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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled trial of the efficacy and safety of DEB025/Alisporivir in combination with peg-IFN alfa2a and ribavirin in hepatitis C genotype 1 treatment-naïve patients

    Summary
    EudraCT number
    		 2010-022867-37
    Trial protocol
    		 HU   DE   BE   GB   PL   IT   ES  
    Global end of trial date
    13 Aug 2013

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2016
    First version publication date
    29 Jul 2015
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CDEB025A2301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01318694
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    CH-4002, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 61-324-1111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, +41 61-324-1111,
    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
    13 Aug 2013
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Aug 2013
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to demonstrate that in treatment-naïve chronic hepatitis C genotype 1 patients triple therapy with DEB025 plus peg-IFNα2a/RBV leads to a superior SVR12 rate as compared to dual therapy with peg-IFNα2a/RBV.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United States: 126
    Country: Number of subjects enrolled
    Australia: 21
    Country: Number of subjects enrolled
    Korea, Republic of: 76
    Country: Number of subjects enrolled
    Taiwan: 58
    Country: Number of subjects enrolled
    Thailand: 88
    Country: Number of subjects enrolled
    Vietnam: 70
    Country: Number of subjects enrolled
    Hong Kong: 19
    Country: Number of subjects enrolled
    Russian Federation: 90
    Country: Number of subjects enrolled
    Argentina: 19
    Country: Number of subjects enrolled
    Mexico: 18
    Country: Number of subjects enrolled
    Canada: 47
    Country: Number of subjects enrolled
    Romania: 95
    Country: Number of subjects enrolled
    Spain: 21
    Country: Number of subjects enrolled
    United Kingdom: 36
    Country: Number of subjects enrolled
    Belgium: 11
    Country: Number of subjects enrolled
    France: 17
    Country: Number of subjects enrolled
    Germany: 46
    Country: Number of subjects enrolled
    Poland: 81
    Country: Number of subjects enrolled
    Hungary: 53
    Country: Number of subjects enrolled
    Italy: 85
    Worldwide total number of subjects
    1077
    EEA total number of subjects
    445
    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)
    1045
    From 65 to 84 years
    32
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Of the 1081 patients included in the randomized set, 4 patients were excluded from the Full Analysis Set (FAS) due to mis-randomization related to information entered in the IVRS system by mistake. These patients did not have a baseline visit and never started study medication.

    Pre-assignment
    Screening details
    		 Participants were screened for eligibility over a period of 42 days.

    Period 1
    Period 1 title
    Double-blind Treatment
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The identity of the treatments was concealed by the use of study drugs that were all identical in packaging, labeling, schedule of administration, appearance, taste, and odor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A: Alisporivir 600 QD RGT
    Arm description
    		 Triple therapy with a response-guided treatment duration (see below) with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for an additional 23 or 47 weeks based on week 4 hepatitis C virus (HCV) RNA results. Response guided treatment: • Patients with a viral load below the level of detection (LOD) at week 4 (< RVR4LOD) had to stop P/R and alisporivir study medications after 24 weeks. • Patients with a viral load at or above the LOD at week 4 (≥ RVR4LOD) had to complete 48 weeks of P/R and alisporivir study treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alisporivir
    Investigational medicinal product code
    Other name
    DEB025
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Three 200 mg soft gel capsules: twice daily (BID) for Week 1, once daily (QD) in the morning the remaining weeks

    Investigational medicinal product name
    Peg-IFNα2a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Weekly dose of 180 μg

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg tablets; patients < 75 Kg body weight at screening: 1000 mg daily, with 2 tablets in the morning and 3 tablets in the evening; ≥ 75 Kg: 1200 mg daily, with 3 tablets in the morning and 3 tablets in the evening. If a patient’s weight increased from < 75 Kg to ≥ 75 Kg, the investigator could increase the dose to 1200 mg per day as per clinical practice. Likewise, the investigator could lower the dose from 1200 mg/day to 1000 mg/day as per clinical practice if the patient’s weight decreased from ≥ 75 Kg to < 75 Kg.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Two placebo capsules to match alisporivir, QD in the evening after Week 1

    Arm title
    		 Arm B: Alisporivir 400 BID RGT
    Arm description
    		 Triple therapy with a response-guided treatment duration (see below) with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 400 mg twice daily (BID) for 24 or 48 weeks based on week 4 hepatitis C virus (HCV) RNA results. Response guided treatment: • Patients with a viral load below the level of detection (LOD) at week 4 (< RVR4LOD) had to stop P/R and alisporivir study medications after 24 weeks. • Patients with a viral load at or above the LOD at week 4 (≥ RVR4LOD) had to complete 48 weeks of P/R and alisporivir study treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alisporivir
    Investigational medicinal product code
    Other name
    DEB025
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Two 200 mg soft gel capsules BID for the duration of treatment

    Investigational medicinal product name
    Peg-IFNα2a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Weekly dose of 180 μg

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg tablets; patients < 75 Kg body weight at screening: 1000 mg daily, with 2 tablets in the morning and 3 tablets in the evening; ≥ 75 Kg: 1200 mg daily, with 3 tablets in the morning and 3 tablets in the evening. If a patient’s weight increased from < 75 Kg to ≥ 75 Kg, the investigator could increase the dose to 1200 mg per day as per clinical practice. Likewise, the investigator could lower the dose from 1200 mg/day to 1000 mg/day as per clinical practice if the patient’s weight decreased from ≥ 75 Kg to < 75 Kg.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    One placebo capsule to match alisporivir: BID for Week 1, QD in the morning of remaining weeks

    Arm title
    		 Arm C: Alisporivir 600 QD
    Arm description
    		 Fixed-duration triple therapy with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for an additional 47 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alisporivir
    Investigational medicinal product code
    Other name
    DEB025
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Three 200 mg soft gel capsules: BID for Week 1, QD in the morning the remaining weeks

    Investigational medicinal product name
    Peg-IFNα2a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Weekly dose of 180 μg

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg tablets; patients < 75 Kg body weight at screening: 1000 mg daily, with 2 tablets in the morning and 3 tablets in the evening; ≥ 75 Kg: 1200 mg daily, with 3 tablets in the morning and 3 tablets in the evening. If a patient’s weight increased from < 75 Kg to ≥ 75 Kg, the investigator could increase the dose to 1200 mg per day as per clinical practice. Likewise, the investigator could lower the dose from 1200 mg/day to 1000 mg/day as per clinical practice if the patient’s weight decreased from ≥ 75 Kg to < 75 Kg.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Two placebo capsules to match alisporivir, QD in the evening after Week 1

