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    Clinical Trial Results:
    Phase 2, Open-Label Study to Investigate the Pharmacokinetics, Efficacy, Safety, and Tolerability of the Combination of Simeprevir (TMC435), Daclatasvir (BMS-790052) and Ribavirin (RBV) in Patients with Recurrent Chronic Hepatitis C Genotype 1b Infection after Orthotopic Liver Transplantation

    Summary
    EudraCT number
    		 2013-002726-23
    Trial protocol
    		 ES   IT  
    Global end of trial date
    28 Jul 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Jul 2016
    First version publication date
    03 Jul 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    TMC435HPC3016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01938625
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development NV
    Sponsor organisation address
    Turnhoutseweg 30, Beerse, Belgium, 2340
    Public contact
    Clinical Registry Group, Janssen Research & Development NV, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development NV, ClinicalTrialsEU@its.jnj.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
    28 Jul 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective was to evaluate the effect of steady-state Simeprevir (SMV) and Daclatasvir (DCV) on the steady-state pharmacokinetics of cyclosporine and tacrolimus when administered as a regimen containing SMV [150 milligram once a day (mg qd)] , DCV (60 mg qd) and Ribavirin (RBV) (1,000 to 1,200 mg per day) in post-orthotopic liver transplantation (OLT) subjects with recurrent hepatitis C virus (HCV) genotype 1b infection and to evaluate the efficacy of a 24-week treatment regimen containing SMV, DCV, and RBV with respect to the proportion of HCV genotype 1b infected post- OLT subjects achieving sustained virologic response 12 weeks after end of treatment (EOT) (SVR12).
    Protection of trial subjects
    The trial was performed in accordance with the principles of good clinical practices [GCP] as outlined in 21 code of federal regulations [CFR] Parts 50, 56, and 312 and the Declaration of Helsinki and its subsequent revisions, and the European Union Clinical Trials Directive that are consistent with Good Clinical Practices and applicable regulatory requirements. During the study, various safety evaluations were performed at different timepoints like clinical laboratory assessments (hematology, serum chemistry and urinalysis), vital signs, 12-lead electrocardiograms (ECGs) and physical examination, all adverse events were reported from signing the informed consent until the follow-up visit.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 7
    Country: Number of subjects enrolled
    Spain: 12
    Country: Number of subjects enrolled
    Italy: 9
    Country: Number of subjects enrolled
    Poland: 7
    Worldwide total number of subjects
    35
    EEA total number of subjects
    35
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    26
    From 65 to 84 years
    9
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 The study was conducted in 2 parts (Part 1 and Part 2). Total 21 subjects were included in Part 1 and 14 subjects were included in Part 2 of the study.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Cyclosporine
    Arm description
    		 Subjects received Cyclosporine as stable immunosuppressant therapy. The subjects also received Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food, Daclatasvir (DCV) 60 mg tablet once daily and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.
    Arm type
    		 Immunosuppressant therapy

    Investigational medicinal product name
    Cyclosporine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Cyclosporine as stable immunosuppressant therapy.

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food for 24 weeks.

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Daclatasvir (DCV) 60 mg tablet once daily for 24 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.

    Arm title
    		 Tacrolimus
    Arm description
    		 Subjects received Tacrolimus as stable immunosuppressant therapy. The subjects also received Simeprevir (SMV) 150 milligram (mg ) once daily capsule administered with food, Daclatasvir (DCV) 60 mg once daily tablet and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.
    Arm type
    		 Immunosuppressant therapy.

    Investigational medicinal product name
    Tacrolimus
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Tacrolimus as stable immunosuppressant therapy.

    Investigational medicinal product name
    Simeprevir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food for 24 weeks.

    Investigational medicinal product name
    Daclatasvir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Daclatasvir (DCV) 60 mg tablet once daily for 24 weeks.

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects received Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.

