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    Clinical Trial Results:
    A Long-Term Follow-up Study to Evaluate the Durability of Virologic Response and/or Viral Resistance Patterns of Subjects With Chronic Hepatitis C Who Have Been Previously Treated with MK-5172 in a Prior Clinical Trial

    Summary
    EudraCT number
    		 2012-002232-85
    Trial protocol
    		 DE   FR   IT   SE   GB   DK   HU   ES   FI   NL   LT   EE   CZ   NO   AT   PL   GR  
    Global end of trial date
    31 Mar 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    25 Mar 2022
    First version publication date
    25 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    5172-017
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01667081
    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., ClinicalTrialsDisclosure@merck.com
    Scientific contact
    Clinical Trials Disclosure, Merck Sharp & Dohme Corp., ClinicalTrialsDisclosure@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
    31 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Mar 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Mar 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This is a three-year (except for participants with chronic kidney disease [CKD] or cirrhosis) multicenter study to follow participants who received at least one dose of grazoprevir (MK-5172) in a previous study to determine whether they remain hepatitis C virus (HCV)-Ribonucleic acid (RNA) negative over time, and to determine if they have developed antiviral resistance. The study will also evaluate long-term adverse events in this population. Participants from MK-5172-052 (NCT02092350) with CKD or cirrhosis will be followed for five years.
    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 Oct 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy
    Long term follow-up duration
    		 5 Years
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 8
    Country: Number of subjects enrolled
    Australia: 41
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Belgium: 4
    Country: Number of subjects enrolled
    Canada: 99
    Country: Number of subjects enrolled
    Czechia: 45
    Country: Number of subjects enrolled
    Denmark: 96
    Country: Number of subjects enrolled
    Estonia: 1
    Country: Number of subjects enrolled
    Finland: 2
    Country: Number of subjects enrolled
    France: 206
    Country: Number of subjects enrolled
    Germany: 67
    Country: Number of subjects enrolled
    Greece: 7
    Country: Number of subjects enrolled
    Hungary: 19
    Country: Number of subjects enrolled
    Israel: 209
    Country: Number of subjects enrolled
    Italy: 39
    Country: Number of subjects enrolled
    Korea, Republic of: 88
    Country: Number of subjects enrolled
    Lithuania: 28
    Country: Number of subjects enrolled
    Malaysia: 10
    Country: Number of subjects enrolled
    Netherlands: 16
    Country: Number of subjects enrolled
    New Zealand: 21
    Country: Number of subjects enrolled
    Norway: 4
    Country: Number of subjects enrolled
    Poland: 39
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Russian Federation: 109
    Country: Number of subjects enrolled
    Spain: 110
    Country: Number of subjects enrolled
    Sweden: 56
    Country: Number of subjects enrolled
    Switzerland: 10
    Country: Number of subjects enrolled
    Taiwan: 120
    Country: Number of subjects enrolled
    Thailand: 25
    Country: Number of subjects enrolled
    Turkey: 19
    Country: Number of subjects enrolled
    United Kingdom: 25
    Country: Number of subjects enrolled
    United States: 882
    Country: Number of subjects enrolled
    Viet Nam: 5
    Worldwide total number of subjects
    2435
    EEA total number of subjects
    764
    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)
    2207
    From 65 to 84 years
    228
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 2438 adult Hepatitis C Virus (HCV)-infected participants who were previously treated in 18 prior clinical trials, enrolled in this study.

    Pre-assignment
    Screening details
    		 Of the 2438 participants, three participants were excluded from all analyses. Two participants enrolled in error failed to receive at least 1 dose of Grazoprevir (GZR) in a prior study (each received a comparator regimen in a prior base study) and 1 participant had insufficient long-term follow-up data (participant withdrew consent on Day 27).

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 GZR 100 mg + EBR 50 mg +/- Ribavirin (RBV)
    Arm description
    		 Participants previously received grazoprevir (GZR) 100mg + Elbasvir (EBR) 50mg with or without RBV in a prior study.
    Arm type
    		 non-interventional

    Investigational medicinal product name
    Grazoprevir (GZR)
    Investigational medicinal product code
    Other name
    MK-5172
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants previously received study treatment with grazoprevir in a prior clinical trial, at the dose and frequency specified in the study protocol. Grazoprevir was not administered to participants in the course of this follow-up study.

