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    Clinical Trial Results:
    A Phase II/III Randomized Clinical Trial to Study the Efficacy and Safety of the Combination Regimen of MK-5172 and MK-8742 in Subjects with Chronic Hepatitis C Virus Infection and Chronic Kidney Disease

    Summary
    EudraCT number
    		 2013-003858-25
    Trial protocol
    		 LT   ES   SE   EE   NL  
    Global end of trial date
    02 Sep 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    04 Sep 2016
    First version publication date
    04 Sep 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    5172-052
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02092350
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Merck Sharp & Dohme Corp.
    Sponsor organisation address
    2000 Galloping Hill Road, Kenilworth, NJ, United States, 07033
    Public contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialDisclosure@merck.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
    02 Sep 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    02 Sep 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This study will evaluate the safety and efficacy of combination treatment with grazoprevir (GZR; MK-5172) + elbasvir (EBR; MK-8742) for cirrhotic and non-cirrhotic participants with chronic Genotype 1 (GT1) hepatitis C virus (HCV) infection and chronic kidney disease (CKD).
    Protection of trial subjects
    This study was conducted in conformance with Good Clinical Practice standards and applicable country and/or local statutes and regulations regarding ethical committee review, informed consent, and the protection of human subjects participating in biomedical research.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Mar 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Scientific research
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 2
    Country: Number of subjects enrolled
    Australia: 7
    Country: Number of subjects enrolled
    Canada: 6
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Israel: 15
    Country: Number of subjects enrolled
    Korea, Republic of: 5
    Country: Number of subjects enrolled
    Lithuania: 9
    Country: Number of subjects enrolled
    Netherlands: 2
    Country: Number of subjects enrolled
    Spain: 15
    Country: Number of subjects enrolled
    Sweden: 5
    Country: Number of subjects enrolled
    United States: 153
    Worldwide total number of subjects
    237
    EEA total number of subjects
    49
    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)
    197
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This multi-site study enrolled adult, male and female participants with hepatitis C virus (HCV) genotype (GT) 1 with chronic kidney disease (CKD).

    Pre-assignment
    Screening details
    		 The screening period lasted for up to 60 days.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Immediate Treatment + Intensive PK
    Arm description
    		 Participants received grazoprevir (GZR) 100 mg tablet + elbasvir (EBR) 50 mg tablet once daily (q.d.) by mouth for 12 weeks, followed by a 24-week follow-up period. A subset of participants also underwent intensive pharmacokinetics (PK) testing.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Elbasvir
    Investigational medicinal product code
    Other name
    MK-8742
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    EBR 50 mg tablet taken q.d. by mouth.

    Investigational medicinal product name
    Grazoprevir
    Investigational medicinal product code
    Other name
    MK-5172
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    GZR 100 mg tablet taken q.d. by mouth.

    Arm title
    		 Deferred Treatment
    Arm description
    		 Participants received placebo to GZR and EBR q.d. by mouth for 12 weeks. Then, after a 4-week drug-free period, participants received a fixed dose combination (FDC) tablet containing GZR 100 mg + EBR 50 mg tablet q.d. by mouth for 12 weeks, followed by a 24-week follow-up period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo to Grazoprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet matched to GZR.

    Investigational medicinal product name
    Grazoprevir + Elbasvir
    Investigational medicinal product code
    Other name
    MK-5172A; Zepatier™
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    A single FDC tablet containing GZR 100 mg + EBR 50 mg taken q.d. by mouth.

    Investigational medicinal product name
    Placebo to Elbasvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo tablet matched to EBR.

    Number of subjects in period 1
    		Immediate Treatment + Intensive PK Deferred Treatment
    Started
    123
    114
    Completed
    113
    102
    Not completed
    10
    12
         Adverse event, serious fatal
    2
    5
         Physician decision
    1
    1
         Consent withdrawn by subject
    2
    2
         Screen Failure
    1
    -
         Adverse event, non-fatal
    -
    3
         Lost to follow-up
    3
    1
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Immediate Treatment + Intensive PK
    Reporting group description
    		 Participants received grazoprevir (GZR) 100 mg tablet + elbasvir (EBR) 50 mg tablet once daily (q.d.) by mouth for 12 weeks, followed by a 24-week follow-up period. A subset of participants also underwent intensive pharmacokinetics (PK) testing.

    Reporting group title
    Deferred Treatment
    Reporting group description
    		 Participants received placebo to GZR and EBR q.d. by mouth for 12 weeks. Then, after a 4-week drug-free period, participants received a fixed dose combination (FDC) tablet containing GZR 100 mg + EBR 50 mg tablet q.d. by mouth for 12 weeks, followed by a 24-week follow-up period.