    Number of subjects in period 1
    		Cyclosporine Tacrolimus
    Started
    10
    25
    Completed
    10
    23
    Not completed
    0
    2
         Adverse event, serious fatal
    -
    1
         Consent withdrawn by subject
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Cyclosporine
    Reporting group description
    		 Subjects received Cyclosporine as stable immunosuppressant therapy. The subjects also received Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food, Daclatasvir (DCV) 60 mg tablet once daily and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.

    Reporting group title
    Tacrolimus
    Reporting group description
    		 Subjects received Tacrolimus as stable immunosuppressant therapy. The subjects also received Simeprevir (SMV) 150 milligram (mg ) once daily capsule administered with food, Daclatasvir (DCV) 60 mg once daily tablet and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.

    Reporting group values
    		 Cyclosporine Tacrolimus Total
    Number of subjects
    		 10 25 35
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 7 19 26
        From 65 to 84 years
    		 3 6 9
        85 years and over
    		 0 0 0
    Title for AgeContinuous
    Units: years
        median (full range (min-max))
    		 64.5 (52 to 69) 61 (27 to 69) -
    Title for Gender
    Units: subjects
        Female
    		 4 9 13
        Male
    		 6 16 22

    End points

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    End points reporting groups
    Reporting group title
    Cyclosporine
    Reporting group description
    		 Subjects received Cyclosporine as stable immunosuppressant therapy. The subjects also received Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food, Daclatasvir (DCV) 60 mg tablet once daily and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.

    Reporting group title
    Tacrolimus
    Reporting group description
    		 Subjects received Tacrolimus as stable immunosuppressant therapy. The subjects also received Simeprevir (SMV) 150 milligram (mg ) once daily capsule administered with food, Daclatasvir (DCV) 60 mg once daily tablet and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.

    Subject analysis set title
    Simeprevir
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of Simeprevir (Part 1 and Part 2) and with serial PK Blood samples.

    Subject analysis set title
    Daclatasvir
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of Daclatasvir (Part 1 and Part 2) and with serial PK Blood samples.

    Primary: Percentage of Subjects With A Sustained Virologic Response (SVR)12 Weeks After The End of Treatment

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    End point title
    		 Percentage of Subjects With A Sustained Virologic Response (SVR)12 Weeks After The End of Treatment [1]
    End point description
    Sustained Virologic Response (SVR) 12 is defined as the proportion of subjects (ITT analysis set) hepatitis C virus HCV RNA < 25 IU/mL detectable or undetectable at 12 weeks after the end of treatment. Intend to treat (ITT) population includes subjects who received at least 1 dose of investigational medication (SMV, DCV and/or RBV).
    End point type
    Primary
    End point timeframe
    Week 36
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    End point values
    		 Cyclosporine Tacrolimus
    Number of subjects analysed
    10
    25
    Units: Percentage of subjects
        number (confidence interval 95%)
    100 (69.2 to 100)
    88 (68.8 to 97.5)
    No statistical analyses for this end point

    Primary: Maximum Observed Whole Blood Concentration (Cmax) of Cyclosporine (CsA)

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    End point title
    		 Maximum Observed Whole Blood Concentration (Cmax) of Cyclosporine (CsA) [2] [3]
    End point description
    The Whole blood Concentration (Cmax) is defined as maximum observed analyte concentration. Pharmacokinetic (PK) population included all randomized subjects who received at least serial dose of the study drug and with 1 PK blood samples.
    End point type
    Primary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose taken on Day -1 and Day 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: Descriptive statistical analysis has been performed for this endpoint.
    [3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistical analysis has been performed for this endpoint..
    End point values
    		 Cyclosporine
    Number of subjects analysed
    10
    Units: nanogram per milliliter (ng/mL)
    arithmetic mean (standard deviation)
        Cyclosporine (CsA): Day -1
    487 ± 243
        (CsA+ SMV+DCV+RBV)): Day 14
    379 ± 198
    No statistical analyses for this end point