    Arm title
    		 Other GZR regimen
    Arm description
    		 Participants previously received at least one dose of GZR in a prior study
    Arm type
    		 non-interventional

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		GZR 100 mg + EBR 50 mg +/- Ribavirin (RBV) Other GZR regimen
    Started
    1909
    526
    Completed
    132
    169
    Not completed
    1777
    357
         Adverse event, serious fatal
    43
    3
         Physician decision
    16
    2
         Consent withdrawn by subject
    90
    35
         amendment 3 modified the follow up criteria
    1529
    269
         Lost to follow-up
    99
    48

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    GZR 100 mg + EBR 50 mg +/- Ribavirin (RBV)
    Reporting group description
    		 Participants previously received grazoprevir (GZR) 100mg + Elbasvir (EBR) 50mg with or without RBV in a prior study.

    Reporting group title
    Other GZR regimen
    Reporting group description
    		 Participants previously received at least one dose of GZR in a prior study

    Reporting group values
    		 GZR 100 mg + EBR 50 mg +/- Ribavirin (RBV) Other GZR regimen Total
    Number of subjects
    		 1909 526 2435
    Age categorical
    Units: Participants
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 1712 495 2207
        From 65-84 years
    		 197 31 228
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 51.9 ± 11.0 49.7 ± 11.4 -
    Sex: Female, Male
    Units: Participants
        Female
    		 785 238 1023
        Male
    		 1124 288 1412
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 5 2 7
        Asian
    		 283 12 295
        Native Hawaiian or Other Pacific Islander
    		 1 1 2
        Black or African American
    		 253 35 288
        White
    		 1345 470 1815
        More than one race
    		 21 6 27
        Unknown or Not Reported
    		 1 0 1
    Ethnicity (NIH/OMB)
    Units: Subjects
        Hispanic or Latino
    		 135 68 203
        Not Hispanic or Latino
    		 1730 444 2174
        Unknown or Not Reported
    		 44 14 58

    End points

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    End points reporting groups
    Reporting group title
    GZR 100 mg + EBR 50 mg +/- Ribavirin (RBV)
    Reporting group description
    		 Participants previously received grazoprevir (GZR) 100mg + Elbasvir (EBR) 50mg with or without RBV in a prior study.

    Reporting group title
    Other GZR regimen
    Reporting group description
    		 Participants previously received at least one dose of GZR in a prior study

    Subject analysis set title
    GZR 100 mg + EBR 50 mg +/- RBV
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received GZR 100mg +EBR 50mg with or without RBV in a prior study.

    Subject analysis set title
    EBR/GZR +/- RBV: NS3 RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received EBR and GZR with or without RBV in a prior study and had treatment-emergent NS3 RASs

    Subject analysis set title
    EBR/GZR +/- RBV: NS5A RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received EBR and GZR with or without RBV in a prior study and had treatment-emergent NS5A RASs

    Subject analysis set title
    EBR/GZR +/-RBV: Both NS3 and NS5A RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received EBR and GZR with or without RBV in a prior study and had both treatment-emergent NS3 and NS5A RASs

    Subject analysis set title
    GZR + pegylated interferon/ribavirin (PR): NS3 RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received GZR and PR for 12 weeks in a prior study and had treatment-emergent NS3 RASs

    Subject analysis set title
    EBR/GZR+/- RBV: NS3 RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received EBR and GZR with or without RBV in a prior study and had treatment-emergent NS3 RASs

    Subject analysis set title
    EBR/GZR +/- RBV: NS5A RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received EBR and GZR with or without RBV in a prior study and had treatment-emergent NS5A RASs

    Subject analysis set title
    EBR/GZR +/-RVB: Both NS3 and NS5A RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received EBR and GZR with or without RBV in a prior study and had both treatment-emergent NS3 and NS5A RASs

    Subject analysis set title
    GZR + RBV or PR: NS3 RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received GZR and RBV or PR for 12 weeks in a prior study and had treatment-emergent NS3 RASs

    Subject analysis set title
    EBR/GZR: NS3 RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received EBR and GZR in a prior study and had treatment-emergent NS3 RASs

    Subject analysis set title
    EBR/GZR: NS5A RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received EBR and GZR in a prior study and had treatment-emergent NS5A RASs

    Subject analysis set title
    EBR/GZR: Both NS3 and NS5A RASs
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants previously received EBR and GZR in a prior study and had both treatment-emergent NS3 and NS5A RASs

