1b to ensure a balanced enrollment of previously PI-naïve and PI-experienced subjects. - Updated language related to hormonal contraceptives for female subjects of childbearing potential, including the use of progestin-only hormonal contraceptive methods. - Updated Inclusion Criterion 13 for subjects to have had confirmation of plasma HIV-1 RNA below LLOQ at least twice during the 24 weeks prior to screening.
    05 Mar 2015
    - Revised the treatment arms in Part 2 of the study for 3-direct-acting antiviral agent (DAA) with and without RBV for 12 and 24 weeks, based on data from AbbVie's Phase 3 program in HCV GT1 monoinfected subjects. - Allowed for the inclusion of HCV GT4 subjects into Part 2. - Revised Selection of Study Population to include updated Inclusion and Exclusion criteria specific to subjects screening for Part 2 of the study, moved Inclusion and Exclusion criteria for subjects screening for Part 1b within protocol appendix, and updated subsections related to prior, concomitant, and prohibited medications. - Added DTG and abacavir (ABC) as qualifying HIV-1 ARVs for HCV GT1 or GT4/HIV-1 coinfected subjects and DRV QD as a qualifying HIV-1 antiretroviral for HCV GT4/HIV-1 coinfected subjects in Part 2, based on data from AbbVie's DDI studies. - Shortened the post-treatment follow-up period from 48 weeks to 24 weeks for Part 1b and Part 2 of the study based on data from AbbVie's Phase 3 program. - Expanded the definition for HCV treatment-experienced subjects. - Expanded and updated the study objectives to accommodate the addition of GT4 population and GT1 population with other HCV treatment experience and/or additional HIV ARV medications. - Updated statistical methods based on the updated study primary and the first of the secondary efficacy endpoints to compare the percentage of GT1 subjects in Part 2 achieving SVR12 to the historical SVR12 rate for sofosbuvir plus ribavirin in order to test for non-inferiority. - Updated determination of sample size based on the updated study design.
    05 Mar 2015
    (continued) - Moved the longitudinal analysis of CD4+ T cell counts to the safety analysis section. - Updated add-on PegIFN/RBV therapy for subjects participating in Part 1a. - Updated criteria for initiation of Part 2 to remove the inclusion of HCV GT1 subjects on a DRV based HIV-1 ART regimen into Part 2. - Updated Discontinuation of Individual Subjects section to allow for a pregnant subject to continue DAAs administration at the discretion of the investigator. - Updated Treatments Administered and Selection and Timing of Dose for Each Subject sections to clarify the 3-DAA and 2-DAA dosing requirements and RBV dosing for subjects with a screening creatinine clearance (CrCl) < 50 mL/min.
    12 Jun 2015
    - Updated Inclusion Criteria (Part 2) Criterion 7 to clarify that subjects must have been positive for anti-HCV Ab and have had an HCV RNA > 1,000 IU/mL at Screening. - Added the inclusion and exclusion criteria specific to Part 1a of the study as appendix, updated the inclusion and exclusion criteria for Part 1b appendix, and made updates throughout the protocol relating to the additional appendix.
    15 Apr 2016
    - Removed the specification for a minimum number of 15 subjects in each of Arms F and G due to shortage of subjects available for screening. - Redefined all analyses to be evaluated for the combined group of subjects from Arms E, F, H, I and J in Part 2. Deleted analyses of the combined group of subjects from Arms E, G, H, I, and J in Part 2. Deleted the fixed-sequence testing procedure for the primary and first secondary efficacy endpoints.to align with dosing recommendations in current labeling where the recommended regimen for GT1b-infected patients with cirrhosis was ABT-450/r/ABT-267 and ABT-333 without RBV for 12 weeks. - Deleted analyses comparing Arms F and G (ABT-450/r/ABT-267 + ABT-333 without and with RBV, respectively, for 12 weeks) due to the small sample sizes. - Added the Sanger sequencing assay of the NS5B region as a reflex test methodology due to the Sanger assay's increased sensitivity and use of direct sequencing.

    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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