    Primary: Trough Whole Blood Concentration (Ctrough) of Cyclosporine

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    End point title
    		 Trough Whole Blood Concentration (Ctrough) of Cyclosporine [4] [5]
    End point description
    The Ctrough is the whole blood concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen. Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of the study drug and with 1 PK blood sample.
    End point type
    Primary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) sample taken on Day -1 and Day 14
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    [5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    End point values
    		 Cyclosporine
    Number of subjects analysed
    10
    Units: nanogram per milligram (ng/mL)
    arithmetic mean (standard deviation)
        Cyclosporine (CsA): Day -1
    79.1 ± 44.2
        (CsA+ SMV+DCV+RBV)): Day 14
    99.9 ± 60.7
    No statistical analyses for this end point

    Primary: Area Under the Whole Blood Concentration-Time Curve From Time Zero to 24 Time (AUC[0-24]) of Cyclosporine

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    End point title
    		 Area Under the Whole Blood Concentration-Time Curve From Time Zero to 24 Time (AUC[0-24]) of Cyclosporine [6] [7]
    End point description
    The AUC (0-24) is the area under the whole blood concentration-time curve during 24 hour time. Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of the study drug and with serial PK blood samples. Here 'n' indicates the number of subjects analysed for this endpoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose on day -1 and day 14
    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: Descriptive statistical analysis has been performed for this endpoint.
    [7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    End point values
    		 Cyclosporine
    Number of subjects analysed
    7
    Units: nanogram hour per milliliter (ng.h/mL)
    arithmetic mean (standard deviation)
        Cyclosporine (CsA): Day -1 (n=5)
    4066 ± 2742
        (CsA+ SMV+DCV+RBV)): Day 14 (n=7)
    4141 ± 2594
    No statistical analyses for this end point

    Primary: Maximum Observed Whole Blood Concentration (Cmax) of Tacrolimus (Tac)

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    End point title
    		 Maximum Observed Whole Blood Concentration (Cmax) of Tacrolimus (Tac) [8] [9]
    End point description
    The whole blood concentration (Cmax) is defined as maximum observed analyte concentration. Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of the study drug and with 1 PK blood sample. Here 'n' indicates number of subjects analysed for this endpoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) taken on Day -1 and Day 14
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    End point values
    		 Tacrolimus
    Number of subjects analysed
    25
    Units: nanogram per milligram (ng/mL)
    arithmetic mean (standard deviation)
        Part 1: Tac (Day-1: n=11)
    10.5 ± 3.44
        Part 1: Tac + SMV + DCV + RBV (Day 14: n=11)
    7.52 ± 2.3
        Part 2: Tac (Day -1: n=13)
    10.9 ± 8.13
        Part 2: Tac + SMV + DCV + RBV (Day 14: n=14)
    9 ± 4.81
    No statistical analyses for this end point

    Primary: Trough Whole Blood Concentration (Ctrough) of Tacrolimus

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    End point title
    		 Trough Whole Blood Concentration (Ctrough) of Tacrolimus [10] [11]
    End point description
    The Ctrough is the whole blood concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen. Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of the study drug and with 1 PK blood sample. Here 'n' indicates number of subjects analysed for this endpoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) on Day -1 and Day 14.
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    End point values
    		 Tacrolimus
    Number of subjects analysed
    25
    Units: nanogram per milligram (ng/mL)
    arithmetic mean (standard deviation)
        Part 1: Tac (Day-1: n=9)
    6.03 ± 2.03
        Part 1: Tac + SMV + DCV + RBV (Day 14: n=11)
    4.77 ± 2.01
        Part 2: Tac (Day -1: n=13)
    4.71 ± 2.08
        Part 2: Tac + SMV + DCV + RBV (Day 14: n=14)
    4.82 ± 1.82
    No statistical analyses for this end point

    Primary: Area Under the Whole Blood Concentration-Time Curve From Time Zero to 24 Hour Time (AUC[0-24h]) of Tacrolimus