    Arm title
    		 Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Arm description
    		 Therapy with P/R and placebo for 48 weeks.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Week 1: three placebo capsules BID to match alisporivir; remaining weeks: three placebo capsules QD in the morning and two placebo capsules QD in the evening

    Investigational medicinal product name
    Peg-IFNα2a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Weekly dose of 180 μg

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg tablets; patients < 75 Kg body weight at screening: 1000 mg daily, with 2 tablets in the morning and 3 tablets in the evening; ≥ 75 Kg: 1200 mg daily, with 3 tablets in the morning and 3 tablets in the evening. If a patient’s weight increased from < 75 Kg to ≥ 75 Kg, the investigator could increase the dose to 1200 mg per day as per clinical practice. Likewise, the investigator could lower the dose from 1200 mg/day to 1000 mg/day as per clinical practice if the patient’s weight decreased from ≥ 75 Kg to < 75 Kg.

    Number of subjects in period 1
    		Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Started
    274
    270
    265
    268
    Completed treatment at week 24
    96 [1]
    94 [2]
    1 [3]
    0 [4]
    Completed treatment at week 48
    114 [5]
    98 [6]
    184 [7]
    170
    Completed
    210
    192
    185
    170
    Not completed
    64
    78
    80
    98
         Adverse event, serious fatal
    -
    1
    -
    -
         Patient withdrew consent
    11
    14
    12
    12
         Adverse event, non-fatal
    17
    33
    31
    13
         Unsatisfactory therapeutic effect
    22
    21
    26
    63
         Administrative problems
    -
    -
    1
    -
         Non-compliance
    4
    4
    6
    7
         Lost to follow-up
    6
    4
    3
    2
         Protocol deviation
    4
    1
    1
    1
    Notes
    [1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Complete treatment after 24 weeks is decided based on if the HCV RNA was below the limit of detection (LOD) after 4 weeks of treatment (Rapid Virologic Response – RVR).
    [2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Complete treatment after 24 weeks is decided based on if the HCV RNA was below the limit of detection (LOD) after 4 weeks of treatment (Rapid Virologic Response – RVR).
    [3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The treatment duration for this arm is 48 weeek.
    [4] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: The treatment duration for this arm is 48 week.
    [5] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Complete treatment after 48 weeks is decided as patients with a viral load at or above the level of detection (LOD) at week 4 (≥ RVR4LOD)
    [6] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Complete treatment after 48 weeks is decided as patients with a viral load at or above the level of detection (LOD) at week 4 (≥ RVR4LOD)
    [7] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
    Justification: Complete treatment after 48 weeks is decided as patients with a viral load at or above the level of detection (LOD) at week 4 (≥ RVR4LOD)
    Period 2
    Period 2 title
    Open-label treatment
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Open-label ALV600 QD
    Arm description
    		 Patients from the Peg-IFNα2a and Ribavirin (P/R) plus Alisporivir Placebo group who failed to achieve a decrease greater than or equal to 2 log10 from baseline in serum hepatitis C virus (HCV) RNA concentration at any time within the first 12 weeks of treatment (Null non-responder), had a viral load above the level of detection (LOQ) at week 24, or had a viral breakthrough were offered open-label treatment with P/R plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for 47 weeks with 24 weeks of treatment-free follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Alisporivir
    Investigational medicinal product code
    Other name
    DEB025
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Three 200 mg soft gel capsules: BID Week 1 and QD in the morning the remaining 47 weeks

    Investigational medicinal product name
    Peg-IFNα2a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Weekly dose of 180 μg

    Investigational medicinal product name
    Ribavirin
    Investigational medicinal product code
    Other name
    Copegus
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg tablets; patients < 75 Kg body weight at screening: 1000 mg daily, with 2 tablets in the morning and 3 tablets in the evening; ≥ 75 Kg: 1200 mg daily, with 3 tablets in the morning and 3 tablets in the evening. If a patient’s weight increased from < 75 Kg to ≥ 75 Kg, the investigator could increase the dose to 1200 mg per day as per clinical practice. Likewise, the investigator could lower the dose from 1200 mg/day to 1000 mg/day as per clinical practice if the patient’s weight decreased from ≥ 75 Kg to < 75 Kg.

    Number of subjects in period 2 [8]
    		Open-label ALV600 QD
    Started
    11
    Completed
    3
    Not completed
    8
         Adverse event, non-fatal
    1
         Unsatisfactory therapeutic effect
    6
         Protocol deviation
    1
    Notes
    [8] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Open label treatment is relevant to only one arm of the double blind treatment period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A: Alisporivir 600 QD RGT
    Reporting group description
    		 Triple therapy with a response-guided treatment duration (see below) with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for an additional 23 or 47 weeks based on week 4 hepatitis C virus (HCV) RNA results. Response guided treatment: • Patients with a viral load below the level of detection (LOD) at week 4 (< RVR4LOD) had to stop P/R and alisporivir study medications after 24 weeks. • Patients with a viral load at or above the LOD at week 4 (≥ RVR4LOD) had to complete 48 weeks of P/R and alisporivir study treatment.

    Reporting group title
    Arm B: Alisporivir 400 BID RGT
    Reporting group description
    		 Triple therapy with a response-guided treatment duration (see below) with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 400 mg twice daily (BID) for 24 or 48 weeks based on week 4 hepatitis C virus (HCV) RNA results. Response guided treatment: • Patients with a viral load below the level of detection (LOD) at week 4 (< RVR4LOD) had to stop P/R and alisporivir study medications after 24 weeks. • Patients with a viral load at or above the LOD at week 4 (≥ RVR4LOD) had to complete 48 weeks of P/R and alisporivir study treatment.

    Reporting group title
    Arm C: Alisporivir 600 QD
    Reporting group description
    		 Fixed-duration triple therapy with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for an additional 47 weeks.

    Reporting group title
    Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Reporting group description
    		 Therapy with P/R and placebo for 48 weeks.