    Primary: Time to Viral Relapse

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    End point title
    		 Time to Viral Relapse [1]
    End point description
    Viral relapse is defined as any participant who has confirmed HCV Ribonucleic acid (RNA) ≥ Lower limit of quantification (LLoQ) of 15 IU/mL and had achieved sustained virologic response (SVR) in the follow up in the prior treatment study. Time to relapse is defined as the time from last dose of study therapy taken in the prior treatment study until the date where HCV RNA is ≥LLoQ. A value of 9999 indicates that median time to viral relapse and interquartile range were not reached due to the low rate of late virologic relapse. The analysis population included all participants who achieved SVR during the follow-up period of the prior treatment study and did not start any new HCV therapy between the end of the prior treatment study and entry in this study.
    End point type
    Primary
    End point timeframe
    Up to ~60 months after enrollment in this study
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 GZR 100 mg + EBR 50 mg +/- Ribavirin (RBV) Other GZR regimen
    Number of subjects analysed
    1837
    495
    Units: Months
        median (inter-quartile range (Q1-Q3))
    9999 (9999 to 9999)
    9999 (9999 to 9999)
    No statistical analyses for this end point

    Primary: Persistence of Treatment-Emergent Nonstructural Protein (NS)3 and NS5A Resistance-associated Substitutions (RASs) in Participants with HCV Genotype (GT) 1a infections

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    End point title
    		 Persistence of Treatment-Emergent Nonstructural Protein (NS)3 and NS5A Resistance-associated Substitutions (RASs) in Participants with HCV Genotype (GT) 1a infections [2]
    End point description
    In adult participants with HCV RNA ≥1000 IU/mL at entry or during the study period, HCV sequence analysis was performed to evaluate the presence of RASs and the persistence of RASs over time. The analysis population included participants who met the criteria of virologic failure either in the prior base study or had HCV RNA Target detected, quantifiable [TD(q)] at entry in current study. Participants did not receive new HCV therapy between the end of the prior base study and entry into this study. Only HCV genotype infections that had adequate reference information were included.
    End point type
    Primary
    End point timeframe
    Up to ~60 months after enrollment in this study
    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: No statistical analysis was planned for this endpoint
    End point values
    		 EBR/GZR +/- RBV: NS3 RASs EBR/GZR +/- RBV: NS5A RASs EBR/GZR +/-RBV: Both NS3 and NS5A RASs GZR + pegylated interferon/ribavirin (PR): NS3 RASs
    Number of subjects analysed
    31
    31
    31
    16
    Units: Participants
        Failure
    22
    25
    18
    11
        24 weeks (wk) post failure
    10
    25
    8
    2
        48 weeks post failure (N analyzed=30, 30, 30, 16)
    6
    22
    4
    2
        96 weeks post failure (N analyzed=21, 21, 21, 15)
    4
    15
    3
    1
        ≥144 weeks post failure (N analyzed=17, 17, 17, 8)
    2
    11
    1
    1
    No statistical analyses for this end point

    Primary: Persistence of Treatment-Emergent NS3 and NS5A RASs in Participants with HCV Genotype 1b Infections

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    End point title
    		 Persistence of Treatment-Emergent NS3 and NS5A RASs in Participants with HCV Genotype 1b Infections [3]
    End point description
    In adult participants with HCV RNA ≥1000 IU/mL at entry or during the study period, HCV sequence analysis was performed to evaluate the presence of RASs and the persistence of RASs over time. The analysis population included participants who met the criteria of virologic failure either in the prior base study or had HCV RNA TD(q) at entry in current study. Participants did not receive new HCV therapy between the end of the prior base study and entry into this study. Only HCV genotype infections that had adequate reference information were included.
    End point type
    Primary
    End point timeframe
    Up to ~60 months after enrollment in this study
    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: No statistical analysis was planned for this endpoint
    End point values
    		 EBR/GZR+/- RBV: NS3 RASs EBR/GZR +/- RBV: NS5A RASs EBR/GZR +/-RVB: Both NS3 and NS5A RASs GZR + RBV or PR: NS3 RASs
    Number of subjects analysed
    9
    9
    9
    5
    Units: Participants
        Failure
    4
    7
    2
    3
        24 weeks post failure
    2
    7
    0
    1
        48 weeks post failure (N analyzed=6, 6, 6, 4)
    1
    5
    0
    1
        96 weeks post failure (N analyzed=4, 4, 4, 4)
    1
    3
    0
    1
        ≥144 weeks post failure (N analyzed=3, 3, 3, 4)
    0
    3
    0
    1
    No statistical analyses for this end point

    Primary: Persistence of Treatment-Emergent NS3 and NS5A RASs in Participants with Genotype 4 Infections