    Reporting group values
    		 Immediate Treatment + Intensive PK Deferred Treatment Total
    Number of subjects
    		 123 114 237
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: years
        arithmetic mean (standard deviation)
    		 56.6 ( 9 ) 55.2 ( 10 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 30 33 63
        Male
    		 93 81 174

    End points

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    End points reporting groups
    Reporting group title
    Immediate Treatment + Intensive PK
    Reporting group description
    		 Participants received grazoprevir (GZR) 100 mg tablet + elbasvir (EBR) 50 mg tablet once daily (q.d.) by mouth for 12 weeks, followed by a 24-week follow-up period. A subset of participants also underwent intensive pharmacokinetics (PK) testing.

    Reporting group title
    Deferred Treatment
    Reporting group description
    		 Participants received placebo to GZR and EBR q.d. by mouth for 12 weeks. Then, after a 4-week drug-free period, participants received a fixed dose combination (FDC) tablet containing GZR 100 mg + EBR 50 mg tablet q.d. by mouth for 12 weeks, followed by a 24-week follow-up period.

    Primary: Percentage of participants with sustained virologic response 12 weeks after completing study therapy (SVR12)

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    End point title
    		 Percentage of participants with sustained virologic response 12 weeks after completing study therapy (SVR12) [1]
    End point description
    SVR12 was defined as HCV ribonucleic acid (RNA) lower than the limit of quantification (LLoQ) 12 weeks after completing study (GZR + EBR) therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL. The modified Full Analysis set (mFAS) includes all participants receiving ≥1 dose of drug and without missing data due to death or early discontinuation from study therapy for reasons unrelated to response to HCV treatment.
    End point type
    Primary
    End point timeframe
    Week 24 (Immediate Treatment + Intensive PK) or Week 40 (Deferred Treatment)
    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: For details of the single-arm statistical analysis, which cannot be shown in the EudraCT system, see www.clinicaltrials.gov record NCT02092350.
    End point values
    		 Immediate Treatment + Intensive PK Deferred Treatment
    Number of subjects analysed
    116
    99
    Units: Percentage of participants
        number (confidence interval 95%)
    99.1 (95.3 to 100)
    98 (92.9 to 99.8)
    No statistical analyses for this end point

    Primary: Number of participants experiencing an adverse event (AE) during the initial treatment and 14-day follow-up periods

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    End point title
    		 Number of participants experiencing an adverse event (AE) during the initial treatment and 14-day follow-up periods [2]
    End point description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group. The All Participants as Treated (APaT) population includes all enrolled participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to Week 14
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Per protocol, only descriptive statistics are presented.
    End point values
    		 Immediate Treatment + Intensive PK Deferred Treatment
    Number of subjects analysed
    122
    113
    Units: Participants
    93
    96
    No statistical analyses for this end point

    Primary: Number of participants discontinuing study drug due to AEs during the initial treatment period

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    End point title
    		 Number of participants discontinuing study drug due to AEs during the initial treatment period [3]
    End point description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. This analysis includes the Immediate Treatment + Intensive PK group and the placebo treatment period for the Deferred Treatment group. The APaT population includes all enrolled participants who received at least one dose of study drug.
    End point type
    Primary
    End point timeframe
    Up to Week 12
    Notes
    [3] - 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: Per protocol, only descriptive statistics are presented.
    End point values
    		 Immediate Treatment + Intensive PK Deferred Treatment
    Number of subjects analysed
    122
    113
    Units: Participants
    0
    5
    No statistical analyses for this end point

    Secondary: Percentage of participants with sustained virologic response 24 weeks after completing study therapy (SVR24)

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    End point title
    		 Percentage of participants with sustained virologic response 24 weeks after completing study therapy (SVR24)
    End point description
    SVR24 was defined as HCV RNA lower than LLoQ 24 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL. The mFAS includes all participants receiving ≥1 dose of drug and without missing data due to death or early discontinuation from study therapy for reasons unrelated to response to HCV treatment.
    End point type
    Secondary
    End point timeframe
    Week 36 (Immediate Treatment + Intensive PK) or Week 52 (Deferred Treatment)
    End point values
    		 Immediate Treatment + Intensive PK Deferred Treatment
    Number of subjects analysed
    114
    99
    Units: Percentage of participants
        number (confidence interval 95%)
    97.4 (92.5 to 99.5)
    98 (92.9 to 99.8)
    No statistical analyses for this end point