    Reporting group values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R) Total
    Number of subjects
    		 274 270 265 268 1077
    Age categorical
    Information on categorical age is provided for the Full Analysis Set (FAS). Four patients were excluded from the FAS due to mis-randomization related to information entered in the interactive voice response system (IVRS) system by mistake. These patients did not have a baseline visit and never started study medications. They were included in the all screened and randomized analysis sets, but excluded from the FAS and safety set (SAF).
    Units: Subjects
        >/=18 to 30 years
    		 28 36 38 26 128
        >30 to 50 years
    		 141 118 124 132 515
        >50 to 65 years
    		 98 111 97 105 411
        >65 to 70 years
    		 7 5 6 5 23
    Age continuous
    Information on age is provided for the Full Analysis Set (FAS). Four patients were excluded from the FAS due to mis-randomization related to information entered in the interactive voice response system (IVRS) system by mistake. These patients did not have a baseline visit and never started study medications. They were included in the all screened and randomized analysis sets, but excluded from the FAS and safety set (SAF).
    Units: years
        arithmetic mean (standard deviation)
    		 45.9 ( 11.08 ) 45.8 ( 11.95 ) 45.5 ( 12.15 ) 46.3 ( 11.53 ) -
    Gender categorical
    Information on gender is provided for the Full Analysis Set (FAS). Four patients were excluded from the FAS due to mis-randomization related to information entered in the interactive voice response system (IVRS) system by mistake. These patients did not have a baseline visit and never started study medications. They were included in the all screened and randomized analysis sets, but excluded from the FAS and safety set (SAF).
    Units: Subjects
        Female
    		 113 106 134 114 467
        Male
    		 161 164 131 154 610

    End points

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    End points reporting groups
    Reporting group title
    Arm A: Alisporivir 600 QD RGT
    Reporting group description
    		 Triple therapy with a response-guided treatment duration (see below) with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for an additional 23 or 47 weeks based on week 4 hepatitis C virus (HCV) RNA results. Response guided treatment: • Patients with a viral load below the level of detection (LOD) at week 4 (< RVR4LOD) had to stop P/R and alisporivir study medications after 24 weeks. • Patients with a viral load at or above the LOD at week 4 (≥ RVR4LOD) had to complete 48 weeks of P/R and alisporivir study treatment.

    Reporting group title
    Arm B: Alisporivir 400 BID RGT
    Reporting group description
    		 Triple therapy with a response-guided treatment duration (see below) with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 400 mg twice daily (BID) for 24 or 48 weeks based on week 4 hepatitis C virus (HCV) RNA results. Response guided treatment: • Patients with a viral load below the level of detection (LOD) at week 4 (< RVR4LOD) had to stop P/R and alisporivir study medications after 24 weeks. • Patients with a viral load at or above the LOD at week 4 (≥ RVR4LOD) had to complete 48 weeks of P/R and alisporivir study treatment.

    Reporting group title
    Arm C: Alisporivir 600 QD
    Reporting group description
    		 Fixed-duration triple therapy with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for an additional 47 weeks.

    Reporting group title
    Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Reporting group description
    		 Therapy with P/R and placebo for 48 weeks.
    Reporting group title
    Open-label ALV600 QD
    Reporting group description
    		 Patients from the Peg-IFNα2a and Ribavirin (P/R) plus Alisporivir Placebo group who failed to achieve a decrease greater than or equal to 2 log10 from baseline in serum hepatitis C virus (HCV) RNA concentration at any time within the first 12 weeks of treatment (Null non-responder), had a viral load above the level of detection (LOQ) at week 24, or had a viral breakthrough were offered open-label treatment with P/R plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for 47 weeks with 24 weeks of treatment-free follow-up.

    Primary: Percent of Patients Who Achieved Sustained Virologic Response by 12 Weeks (SVR12)

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    End point title
    		 Percent of Patients Who Achieved Sustained Virologic Response by 12 Weeks (SVR12) [1]
    End point description
    SVR12 was defined as hepatitis C virus (HCV) RNA less than the limit of quantification (LOQ) at week 12 of follow-up (FU) after stopping treatment. LOQ was defined as HCV RNA < 25 International Units (IU)/mL. For this endpoint, n equals the number of patients who were at the corresponding category, M equals the total number of patients with a value for the corresponding exposure after imputation, and N equals the total number of patients in the treatment group. The percent shown is n/M; the value for "subjects analysed" equals N. This end point analyzed the Full Analysis Set (N), which included all patients to whom study treatment had been assigned.
    End point type
    Primary
    End point timeframe
    12 weeks after treatment completion
    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: Due to the clinical hold, the character of the study status changed from confirmatory to nonconfirmatory. Therefore, statistical comparison planned in the protocol was not done.
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    274 [2]
    270 [3]
    265 [4]
    268 [5]
    Units: percent of patients
    number (not applicable)
        Overall
    68.6
    68.9
    69.4
    52.5
        ≤ 12 weeks of treatment
    30.3
    38.2
    40.6
    30.4
        > 12 to ≤ 16 weeks of treatment
    65.1
    68.1
    65.2
    40.9
        > 16 to ≤ 20 weeks of treatment
    78
    78.8
    79.7
    60.7
        > 20 to ≤ 24 weeks of treatment
    82.5
    80.3
    73.5
    66.7
        > 24 weeks of treatment
    75.6
    90.3
    76.5
    60.4
    Notes
    [2] - M were: Overall = 274; ≤12 = 33; >12-≤16 = 83; >16-≤20 = 59; >20-≤24 = 57; >24 = 41
    [3] - M were: Overall = 270; ≤12 = 55; >12-≤16 = 69; >16-≤20 = 52; >20-≤24 = 61; >24 = 31
    [4] - M were: Overall = 265; ≤12 = 32; >12-≤16 = 69; >16-≤20 = 64; >20-≤24 = 49; >24 = 51
    [5] - M were: Overall = 265; ≤12 = 23; >12-≤16 = 88; >16-≤20 = 56; >20-≤24 = 45; >24 = 53
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Achieved Sustained Virologic Response by 24 Weeks (SVR24)

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    End point title
    		 Percent of Patients Who Achieved Sustained Virologic Response by 24 Weeks (SVR24)
    End point description
    SVR24 was defined as hepatitis C virus (HCV) RNA less than the limit of quantification (LOQ) at week 24 of follow-up (FU) after stopping treatment. LOQ was defined as HCV RNA < 25 International Units (IU)/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    24 weeks after treatment completion
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    273
    268
    265
    265
    Units: percent of patients
        number (not applicable)
    68.5
    69
    68.3
    51.7
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Achieved Extended Rapid Virologic Response (eRVR)