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    End point title
    		 Persistence of Treatment-Emergent NS3 and NS5A RASs in Participants with Genotype 4 Infections [4]
    End point description
    In adult participants with HCV RNA ≥1000 IU/mL at entry or during the study period, HCV sequence analysis was performed to evaluate the presence of RASs and the persistence of RASs over time. The analysis population included participants who met the criteria of virologic failure either in the prior base study or had HCV RNA TD(q) at entry in current study. Participants did not receive new HCV therapy between the end of the prior base study and entry into this study. Only HCV genotype infections that had adequate reference information were included.
    End point type
    Primary
    End point timeframe
    Up to ~60 months after enrollment in this study
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 EBR/GZR: NS3 RASs EBR/GZR: NS5A RASs EBR/GZR: Both NS3 and NS5A RASs
    Number of subjects analysed
    5
    5
    5
    Units: Participants
        Failure
    2
    4
    2
        24 weeks post failure
    1
    3
    1
        48 weeks post failure
    1
    2
    1
        96 weeks post failure
    1
    2
    1
        ≥144 weeks post failure
    1
    2
    1
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced a Drug-Related Adverse Event (AE) During the Long-Term Follow-Up

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    End point title
    		 Number of Participants Who Experienced a Drug-Related Adverse Event (AE) During the Long-Term Follow-Up [5]
    End point description
    An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The study investigator determined whether the adverse event was drug-related. The analysis population included all participants treated with GZR in a prior study. Three participants were excluded from analysis; two participants enrolled in error failed to receive at least one dose of GZR in a prior study (each received a comparator regimen in a prior base study) and one participant had insufficient long-term follow-up data (participant withdrew consent on Day 27).
    End point type
    Primary
    End point timeframe
    Up to ~ 60 months after enrollment in this study
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 GZR 100 mg + EBR 50 mg +/- Ribavirin (RBV) Other GZR regimen
    Number of subjects analysed
    1909
    526
    Units: Participants
    1
    1
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced a Drug-Related Serious Adverse Event (SAE) During the Long-Term Follow-Up

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    End point title
    		 Number of Participants Who Experienced a Drug-Related Serious Adverse Event (SAE) During the Long-Term Follow-Up [6]
    End point description
    An SAE is any adverse experience occurring at any dose that either results in death, is life threatening, results in a persistent or significant disability/incapacity, results in or prolongs an existing inpatient hospitalization, is a congenital anomaly/birth defect, is a cancer, is an overdose, or other important medical events that may be considered an SAE when the event may jeopardize the participant and may require medical or surgical intervention to prevent one of the outcomes listed previously. The study investigator determined whether the adverse event was drug-related. The analysis population included all participants treated with GZR in a prior study. Three participants were excluded from analysis; two participants enrolled in error failed to receive at least one dose of GZR in a prior study (each received a comparator regimen in a prior base study) and one participant had insufficient long-term follow-up data.
    End point type
    Primary
    End point timeframe
    Up to ~60 months after enrollment in this study
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 GZR 100 mg + EBR 50 mg +/- Ribavirin (RBV) Other GZR regimen
    Number of subjects analysed
    1909
    526
    Units: Participants
    1
    1
    No statistical analyses for this end point

    Primary: Number of Participants Who Experienced an Event of Clinical Interest (ECI) During the Long-Term Follow-Up

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    End point title
    		 Number of Participants Who Experienced an Event of Clinical Interest (ECI) During the Long-Term Follow-Up [7]
    End point description
    An ECI includes spontaneous bacterial peritonitis, variceal bleeding, ascites, encephalopathy, hepatorenal syndrome, hepatocellular carcinoma, liver transplant, cardiovascular disease limited to angina and myocardial infarction, neurologic disorders limited to transient ischemic attack (TIA) or stroke, graft rejection in participants who have undergone liver or kidney transplant, or one of the following in participants from the MK-5172-052 (NCT02092350) base study: kidney transplant, decreased estimated glomerular filtration rate (eGFR), new onset diabetes, cryoglobulinemia, or post transplantation glomerulonephritis. The analysis population included all participants treated with GZR in a prior study. Three participants were excluded from analysis; two participants enrolled in error failed to receive at least one dose of GZR in a prior study (each received a comparator regimen in a prior base study) and one participant had insufficient long-term follow-up data.
    End point type
    Primary
    End point timeframe
    Up to ~60 months after enrollment in this study
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was planned for this endpoint
    End point values
    		 GZR 100 mg + EBR 50 mg +/- Ribavirin (RBV) Other GZR regimen
    Number of subjects analysed
    1909
    526
    Units: Participants
    98
    4
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    From first visit in follow-up (Screening/Baseline) up to ~60 months after enrollment in this study
    Adverse event reporting additional description
    The all-cause mortality population includes all enrolled participants treated with GZR in a prior study (n=2436). The AE population excludes 3 enrolled participants- two enrolled in error who received a comparator regimen in a prior base study and one participant had insufficient long-term follow up data (participant withdrew consent on day 27).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Other GZR Regimen
    Reporting group description
    		 -