    Secondary: Percentage of participants with sustained virologic response 4 weeks after completing study therapy (SVR4)

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    End point title
    		 Percentage of participants with sustained virologic response 4 weeks after completing study therapy (SVR4)
    End point description
    SVR4 was defined as HCV RNA lower than LLoQ 4 weeks after completing study therapy. HCV RNA was measured using the COBAS™ AmpliPrep/COBAS™ Taqman™ HCV Test, v2.0®, which has a LLoQ of 15 IU/mL. The mFAS includes all participants receiving ≥1 dose of drug and without missing data due to death or early discontinuation from study therapy for reasons unrelated to response to HCV treatment.
    End point type
    Secondary
    End point timeframe
    Week 16 (Immediate Treatment + Intensive PK) or Week 32 (Deferred Treatment)
    End point values
    		 Immediate Treatment + Intensive PK Deferred Treatment
    Number of subjects analysed
    118
    101
    Units: Percentage of participants
        number (confidence interval 95%)
    100 (96.9 to 100)
    99 (94.6 to 100)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Immediate Treatment + Intensive PK: up to Week 36; Deferred Treatment GZR Placebo + EBR Placebo: up to Week 16; Deferred Treatment GZR 100 mg + EBR 50 mg: Week 16 to up to Week 52.
    Adverse event reporting additional description
    An AE is defined as any untoward medical occurrence in a participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The All Participants as Treated (APaT) population includes all enrolled participants who received at least one dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Immediate + Intensive PK: GZR 100 mg + EBR 50 mg 12 Weeks
    Reporting group description
    		 Participants received GZR 100 mg tablet + EBR 50 mg tablet q.d. by mouth for 12 weeks. A subset of participants also underwent intensive PK testing.

    Reporting group title
    Deferred treatment: GZR Placebo + EBR Placebo 12 Weeks
    Reporting group description
    		 Participants received placebo to GZR and EBR q.d. by mouth for 12 weeks, followed by a 4-week drug-free period.

    Reporting group title
    Deferred treatment: GZR 100 mg + EBR 50 mg 12 Weeks
    Reporting group description
    		 Participants received a FDC tablet containing GZR 100 mg + EBR 50 mg tablet q.d. by mouth for 12 weeks, followed by a 24-week follow-up period.