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    End point title
    		 Area Under the Whole Blood Concentration-Time Curve From Time Zero to 24 Hour Time (AUC[0-24h]) of Tacrolimus [12] [13]
    End point description
    The AUC (0-24 h) is the area under the whole blood concentration-time curve from during 24 hour time. Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of the study drug and with serial PK blood samples. Here 'n' indicates number of subjects analysed for this endpoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose taken on Day -1 and Day 14 after tacrolimus dose
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    End point values
    		 Tacrolimus
    Number of subjects analysed
    25
    Units: nanogram hour per milliliter (ng.h/mL)
    arithmetic mean (standard deviation)
        Part 1: Tac (Day-1: n=9)
    177 ± 58.1
        Part 1: Tac + SMV + DCV + RBV (Day 14: n=10)
    129 ± 50.2
        Part 2: Tac (Day -1: n=13)
    147 ± 69
        Part 2: Tac + SMV + DCV + RBV (Day 14: n=14)
    144 ± 56.7
    No statistical analyses for this end point

    Primary: Maximum Observed Plasma Concentration (Cmax) of Simeprevir (SMV) and Daclatasvir (DCV)

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    End point title
    		 Maximum Observed Plasma Concentration (Cmax) of Simeprevir (SMV) and Daclatasvir (DCV) [14]
    End point description
    The plasma concentration (Cmax) is defined as maximum observed analyte concentration. Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of the study drug and with 1 PK blood sample. Here 'n' indicates number of subjects analysed for this endpoint.
    End point type
    Primary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose taken on Day 14
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Descriptive statistical analysis has been performed for this endpoint.
    End point values
    		 Simeprevir Daclatasvir
    Number of subjects analysed
    14
    13
    Units: nanogram per milligram (ng/mL)
    arithmetic mean (standard deviation)
        Part 1: CsA+SMV+DCV+RBV: Day 14 (n=10,10)
    17640 ± 9365
    2532 ± 1736
        Part 1: Tac+SMV+DCV+RBV: Day 14 (n=11,9)
    6897 ± 4620
    1632 ± 589
        Part 2: Tac+SMV+DCV+RBV: Day 14 (n=14,13)
    7764 ± 5402
    1310 ± 779
    No statistical analyses for this end point

    Secondary: Trough Plasma Concentration (Ctrough) of Simeprevir (SMV) And Daclatasvir (DCV)

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    End point title
    		 Trough Plasma Concentration (Ctrough) of Simeprevir (SMV) And Daclatasvir (DCV)
    End point description
    The Ctrough is the plasma concentration before dosing or at the end of the dosing interval of any dose other than the first dose in a multiple dosing regimen. Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of the study drug and with 1 PK blood sample. Here 'n' indicates number of subjects analysed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) and taken on day 14, week 4, 8 and 12.
    End point values
    		 Simeprevir Daclatasvir
    Number of subjects analysed
    14
    13
    Units: nanogram per milligram (ng/mL)
    arithmetic mean (standard deviation)
        Part 1: CsA+SMV+DCV+RBV: Day 14 (n=10,10)
    11653 ± 8338
    1368 ± 1319
        Part 1: Tac+SMV+DCV+RBV: Day 14 (n=11,9)
    2589 ± 3131
    564 ± 524
        Part 2: Tac+SMV+DCV+RBV: Day 14 (n=14, 13)
    3457 ± 3852
    468 ± 437
    No statistical analyses for this end point

    Secondary: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Simeprevir (SMV) and Daclatasvir (DCV)

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    End point title
    		 Time to Reach Maximum Observed Plasma Concentration (Tmax) of Simeprevir (SMV) and Daclatasvir (DCV)
    End point description
    The Tmax is defined as actual sampling time to reach maximum observed analyte concentration. Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of the study drug and with 1 PK blood sample. Here 'n' indicates number of subjects analysed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose on Week 2
    End point values
    		 Simeprevir Daclatasvir
    Number of subjects analysed
    14
    13
    Units: hour (h)
    median (full range (min-max))
        Part 1: CsA+SMV+DCV+RBV: Day 14 (n=10,10)
    5 (4.92 to 9)
    3.5 (1 to 6)
        Part 1: Tac+SMV+DCV+RBV: Day 14 (n=11,9)
    5.58 (2 to 9.03)
    2 (0.92 to 6)
        Part 2: Tac+SMV+DCV+RBV: Day 14 (n=14, 13)
    6 (4 to 9)
    3.92 (1 to 6)
    No statistical analyses for this end point