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    End point title
    		 Percent of Patients Who Achieved Extended Rapid Virologic Response (eRVR)
    End point description
    eRVR was defined as RVR less than the limit of quantification (LOQ) achieved and maintained until 12 weeks after the start of treatment. LOQ was defined as HCV RNA < 25 International Units (IU)/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    12 weeks after treatment start
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    259
    242
    247
    256
    Units: percent of patients
        number (not applicable)
    60.2
    71.1
    56.7
    28.1
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Achieved Early Virologic Response (EVR)

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    End point title
    		 Percent of Patients Who Achieved Early Virologic Response (EVR)
    End point description
    EVR was defined as serum hepatitis C virus (HCV) RNA reduction greater than or equal to 2Log10 or serum HCV RNA less than the limit of quantification (LOQ) after 12 weeks of treatment. LOQ was defined as HCV RNA < 25 International Units (IU)/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    12 weeks after treatment start
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    259
    242
    247
    256
    Units: percent of patients
        number (not applicable)
    97.7
    98.3
    99.6
    89.8
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Achieved Partial Early Virologic Response (pEVR)

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    End point title
    		 Percent of Patients Who Achieved Partial Early Virologic Response (pEVR)
    End point description
    pEVR was defined as serum hepatitis C virus (HCV) RNA reduction greater than or equal to 2Log10 and greater than or equal to the limit of quantification (LOQ) after 12 weeks of treatment. LOQ was defined as HCV RNA < 25 International Units (IU)/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    12 weeks after treatment start
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    259
    242
    247
    256
    Units: percent of patients
        number (not applicable)
    8.1
    2.1
    10.5
    19.5
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Achieved Complete Early Viral Response (cEVR)

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    End point title
    		 Percent of Patients Who Achieved Complete Early Viral Response (cEVR)
    End point description
    cEVR was defined as serum hepatitis C virus (HCV) RNA less than the limit of quantification (LOQ) after 12 weeks of treatment. LOQ was defined as HCV RNA < 25 International Units (IU)/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    12 weeks after treatment start
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    259
    242
    247
    256
    Units: percent of patients
        number (not applicable)
    89.6
    96.3
    89.1
    70.3
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Achieved End-of-Alisporivir-Treatment Response (EDTR)

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    End point title
    		 Percent of Patients Who Achieved End-of-Alisporivir-Treatment Response (EDTR)
    End point description
    EDTR was defined as hepatitis C virus (HCV) RNA less than the limit of quantification (LOQ) at the end of treatment with alisporivir (completed or prematurely discontinued). LOQ was defined as HCV RNA < 25 International Units (IU)/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    Whenever completion of alisporivir treatment occurred or 12 and 48 weeks after treatment completion
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    271
    267
    264
    264
    Units: percent of patients
        number (not applicable)
    90
    93.6
    90.2
    75
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Achieved End-of-Treatment Response (ETR)

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    End point title
    		 Percent of Patients Who Achieved End-of-Treatment Response (ETR)
    End point description
    ETR was defined as hepatitis C virus (HCV) RNA less than the limit of quantification (LOQ) at the end of treatment. LOQ was defined as HCV RNA < 25 International Units (IU)|/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    Whenever treatment completion occurred or 12 and 48 weeks after treatment completion
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    271
    268
    264
    265
    Units: percent of patients
        number (not applicable)
    88.2
    87.7
    87.5
    80
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Achieved Rapid Virologic Response (RVR)

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    End point title
    		 Percent of Patients Who Achieved Rapid Virologic Response (RVR)
    End point description
    RVR was defined as serum hepatitis C virus (HCV) RNA less than the limit of quantification (LOQ) after 4 weeks of treatment. LOQ was defined as HCV RNA < 25 International Units (IU)/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    4 weeks after treatment start
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    268
    258
    258
    261
    Units: percent of patients
        number (not applicable)
    60.1
    72.5
    56.6
    28.4
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Were Null Non-responders

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    End point title
    		 Percent of Patients Who Were Null Non-responders
    End point description
    A null non-responder was defined as a subject who failed to achieve a decrease of greater than or equal to 2log10 from baseline in serum hepatitis C virus (HCV) RNA concentration at any time within the first 12 weeks of treatment. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    Within 12 weeks of treatment start
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    273
    268
    265
    265
    Units: percent of patients
        number (not applicable)
    2.2
    2.2
    1.5
    7.5
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Were Partial Non-responders

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    End point title
    		 Percent of Patients Who Were Partial Non-responders
    End point description
    A partial non-responder was defined as a subject whose hepatitis C virus (HCV) RNA levels decreased greater than or equal to 2log10 from baseline at any time within the first 12 weeks of treatment but never became undetectable during treatment. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    24 or 48 weeks after treatment start
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    273
    268
    265
    265
    Units: percent of patients
        number (not applicable)
    6.6
    3.4
    5.3
    8.3
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Were Non-responders

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    End point title
    		 Percent of Patients Who Were Non-responders
    End point description
    A non-responder was defined as a subject who failed to achieve undetectable levels of serum hepatitis C virus (HCV) RNA during treatment. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    24 or 48 weeks after treatment start
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    273
    268
    265
    265
    Units: percent of patients
        number (not applicable)
    8.8
    5.6
    6.8
    15.8
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Achieved Sustained Virologic Response by 4 Weeks (SVR4)

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    End point title
    		 Percent of Patients Who Achieved Sustained Virologic Response by 4 Weeks (SVR4)
    End point description
    SVR4 was defined as hepatitis C virus (HCV) RNA less than the limit of quantification (LOQ) at week 4 of follow-up (FU) after stopping treatment. LOQ was defined as HCV RNA < 25 International Units (IU)/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    4 weeks after treatment completion
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    273
    268
    265
    265
    Units: percent of patients
        number (not applicable)
    76.2
    76.5
    75.1
    58.1
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Relapsed

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    End point title
    		 Percent of Patients Who Relapsed
    End point description
    Relapse was defined as levels of hepatitis C virus (HCV) RNA greater than the limit of detection (LOD) during post-treatment follow-up (FU) in patients with HCV RNA less than LOD at the end of treatment who achieved end-of-treatment response (ETR) above the LOD and had >=1 post-treatment HCV RNA measurement. LOD was defined as < 10 International Units (IU)/mL. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    24 or 48 weeks after treatment completion
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    224
    214
    215
    180
    Units: percent of patients
        number (not applicable)
    17.9
    13.1
    15.3
    26.1
    No statistical analyses for this end point

    Secondary: Percent of Patients With Normalized Alanine Aminotransferase (ALT) at The End of Treatment