    Serious adverse events
    		 Immediate + Intensive PK: GZR 100 mg + EBR 50 mg 12 Weeks Deferred treatment: GZR Placebo + EBR Placebo 12 Weeks Deferred treatment: GZR 100 mg + EBR 50 mg 12 Weeks
    Total subjects affected by serious adverse events
         subjects affected / exposed
    30 / 122 (24.59%)
    22 / 113 (19.47%)
    25 / 102 (24.51%)
         number of deaths (all causes)
    2
    4
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Papillary thyroid cancer
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic aneurysm
         subjects affected / exposed
    0 / 122 (0.00%)
    2 / 113 (1.77%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Aortic stenosis
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cryoglobulinaemia
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Extremity necrosis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    2 / 122 (1.64%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Peripheral venous disease
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Shock haemorrhagic
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute pulmonary oedema
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Acute respiratory failure
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hypoxia
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mediastinal effusion
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pleural effusion
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumothorax
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pulmonary oedema
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Disorientation
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Investigations
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Electrocardiogram abnormal
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lipase increased
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Arteriovenous fistula aneurysm
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Arteriovenous fistula site complication
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dialysis related complication
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Facial bones fracture
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Foreign body
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Genital injury
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Post procedural haematoma
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative fever
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Procedural pain
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Subdural haematoma
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Wound dehiscence
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    2 / 102 (1.96%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure congestive
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiomyopathy
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Coronary artery occlusion
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericardial effusion
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pericarditis
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Tricuspid valve incompetence
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Dizziness
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hydrocephalus
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorder
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Presyncope
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Seizure
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Iron deficiency anaemia
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Constipation
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Localised intraabdominal fluid collection
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Retroperitoneal haematoma
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 122 (0.00%)
    2 / 113 (1.77%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Chronic kidney disease
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 113 (0.88%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    Tubulointerstitial nephritis
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Costochondritis
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Myositis
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pain in extremity
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Citrobacter sepsis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Enterobacter sepsis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Haematoma infection
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infected fistula
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower respiratory tract infection
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Mediastinitis
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nocardiosis
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Osteomyelitis
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    2 / 122 (1.64%)
    1 / 113 (0.88%)
    3 / 102 (2.94%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Pneumonia bacterial
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Postoperative wound infection
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    2 / 122 (1.64%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Septic shock
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 122 (0.82%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Fluid overload
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperglycaemia
         subjects affected / exposed
    0 / 122 (0.00%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyperkalaemia
         subjects affected / exposed
    1 / 122 (0.82%)
    1 / 113 (0.88%)
    0 / 102 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 122 (0.00%)
    0 / 113 (0.00%)
    1 / 102 (0.98%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Immediate + Intensive PK: GZR 100 mg + EBR 50 mg 12 Weeks Deferred treatment: GZR Placebo + EBR Placebo 12 Weeks Deferred treatment: GZR 100 mg + EBR 50 mg 12 Weeks
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    67 / 122 (54.92%)
    68 / 113 (60.18%)
    39 / 102 (38.24%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 122 (5.74%)
    6 / 113 (5.31%)
    2 / 102 (1.96%)
         occurrences all number
    7
    6
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    8 / 122 (6.56%)
    18 / 113 (15.93%)
    4 / 102 (3.92%)
         occurrences all number
    9
    22
    4
    Headache
         subjects affected / exposed
    23 / 122 (18.85%)
    18 / 113 (15.93%)
    7 / 102 (6.86%)
         occurrences all number
    26
    23
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 122 (5.74%)
    6 / 113 (5.31%)
    4 / 102 (3.92%)
         occurrences all number
    9
    6
    4
    Fatigue
         subjects affected / exposed
    13 / 122 (10.66%)
    17 / 113 (15.04%)
    10 / 102 (9.80%)
         occurrences all number
    15
    17
    10
    Pyrexia
         subjects affected / exposed
    6 / 122 (4.92%)
    6 / 113 (5.31%)
    3 / 102 (2.94%)
         occurrences all number
    7
    6
    4
    Gastrointestinal disorders
    Abdominal discomfort
         subjects affected / exposed
    2 / 122 (1.64%)
    6 / 113 (5.31%)
    1 / 102 (0.98%)
         occurrences all number
    2
    6
    1
    Abdominal pain
         subjects affected / exposed
    10 / 122 (8.20%)
    3 / 113 (2.65%)
    3 / 102 (2.94%)
         occurrences all number
    13
    3
    3
    Constipation
         subjects affected / exposed
    8 / 122 (6.56%)
    6 / 113 (5.31%)
    3 / 102 (2.94%)
         occurrences all number
    8
    7
    3
    Diarrhoea
         subjects affected / exposed
    6 / 122 (4.92%)
    15 / 113 (13.27%)
    5 / 102 (4.90%)
         occurrences all number
    6
    22
    6
    Nausea
         subjects affected / exposed
    18 / 122 (14.75%)
    18 / 113 (15.93%)
    11 / 102 (10.78%)
         occurrences all number
    24
    21
    12
    Vomiting
         subjects affected / exposed
    9 / 122 (7.38%)
    9 / 113 (7.96%)
    7 / 102 (6.86%)
         occurrences all number
    13
    11
    10
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    9 / 122 (7.38%)
    2 / 113 (1.77%)
    5 / 102 (4.90%)
         occurrences all number
    10
    2
    6
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    4 / 122 (3.28%)
    12 / 113 (10.62%)
    1 / 102 (0.98%)
         occurrences all number
    4
    12
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    10 / 122 (8.20%)
    12 / 113 (10.62%)
    2 / 102 (1.96%)
         occurrences all number
    10
    12
    2
    Musculoskeletal and connective tissue disorders
    Musculoskeletal pain
         subjects affected / exposed
    0 / 122 (0.00%)
    6 / 113 (5.31%)
    1 / 102 (0.98%)
         occurrences all number
    0
    6
    1
    Myalgia
         subjects affected / exposed
    0 / 122 (0.00%)
    8 / 113 (7.08%)
    2 / 102 (1.96%)
         occurrences all number
    0
    9
    2
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    7 / 122 (5.74%)
    3 / 113 (2.65%)
    4 / 102 (3.92%)
         occurrences all number
    8
    3
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    07 Apr 2014
    AM2: The purpose of this amendment was to update the list of prohibited medications to include rosuvastatin and atorvastatin at specified dose limits, to update HCV RNA <LLoQ instead of <25 IU/mL, and to clarify that prohibited medications can be resumed 2 weeks after taking the final dose of study drug.
    28 May 2014
    AM3: The purpose of this amendment was to update the list of allowed and prohibited statin drugs and to add a list of prohibited hepatotoxic agents.
    10 Jun 2014
    AM4: The purpose of this amendment was to update laboratory exclusion values for platelets and to update inclusion criteria pertaining to liver disease.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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