    Secondary: Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Simeprevir (SMV) and Daclatasvir (DCV)

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    End point title
    		 Area Under the Curve From Time Zero to End of Dosing Interval (AUCtau) of Simeprevir (SMV) and Daclatasvir (DCV)
    End point description
    The AUCtau is the measure of the plasma drug concentration from time zero to end of dosing interval. It is used to characterize drug absorption. Pharmacokinetic (PK) population included all randomized subjects who received at least 1 dose of the study drug and with 1 PK blood sample. Here 'n' indicates number of subject analysed for this endpoint.
    End point type
    Secondary
    End point timeframe
    Pre-dose (within 15 minutes before the intake of study drug) and 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 12, and 24 hours post-dose taken on Day 14
    End point values
    		 Simeprevir Daclatasvir
    Number of subjects analysed
    14
    13
    Units: nanogram hour per milliliter (ng.h/mL)
    arithmetic mean (standard deviation)
        Part 1: CsA+SMV+DCV+RBV: Day 14 (n=10,10)
    339848 ± 205582
    46114 ± 37087
        Part 1: Tac+SMV+DCV+RBV: Day 14 (n=11,9)
    107792 ± 89990
    22349 ± 11376
        Part 2: Tac+SMV+DCV+RBV: Day 14 (n=14,13)
    116242 ± 96234
    18441 ± 13379
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With A Sustained Virologic Response (SVR) 4 And 24 Weeks After The End of Treatment

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    End point title
    		 Percentage of Subjects With A Sustained Virologic Response (SVR) 4 And 24 Weeks After The End of Treatment
    End point description
    SVR 4 and SVR 24 are defined as the proportion of subjects with HCV RNA <25 IU/mL detectable or undetectable at the hepatitis C virus (HCV) ribonucleic acid (RNA) <25 IU/mL detectable or undetectable at week 4 or week 24 after the end of treatment, respectively. Intent to treat (ITT) population includes subjects who received at least 1 dose of investigational medication (SMV, DCV and/or RBV).
    End point type
    Secondary
    End point timeframe
    Week 28 and 48
    End point values
    		 Cyclosporine Tacrolimus
    Number of subjects analysed
    10
    25
    Units: Percentage of subjects
    number (confidence interval 95%)
        SVR 4
    100 (69.2 to 100)
    88 (68.8 to 97.5)
        SVR 24
    100 (69.2 to 100)
    88 (68.8 to 97.5)
    No statistical analyses for this end point

    Secondary: On-Treatment Virologic Response With Undetectable HCV RNA (less than 25 IU/mL undetectable) and HCV RNA Detectable Less Than 25 IU/mL Detectable