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    End point title
    		 Percent of Patients With Normalized Alanine Aminotransferase (ALT) at The End of Treatment
    End point description
    Normalized ALT was defined as less than or equal to the upper limit of normal (ULN). This end point measured ALT in patients with abnormal (greater than the ULN) ALT at baseline and those with >=1 ALT measurement during triple therapy for the triple therapy end point and >=1 on-treatment ALT measurement for the treatment end point. ULN was defined as 37 International Units (IU)/L for females, 48 IU/L for males. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    24 or 48 weeks after treatment start
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    188
    178
    185
    183
    Units: percent of patients
    number (not applicable)
        Normalized at triple therapy end
    92.6
    93.3
    88.6
    82
        Normalized at treatment end
    80.9
    80.3
    80
    78.7
    No statistical analyses for this end point

    Secondary: Percent of Patients With Normalized Alanine Aminotransferase (ALT) at The End of Study

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    End point title
    		 Percent of Patients With Normalized Alanine Aminotransferase (ALT) at The End of Study
    End point description
    Normalized ALT was defined as less than or equal to the upper limit of normal (ULN). This end point measured ALT in patients with abnormal (greater than the ULN) ALT at baseline and those with >=1 post-baseline ALT measurement for the study end point. ULN was defined as 37 International Units (IU)/L for females, 48 IU/L for males. This end point analyzed the Full Analysis Set, which included all patients to whom study treatment had been assigned.
    End point type
    Secondary
    End point timeframe
    72 weeks
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    189
    178
    185
    183
    Units: percent of patients
        number (not applicable)
    83.6
    80.3
    78.9
    72.1
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Developed Thrombocytopenia

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    End point title
    		 Percent of Patients Who Developed Thrombocytopenia
    End point description
    Thrombocytopenia was defined as platelets less than 50 x 109/L (50 x 103/μL), corresponding to Division of Microbiology and Infectious Diseases (DMID) toxicity grade 3 or more during treatment between the different treatment arms. Only patients with a DMID grade less than 3 at baseline were counted. A patient with multiple grade 3/4 was counted only once. This end point analyzed the Safety Set, which included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    24 or 48 weeks
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    270
    265
    264
    264
    Units: percent of patients
        number (not applicable)
    6.7
    23
    12.5
    1.9
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Developed Neutropenia

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    End point title
    		 Percent of Patients Who Developed Neutropenia
    End point description
    Neutropenia was defined as neutrophils less than 0.75 x 109/L (0.75 x 103/μL) corresponding to a DMID toxicity grade 3 or more, during treatment between the different treatment arms. Only patients with a DMID grade less than 3 at baseline were counted. A patient with multiple grade 3/4 was counted only once. This end point analyzed the Safety Set, which included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    24 or 48 weeks
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    270
    263
    264
    264
    Units: percent of patients
        number (not applicable)
    28.9
    32.7
    30.3
    15.5
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Developed Anemia

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    End point title
    		 Percent of Patients Who Developed Anemia
    End point description
    Anemia was defined as hemoglobin (Hb) less than 80g/L (< 8 g/dL), corresponding to a DMID toxicity grade 3 or more, during treatment between the different treatment arms. Only patients with a DMID grade less than 3 at baseline were counted. A patient with multiple grade 3/4 was counted only once. This end point analyzed the Safety Set, which included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    24 or 48 weeks
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    271
    267
    264
    264
    Units: percent of patients
        number (not applicable)
    1.8
    3.7
    0.8
    1.9
    No statistical analyses for this end point

    Secondary: Percent of Patients Who Developed Hyperbilirubinemia

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    End point title
    		 Percent of Patients Who Developed Hyperbilirubinemia
    End point description
    Hyperbilirubinemia was defined as total bilirubin value greater than 5× the upper limit of normal (ULN) (DMID toxicity grade 3 or more) during treatment between the different treatment arms. Only patients with a DMID grade less than 3 at baseline were counted. A patient with multiple grade 3/4 was counted only once. ULN was defined as total bilirubin 21 μmol/L. This end point analyzed the Safety Set, which included all patients who received at least one dose of study medication.
    End point type
    Secondary
    End point timeframe
    24 or 48 weeks
    End point values
    		 Arm A: Alisporivir 600 QD RGT Arm B: Alisporivir 400 BID RGT Arm C: Alisporivir 600 QD Arm D: Peg-IFNα2a and Ribavirin (P/R)
    Number of subjects analysed
    271
    267
    264
    264
    Units: percent of patients
        number (not applicable)
    4.4
    16.9
    2.3
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are collected from First Patient First Visit (FPFV) until Last Patient Last Visit (LPLV). All adverse events reported in this record are from date of First Patient First Treatment until Last Patient Last Visit
    Adverse event reporting additional description
    Consistent with EudraCT disclosure specifications, Novartis has reported under the Serious adverse events field “number of deaths resulting from adverse events” all those deaths, resulting from serious adverse events that are deemed to be causally related to treatment by the investigator.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.0
    Reporting groups
    Reporting group title
    Arm B: Alisporivir 400 BID RGT
    Reporting group description
    		 Triple therapy with a response-guided treatment duration (see below) with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 400 mg twice daily (BID) for 24 or 48 weeks based on week 4 hepatitis C virus (HCV) RNA results. Response guided treatment (RGT): • Patients with a viral load below the level of detection (LOD) at week 4 (< RVR4LOD) had to stop P/R and alisporivir study medications after 24 weeks. • Patients with a viral load at or above the LOD at week 4 (≥ RVR4LOD) had to complete 48 weeks of P/R and alisporivir study treatment.

    Reporting group title
    Arm A: Alisporivir 600 QD RGT
    Reporting group description
    		 Triple therapy with a response-guided treatment duration (see below) with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for an additional 23 or 47 weeks based on week 4 hepatitis C virus (HCV) RNA results. Response guided treatment (RGT): • Patients with a viral load below the level of detection (LOD) at week 4 (< RVR4LOD) had to stop P/R and alisporivir study medications after 24 weeks. • Patients with a viral load at or above the LOD at week 4 (≥ RVR4LOD) had to complete 48 weeks of P/R and alisporivir study treatment.

    Reporting group title
    Arm C: Alisporivir 600 QD 48 week
    Reporting group description
    		 Fixed-duration triple therapy with Peg-IFNα2a and Ribavirin (P/R) plus alisporivir 600 mg twice daily (BID) for one week followed by P/R plus alisporivir 600 mg once daily (QD) for an additional 47 weeks.