    Reporting group title
    GZR 100 mg + EBR 50 mg +/- RBV
    Reporting group description
    		 -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Non-serious adverse events did not meet the frequency threshold of 5% for reporting
    Serious adverse events
    		 Other GZR Regimen GZR 100 mg + EBR 50 mg +/- RBV
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 526 (0.76%)
    100 / 1909 (5.24%)
         number of deaths (all causes)
    3
    44
         number of deaths resulting from adverse events
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma pancreas
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Diffuse large B-cell lymphoma
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Hepatocellular carcinoma
         subjects affected / exposed
    1 / 526 (0.19%)
    12 / 1909 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 12
         deaths causally related to treatment / all
    0 / 1
    0 / 3
    Lung neoplasm malignant
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Non-small cell lung cancer
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pancreatic carcinoma
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Death
         subjects affected / exposed
    0 / 526 (0.00%)
    8 / 1909 (0.42%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    0 / 8
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Sudden death
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Immune system disorders
    Kidney transplant rejection
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asphyxia
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Respiratory arrest
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 1909 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Investigations
    Glomerular filtration rate decreased
         subjects affected / exposed
    0 / 526 (0.00%)
    5 / 1909 (0.26%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Injury
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Overdose
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Transplant dysfunction
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Acute coronary syndrome
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Acute myocardial infarction
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina pectoris
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Angina unstable
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    0 / 526 (0.00%)
    4 / 1909 (0.21%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 4
    Cardiac failure
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Coronary artery disease
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial infarction
         subjects affected / exposed
    0 / 526 (0.00%)
    3 / 1909 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Myocardial ischaemia
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Pulseless electrical activity
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Embolic stroke
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic cerebral infarction
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ischaemic stroke
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Optic neuritis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 1909 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 1909 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    0 / 526 (0.00%)
    3 / 1909 (0.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Ascites
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Chronic hepatic failure
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cirrhosis
         subjects affected / exposed
    1 / 526 (0.19%)
    0 / 1909 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Chronic kidney disease
         subjects affected / exposed
    0 / 526 (0.00%)
    7 / 1909 (0.37%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 7
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    End stage renal disease
         subjects affected / exposed
    0 / 526 (0.00%)
    17 / 1909 (0.89%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 17
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Glomerulonephritis chronic
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal failure
         subjects affected / exposed
    0 / 526 (0.00%)
    6 / 1909 (0.31%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Renal impairment
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Device related sepsis
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Peritonitis
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Sepsis
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Septic shock
         subjects affected / exposed
    0 / 526 (0.00%)
    2 / 1909 (0.10%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 2
    Wound infection
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Failure to thrive
         subjects affected / exposed
    0 / 526 (0.00%)
    1 / 1909 (0.05%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Other GZR Regimen GZR 100 mg + EBR 50 mg +/- RBV
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 526 (0.00%)
    0 / 1909 (0.00%)

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Jan 2013
    AM 01: Updated definitions of relapse criteria to be consistent with the FDA assay label.
    16 Dec 2014
    AM 02: Added 4 visits to collect outcome data over a longer period of time in patients with CKD from the P052 base study and patients with advanced liver disease from the P059 base study.
    04 Jul 2016
    AM 03: The protocol was amended to align with updated HCV treatment data. Late relapse of HCV is rare in patients treated with direct-acting antivirals (DAAs). Participants who achieved SVR in their base protocol were no longer enrolled in this study and current participants who entered this study with undetectable HCV RNA were discontinued at their next study visit. Participants with CKD remained in the study regardless of prior virologic response. In addition, participants who failed due to reinfection or were retreated for HCV were discontinued at the next study visit. Participants from the P059 study were no longer followed for >3 years.
    21 May 2018
    AM 04: Updated to include enrollment of pediatric participants who experienced virologic failure associated with ≥1 treatment-emergent RASs in the P079 base study.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30038064
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