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    End point title
    		 On-Treatment Virologic Response With Undetectable HCV RNA (less than 25 IU/mL undetectable) and HCV RNA Detectable Less Than 25 IU/mL Detectable
    End point description
    Rapid virologic response (RVR), defined as undetectable HCV RNA at Week 4 of treatment; extended rapid virologic response (eRVR), defined as undetectable HCV RNA at Week 4 and Week 12 of treatment and complete early virologic response (cEVR), defined as undetectable HCV RNA at Week 12. RVR signifies Rapid virologic response: undetectable HCV RNA at Week 4 while on treatment. cEVR signifies Complete early rapid virologic response: undetectable HCV RNA at Week 12 while on treatment. eRVR signifies extended Rapid Virologic Response: undetectable HCV RNA at Week 4 and Week 12 while on treatment. Intent to treat (ITT) population includes subjects who received at least 1 dose of investigational medication (SMV, DCV and/or RBV).
    End point type
    Secondary
    End point timeframe
    Up to end of treatment (Weeks 2, 4, 12, and 24)
    End point values
    		 Cyclosporine Tacrolimus
    Number of subjects analysed
    10
    25
    Units: International Unit per milliliter(IU/mL)
    number (not applicable)
        Week 2 (<25 IU/mL detectable)
    3
    9
        Week 2 (<25 IU/mL undetectable)
    1
    3
        Week 4 (<25 IU/mL detectable)
    3
    6
        Week 4 (<25 IU/mL undetectable)(RVR)
    7
    17
        Week 12 (<25 IU/mL undetectable) (cEVR)
    10
    24
        Week 24 (<25 IU/mL undetectable)
    10
    21
        Week 4 and Week 12 (<25 IU/mL undetectable) (eRVR)
    7
    16
        EOT (<25 IU/mL undetectable)
    10
    22
    No statistical analyses for this end point

    Secondary: Number of Subjects With On-Treatment Failure After Treatment With Regimen Simeprevir, Daclatasvir and RBV

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    End point title
    		 Number of Subjects With On-Treatment Failure After Treatment With Regimen Simeprevir, Daclatasvir and RBV
    End point description
    On-treatment failure is defined as HCV RNA level is greater than or equal to 25 IU/mL at end of treatment. Intent to treat (ITT) population includes subjects who received at least 1 dose of investigational medication (SMV, DCV and/or RBV).
    End point type
    Secondary
    End point timeframe
    Screening, Baseline and Week 1 to 24
    End point values
    		 Cyclosporine Tacrolimus
    Number of subjects analysed
    10
    11
    Units: Number of subjects
    0
    3
    No statistical analyses for this end point

    Secondary: Number of Subjects With Adverse Events

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    End point title
    		 Number of Subjects With Adverse Events
    End point description
    An AE is any untoward medical occurrence in a subject who received study drug without regard to possibility of causal relationship. An SAE is an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly. Safety population included all randomized subjects who received at least 1 dose of the study drug.
    End point type
    Secondary
    End point timeframe
    Up to 48 Weeks
    End point values
    		 Cyclosporine Tacrolimus
    Number of subjects analysed
    10
    25
    Units: Number of Subjects
    10
    25
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Screening to Follow-up (up to 24 Weeks after actual end of treatment)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Cyclosporine
    Reporting group description
    		 Subjects received Cyclosporine as stable immunosuppressant therapy. The subjects also received Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food, Daclatasvir (DCV) 60 mg tablet once daily and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.

    Reporting group title
    Tacrolimus
    Reporting group description
    		 Subjects received Tacrolimus as stable immunosuppressant therapy. The subjects also received Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food, Daclatasvir (DCV) 60 mg tablet once daily and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.

    Reporting group title
    Overall
    Reporting group description
    		 All the subjects received Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food, Daclatasvir (DCV) 60 mg tablet once daily and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks.

    Reporting group title
    Cyclosporine Follow-Up
    Reporting group description
    		 Subjects received Cyclosporine as stable immunosuppressant therapy. Follow-up Period after treatment with Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food, Daclatasvir (DCV) 60 mg tablet once daily and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg)with food for 24 weeks after the treatment has been stopped.

    Reporting group title
    Tacrolimus Follow-Up
    Reporting group description
    		 Subjects received tacrolimus as stable immunosuppressant therapy. Follow-up Period after treatment with Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food, Daclatasvir (DCV) 60 mg tablet once daily and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg)with food for 24 weeks after the treatmant has been stopped.

    Reporting group title
    Overall Follow-Up
    Reporting group description
    		 Follow-up Period after treatment with Simeprevir (SMV) 150 milligram (mg ) capsule administered once daily with food, Daclatasvir (DCV) 60 mg tablet once daily and Ribavirin (RBV) 1,000 or 1,200 mg/day (bid regimen) tablet (5/6 x 200 mg) with food for 24 weeks after the treatment has been stopped.