    Reporting group title
    Arm D: Peg-IFNα2a and Ribavirin (P/R) 48 wk
    Reporting group description
    		 Therapy with P/R and placebo for 48 weeks.

    Serious adverse events
    		 Arm B: Alisporivir 400 BID RGT Arm A: Alisporivir 600 QD RGT Arm C: Alisporivir 600 QD 48 week Arm D: Peg-IFNα2a and Ribavirin (P/R) 48 wk
    Total subjects affected by serious adverse events
         subjects affected / exposed
    28 / 268 (10.45%)
    24 / 273 (8.79%)
    21 / 265 (7.92%)
    28 / 265 (10.57%)
         number of deaths (all causes)
    1
    0
    0
    0
         number of deaths resulting from adverse events
    1
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Breast cancer
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervix carcinoma
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Craniopharyngioma
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Leiomyosarcoma
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Meningioma
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatic neoplasm
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pituitary tumour benign
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Prostatic adenoma
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Squamous cell carcinoma of the cervix
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Aortic dissection
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive crisis
         subjects affected / exposed
    3 / 268 (1.12%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypotension
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vasculitis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Drug interaction
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza like illness
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lipogranuloma
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multi-organ failure
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Non-cardiac chest pain
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pain
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pyrexia
         subjects affected / exposed
    2 / 268 (0.75%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Bartholinitis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysfunctional uterine bleeding
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ovarian disorder
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Epistaxis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary fibrosis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    2 / 265 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tonsillar hypertrophy
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Major depression
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mania
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia, paranoid type
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac failure
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive heart disease
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tachycardia
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intraventricular haemorrhage
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Paraesthesia
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Subarachnoid haemorrhage
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 268 (0.37%)
    2 / 273 (0.73%)
    0 / 265 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 2
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Febrile neutropenia
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neutropenia
         subjects affected / exposed
    0 / 268 (0.00%)
    2 / 273 (0.73%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancytopenia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Spontaneous haematoma
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thrombocytopenia
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Acute vestibular syndrome
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Deafness neurosensory
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vertigo
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Dacryoadenitis acquired
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    2 / 2
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Diarrhoea
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haematemesis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoidal haemorrhage
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nausea
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Pancreatitis acute
         subjects affected / exposed
    3 / 268 (1.12%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 0
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Small intestinal obstruction
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    2 / 268 (0.75%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis acute
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholelithiasis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatosplenomegaly
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Eczema
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urticaria
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Endocrine disorders
    Autoimmune thyroiditis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyperthyroidism
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Thyroiditis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    2 / 265 (0.75%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Bursitis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Exostosis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    2 / 265 (0.75%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchitis
         subjects affected / exposed
    2 / 268 (0.75%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Bronchopneumonia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cellulitis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cervicitis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Enterocolitis infectious
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastroenteritis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Influenza
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lobar pneumonia
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal abscess
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 268 (0.37%)
    1 / 273 (0.37%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary tuberculosis
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Salpingo-oophoritis
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Tooth abscess
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    1 / 265 (0.38%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 268 (0.00%)
    2 / 273 (0.73%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetic ketoacidosis
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypomagnesaemia
         subjects affected / exposed
    1 / 268 (0.37%)
    0 / 273 (0.00%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hyponatraemia
         subjects affected / exposed
    0 / 268 (0.00%)
    0 / 273 (0.00%)
    1 / 265 (0.38%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 268 (0.00%)
    1 / 273 (0.37%)
    0 / 265 (0.00%)
    0 / 265 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Arm B: Alisporivir 400 BID RGT Arm A: Alisporivir 600 QD RGT Arm C: Alisporivir 600 QD 48 week Arm D: Peg-IFNα2a and Ribavirin (P/R) 48 wk
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    261 / 268 (97.39%)
    256 / 273 (93.77%)
    250 / 265 (94.34%)
    241 / 265 (90.94%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    49 / 268 (18.28%)
    29 / 273 (10.62%)
    32 / 265 (12.08%)
    7 / 265 (2.64%)
         occurrences all number
    59
    31
    36
    17
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    46 / 268 (17.16%)
    43 / 273 (15.75%)
    46 / 265 (17.36%)
    47 / 265 (17.74%)
         occurrences all number
    52
    48
    53
    54
    Chills
         subjects affected / exposed
    30 / 268 (11.19%)
    23 / 273 (8.42%)
    33 / 265 (12.45%)
    21 / 265 (7.92%)
         occurrences all number
    34
    27
    37
    30
    Fatigue
         subjects affected / exposed
    97 / 268 (36.19%)
    84 / 273 (30.77%)
    87 / 265 (32.83%)
    83 / 265 (31.32%)
         occurrences all number
    106
    91
    92
    95
    Influenza like illness
         subjects affected / exposed
    52 / 268 (19.40%)
    55 / 273 (20.15%)
    38 / 265 (14.34%)
    38 / 265 (14.34%)
         occurrences all number
    62
    70
    51
    49
    Injection site erythema
         subjects affected / exposed
    10 / 268 (3.73%)
    14 / 273 (5.13%)
    17 / 265 (6.42%)
    8 / 265 (3.02%)
         occurrences all number
    10
    14
    17
    9
    Irritability
         subjects affected / exposed
    16 / 268 (5.97%)
    19 / 273 (6.96%)
    21 / 265 (7.92%)
    21 / 265 (7.92%)
         occurrences all number
    17
    19
    24
    23
    Pyrexia
         subjects affected / exposed
    92 / 268 (34.33%)
    78 / 273 (28.57%)
    81 / 265 (30.57%)
    74 / 265 (27.92%)
         occurrences all number
    112
    101
    120
    98
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    53 / 268 (19.78%)
    47 / 273 (17.22%)
    57 / 265 (21.51%)
    51 / 265 (19.25%)
         occurrences all number
    56
    57
    68
    58
    Dyspnoea
         subjects affected / exposed
    26 / 268 (9.70%)
    37 / 273 (13.55%)
    23 / 265 (8.68%)
    24 / 265 (9.06%)
         occurrences all number
    26
    40
    24
    25
    Epistaxis
         subjects affected / exposed
    25 / 268 (9.33%)
    12 / 273 (4.40%)
    15 / 265 (5.66%)
    10 / 265 (3.77%)
         occurrences all number
    31
    12
    16
    12
    Oropharyngeal pain
         subjects affected / exposed
    13 / 268 (4.85%)
    13 / 273 (4.76%)
    19 / 265 (7.17%)
    11 / 265 (4.15%)
         occurrences all number
    15
    15
    29
    13
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    19 / 268 (7.09%)
    16 / 273 (5.86%)
    24 / 265 (9.06%)
    27 / 265 (10.19%)
         occurrences all number
    19
    17
    26
    32
    Depression
         subjects affected / exposed
    25 / 268 (9.33%)
    20 / 273 (7.33%)
    26 / 265 (9.81%)
    22 / 265 (8.30%)
         occurrences all number
    26
    25
    27
    26
    Insomnia
         subjects affected / exposed
    57 / 268 (21.27%)
    49 / 273 (17.95%)
    48 / 265 (18.11%)
    58 / 265 (21.89%)
         occurrences all number
    63
    59
    55
    63
    Investigations
    Weight decreased
         subjects affected / exposed
    28 / 268 (10.45%)
    24 / 273 (8.79%)
    26 / 265 (9.81%)
    16 / 265 (6.04%)
         occurrences all number
    28
    26
    29
    16
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    34 / 268 (12.69%)
    33 / 273 (12.09%)
    25 / 265 (9.43%)
    30 / 265 (11.32%)
         occurrences all number
    36
    36
    26
    34
    Dysgeusia
         subjects affected / exposed
    22 / 268 (8.21%)
    14 / 273 (5.13%)
    13 / 265 (4.91%)
    11 / 265 (4.15%)
         occurrences all number
    23
    14
    14
    12
    Headache
         subjects affected / exposed
    93 / 268 (34.70%)
    88 / 273 (32.23%)
    93 / 265 (35.09%)
    80 / 265 (30.19%)
         occurrences all number
    126
    117
    145
    104
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    124 / 268 (46.27%)
    113 / 273 (41.39%)
    91 / 265 (34.34%)
    85 / 265 (32.08%)
         occurrences all number
    140
    131
    108
    123
    Leukopenia
         subjects affected / exposed
    27 / 268 (10.07%)
    48 / 273 (17.58%)
    48 / 265 (18.11%)
    27 / 265 (10.19%)
         occurrences all number
    33
    66
    61
    37
    Lymphopenia
         subjects affected / exposed
    7 / 268 (2.61%)
    15 / 273 (5.49%)
    16 / 265 (6.04%)
    8 / 265 (3.02%)
         occurrences all number
    11
    17
    24
    12
    Neutropenia
         subjects affected / exposed
    80 / 268 (29.85%)
    84 / 273 (30.77%)
    86 / 265 (32.45%)
    66 / 265 (24.91%)
         occurrences all number
    116
    127
    130
    109
    Thrombocytopenia
         subjects affected / exposed
    73 / 268 (27.24%)
    47 / 273 (17.22%)
    49 / 265 (18.49%)
    14 / 265 (5.28%)
         occurrences all number
    85
    49
    58
    20
    Eye disorders
    Ocular icterus
         subjects affected / exposed
    14 / 268 (5.22%)
    11 / 273 (4.03%)
    5 / 265 (1.89%)
    4 / 265 (1.51%)
         occurrences all number
    14
    13
    5
    4
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    23 / 268 (8.58%)
    17 / 273 (6.23%)
    22 / 265 (8.30%)
    14 / 265 (5.28%)
         occurrences all number
    27
    19
    26
    16
    Constipation
         subjects affected / exposed
    16 / 268 (5.97%)
    12 / 273 (4.40%)
    7 / 265 (2.64%)
    11 / 265 (4.15%)
         occurrences all number
    19
    12
    9
    12
    Diarrhoea
         subjects affected / exposed
    26 / 268 (9.70%)
    29 / 273 (10.62%)
    36 / 265 (13.58%)
    35 / 265 (13.21%)
         occurrences all number
    36
    36
    44
    39
    Dyspepsia
         subjects affected / exposed
    15 / 268 (5.60%)
    21 / 273 (7.69%)
    32 / 265 (12.08%)
    15 / 265 (5.66%)
         occurrences all number
    16
    24
    33
    16
    Gastrooesophageal reflux disease
         subjects affected / exposed
    9 / 268 (3.36%)
    10 / 273 (3.66%)
    5 / 265 (1.89%)
    14 / 265 (5.28%)
         occurrences all number
    10
    10
    6
    15
    Nausea
         subjects affected / exposed
    66 / 268 (24.63%)
    65 / 273 (23.81%)
    62 / 265 (23.40%)
    43 / 265 (16.23%)
         occurrences all number
    73
    78
    71
    51
    Vomiting
         subjects affected / exposed
    39 / 268 (14.55%)
    25 / 273 (9.16%)
    28 / 265 (10.57%)
    18 / 265 (6.79%)
         occurrences all number
    42
    28
    29
    21
    Hepatobiliary disorders
    Hyperbilirubinaemia
         subjects affected / exposed
    61 / 268 (22.76%)
    32 / 273 (11.72%)
    25 / 265 (9.43%)
    2 / 265 (0.75%)
         occurrences all number
    70
    33
    26
    2
    Jaundice
         subjects affected / exposed
    20 / 268 (7.46%)
    7 / 273 (2.56%)
    3 / 265 (1.13%)
    1 / 265 (0.38%)
         occurrences all number
    21
    7
    3
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    44 / 268 (16.42%)
    58 / 273 (21.25%)
    55 / 265 (20.75%)
    45 / 265 (16.98%)
         occurrences all number
    44
    58
    55
    45
    Dry skin
         subjects affected / exposed
    22 / 268 (8.21%)
    21 / 273 (7.69%)
    30 / 265 (11.32%)
    22 / 265 (8.30%)
         occurrences all number
    22
    21
    31
    23
    Pruritus
         subjects affected / exposed
    55 / 268 (20.52%)
    58 / 273 (21.25%)
    48 / 265 (18.11%)
    54 / 265 (20.38%)
         occurrences all number
    69
    75
    58
    61
    Rash
         subjects affected / exposed
    39 / 268 (14.55%)
    45 / 273 (16.48%)
    45 / 265 (16.98%)
    44 / 265 (16.60%)
         occurrences all number
    43
    51
    51
    54
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    22 / 268 (8.21%)
    15 / 273 (5.49%)
    23 / 265 (8.68%)
    11 / 265 (4.15%)
         occurrences all number
    22
    15
    23
    11
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    30 / 268 (11.19%)
    34 / 273 (12.45%)
    38 / 265 (14.34%)
    28 / 265 (10.57%)
         occurrences all number
    35
    36
    42
    33
    Back pain
         subjects affected / exposed
    14 / 268 (5.22%)
    13 / 273 (4.76%)
    14 / 265 (5.28%)
    19 / 265 (7.17%)
         occurrences all number
    15
    13
    15
    19
    Muscle spasms
         subjects affected / exposed
    15 / 268 (5.60%)
    8 / 273 (2.93%)
    7 / 265 (2.64%)
    10 / 265 (3.77%)
         occurrences all number
    18
    12
    8
    10
    Myalgia
         subjects affected / exposed
    53 / 268 (19.78%)
    58 / 273 (21.25%)
    56 / 265 (21.13%)
    52 / 265 (19.62%)
         occurrences all number
    62
    71
    64
    62
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    4 / 268 (1.49%)
    13 / 273 (4.76%)
    14 / 265 (5.28%)
    12 / 265 (4.53%)
         occurrences all number
    4
    14
    18
    15
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    59 / 268 (22.01%)
    61 / 273 (22.34%)
    58 / 265 (21.89%)
    41 / 265 (15.47%)
         occurrences all number
    68
    64
    63
    44
    Hypertriglyceridaemia
         subjects affected / exposed
    23 / 268 (8.58%)
    11 / 273 (4.03%)
    22 / 265 (8.30%)
    13 / 265 (4.91%)
         occurrences all number
    25
    12
    25
    18