    Serious adverse events
    		 Cyclosporine Tacrolimus Overall Cyclosporine Follow-Up Tacrolimus Follow-Up Overall Follow-Up
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 10 (40.00%)
    4 / 25 (16.00%)
    8 / 35 (22.86%)
    1 / 10 (10.00%)
    3 / 25 (12.00%)
    4 / 35 (11.43%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Lymphoma
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Facial bones fracture
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Hepatic encephalopathy
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lymphocytosis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 10 (30.00%)
    0 / 25 (0.00%)
    3 / 35 (8.57%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 3
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Abdominal pain upper
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritoneal haemorrhage
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Vomiting
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Prostatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholestasis
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Micturition disorder
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal impairment
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Empyema
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Escherichia urinary tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Genital herpes
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peritonitis bacterial
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin infection
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Cyclosporine Tacrolimus Overall Cyclosporine Follow-Up Tacrolimus Follow-Up Overall Follow-Up
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    10 / 10 (100.00%)
    23 / 25 (92.00%)
    33 / 35 (94.29%)
    2 / 10 (20.00%)
    3 / 25 (12.00%)
    5 / 35 (14.29%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 25 (12.00%)
    3 / 35 (8.57%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    3
    3
    0
    0
    0
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 10 (50.00%)
    7 / 25 (28.00%)
    12 / 35 (34.29%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    5
    8
    13
    0
    0
    0
    Fatigue
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 25 (4.00%)
    3 / 35 (8.57%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    2
    1
    3
    0
    0
    0
    Gait disturbance
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    General physical health deterioration
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 25 (8.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Mucous membrane disorder
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Oedema peripheral
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Pyrexia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 25 (4.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    5
    2
    7
    0
    0
    0
    Reproductive system and breast disorders
    Vulvovaginal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    2 / 10 (20.00%)
    3 / 25 (12.00%)
    5 / 35 (14.29%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    3
    3
    6
    0
    0
    0
    Dysphonia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Dyspnoea
         subjects affected / exposed
    2 / 10 (20.00%)
    1 / 25 (4.00%)
    3 / 35 (8.57%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    2
    1
    3
    0
    0
    0
    Productive cough
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Pulmonary hypertension
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Psychiatric disorders
    Anger
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 25 (4.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    Hallucination, visual
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 25 (8.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    9
    9
    0
    0
    0
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Congenital, familial and genetic disorders
    Cataract congenital
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Headache
         subjects affected / exposed
    1 / 10 (10.00%)
    4 / 25 (16.00%)
    5 / 35 (14.29%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    4
    5
    0
    0
    0
    Restless legs syndrome
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    7 / 10 (70.00%)
    11 / 25 (44.00%)
    18 / 35 (51.43%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    17
    16
    33
    0
    0
    0
    Haemolytic anaemia
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 25 (8.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Leukopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 25 (4.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences all number
    2
    2
    4
    0
    1
    1
    Thrombocytopenia
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    2
    0
    2
    0
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 10 (0.00%)
    3 / 25 (12.00%)
    3 / 35 (8.57%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    3
    3
    0
    0
    0
    Eye disorders
    Ocular icterus
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 25 (4.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    Visual acuity reduced
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Aphthous stomatitis
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 25 (4.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    Constipation
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 25 (4.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    Diarrhoea
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 25 (12.00%)
    4 / 35 (11.43%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    3
    4
    0
    0
    0
    Haemorrhoids
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    Lip dry
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Nausea
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 25 (12.00%)
    4 / 35 (11.43%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    5
    6
    0
    0
    0
    Tongue dry
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 25 (8.00%)
    3 / 35 (8.57%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    4
    5
    0
    0
    0
    Hepatobiliary disorders
    Cholangitis
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    2 / 10 (20.00%)
    2 / 25 (8.00%)
    4 / 35 (11.43%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    6
    7
    13
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dry skin
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 25 (8.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Erythema
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Photosensitivity reaction
         subjects affected / exposed
    1 / 10 (10.00%)
    3 / 25 (12.00%)
    4 / 35 (11.43%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    3
    4
    0
    0
    0
    Pruritus
         subjects affected / exposed
    1 / 10 (10.00%)
    5 / 25 (20.00%)
    6 / 35 (17.14%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences all number
    1
    6
    7
    0
    1
    1
    Rash
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 25 (4.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    2
    3
    0
    0
    0
    Renal and urinary disorders
    Renal failure
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 25 (8.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Muscle spasms
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Myalgia
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 25 (8.00%)
    3 / 35 (8.57%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    2
    3
    0
    0
    0
    Infections and infestations
    Oral candidiasis
         subjects affected / exposed
    0 / 10 (0.00%)
    2 / 25 (8.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    0
    2
    2
    0
    0
    0
    Oral herpes
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 25 (4.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    1 / 25 (4.00%)
    1 / 35 (2.86%)
         occurrences all number
    2
    1
    3
    0
    1
    1
    Urinary tract infection
         subjects affected / exposed
    1 / 10 (10.00%)
    2 / 25 (8.00%)
    3 / 35 (8.57%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    2
    3
    0
    0
    0
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    0
    1
    0
    0
    0
    Hyperuricaemia
         subjects affected / exposed
    1 / 10 (10.00%)
    1 / 25 (4.00%)
    2 / 35 (5.71%)
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
         occurrences all number
    1
    1
    2
    0
    0
    0
    Hyposideraemia
         subjects affected / exposed
    0 / 10 (0.00%)
    0 / 25 (0.00%)
    0 / 35 (0.00%)
    1 / 10 (10.00%)
    0 / 25 (0.00%)
    1 / 35 (2.86%)
         occurrences all number
    0
    0
    0
    1
    0
    1

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2013
    The amendement included the addition of precautionary language on photosensitivity to the Prohibitions and Restrictions section of the protocol. As a follow-up to a recommendation by the US Food and Drug Administration (FDA), it was decided to reintroduce the recommendations with regard to photosensitivity, in all Simeprevir (SMV) studies in which subjects were still being dosed with SMV and in future SMV studies.
    30 Jun 2014
    The amendment included changes based on Day 14 pharmacokinetic results from subjects enrolled in Part 1 of the study, subjects who received cyclosporine as immunosuppressant therapy were excluded from Part 2 of the study. Repeat intensive pharmacokinetic sampling to be performed in those Part 1 subjects receiving cyclosporine and whose Simeprevir (SMV) doses were adjusted was added. Repeat intensive pharmacokinetic sampling for SMV and Daclatasvir (DCV) in Part 2 subjects was added in case revision to the dose and/or dosing regimen of SMV and/or DCV were made based on the Week 4 interim analyses. Given the fact that, after review of the Phase 3 data, elevations in direct and indirect bilirubin observed in Phase 3 clinical studies were not considered clinically relevant, specific management of grade 4 isolated bilirubin elevations was updated. Subjects with isolated grade 4 bilirubin elevation in absence of evidence of hepatic decompensation could continue intake of study medication with close monitoring of further increases in bilirubin, or discontinue, at the discretion of the investigator. In addition, rash management guidelines were clarified for photosensitivity conditions. Background information on the study drug was updated (replacement HPC2002 data with data from Phase 2 study AI-444-062) and marketing status of SMV was added (approval US and other regions and ongoing procedures worldwide). Definitions of SVR and treatment failure were revised as per Heath Authority recommendations. Clarification that the screening period of 4 weeks started from the time of signing the Informed Consent Form (ICF) was added. The possibility to have additional interim analyses for Health Authority submission and publication purpose was added. It was clarified that one hepatitis C virus (HCV RNA) retest had to be performed as soon as possible if Week 4 HCV RNA is >100 IU/mL and that subjects could continue study drug if HCV RNA is ≤100 International Unit per at the retest.

    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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