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Nov 2010
    This amendment took into consideration feedback from the USA Food and Drug Administration (FDA). The agency recommended to evaluate an additional dose regimen to determine whether higher Cmin values expected with a 400 mg BID dose translates into greater efficacy compared to a QD regimen. The sample size for each group, study design & objectives, treatment blinding, and statistical methodology were adapted to take into consideration this new treatment group.
    22 Feb 2011
    This amendment took into consideration feedback from the USA FDA and Health Canada. The FDA advised that the number of patients in the study was sufficient to provide 90% power for the primary endpoint if a significance level of < 0.00125 was used. In order to meet this standard, the sample size was increased by 180 randomized patients (from 860 to 1040 patients) divided equally across the treatment arms. Health Canada requested that the definition of post-menopausal status was modified, requiring 12 months of amenorrhea irrespective of the follicle-stimulating hormone level.
    31 May 2011
    This amendment introduced the following changes: * Provide an opportunity of triple therapy treatment with alisporivir and P/R to patients who did not respond to double therapy (P/R). An additional treatment arm (Open Label Arm D) has been added to the study design, schedule of evaluations, statistical analysis and other relevant sections. * Address the requests from the FDA to add an ECG monitoring plan was added with central ECG evaluation. In addition, the management of patients with ALT elevation was modified. * Allow more flexibility on the scheduling of evaluations (scheduling of bone density evaluation), and on the use of prohibited medications * Take into consideration recent scientific information * Vitamin D: This protocol amendment also includes monitoring of vitamin D following recent scientific advances in the field of viral hepatitis highlighting frequent vitamin D deficiency in the HCV infected population. * Pregnancy test: The hCG level required to declare the pregnancy test positive was changed from > 5 mIU/mL to > 10 mIU/mL to match the specifications of the test being used by the central laboratory. * To reflect current clinical practice (change in acceptable ANA level, method used to collect vital signs).
    08 Sep 2011
    This amendment introduced the following changes at the request of the USA FDA: * All patients with < 2 log10 decline in HCV RNA at week 12 were considered as a null-non responder regardless of treatment arm. These patients were discontinued from study treatments. Previously, only patients receiving placebo/P/R would have had discontinued treatment * The study title was changed to clarify which drugs were being studied as the terminology “standard of care” might be understood differently in different countries based on the treatment available locally * The interruption of alisporivir and the use of prohibited medications were clarified
    27 Apr 2012
    This amendment introduced the following changes: By 16 Apr 2012, Novartis had received six SAE reports of acute pancreatitis (and one report of pancreatitis later interpreted as primary diabetic keto-acidiosis with secondary enzyme elevations) in patients taking alisporivir /placebo and P/R. Health Authorities and Investigators were notified as per local regulatory requirements. The first five patients fully recovered and the last patient died. Subsequently, the FDA requested that the alisporivir program be put on partial clinical hold to reduce risk to patients and to re-evaluate the benefit/risk of alisporivir in combination with peg-IFN_2a to treat chronic hepatitis C in the context of these SAEs. To implement the FDA request, safety amendment (protocol amendment 5) was issued with immediate effect (urgent safety measure). Investigators were notified on 18th April to stop treatment with alisporivir /placebo.
    10 Aug 2012
    This amendment detailed changes in the study conduct and analysis plan as a consequence of the partial clinical hold: * Relevant sections have been updated with the changes in study conduct triggered by the discontinuation of alisporivir /placebo * The definition of non-responders was clarified *The definition of SVR12, SVR24, and SVR48 was changed * The changes expected on liver biopsy for the diagnosis of chronic hepatitis C virus infection were clarified * Study purpose and objectives were changed to take into consideration the premature discontinuation of alisporivir /placebo treatment and change of primary endpoint * The study design was updated to include the premature discontinuation ofalisporivir /placebo treatment in all patients, the closing of the enrolment to the open-label period and the unblinding of the HCV RNA results * Justification for change from SVR 24 to SVR 12 was added to the section on rationale of study design and in all other relevant sections. * Rationale for continuing P/R treatment despite alisporivir treatment discontinuation was added * The interim analysis was added * The administrative analysis was removed * Ribavirin dose change based on weight was added to the study medication sections * Unblinding of study treatment was modified * Management of ALT elevation was clarified * Guidelines for the management of hypertriglyceridemia were added * Guidelines for the management of hematologic adverse events were modified * Hematopoietic factors were removed from the list of prohibited medications * Requirement for male patient whose female partner is pregnant to immediately discontinue study treatment was added as possible reason for discontinuation * Visit schedule for patients discontinued study treatment was changed * The data to be collected for screening failures was modified * A wording error in the definition of adverse events was corrected * The timing and scope of the DMC analyses were changed

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    18 Apr 2012
    Protocol amendment 5 was issued with immediate effect (urgent safety measure). Investigators were notified on April 18th 2012 to stop treatment with alisporivir/placebo.
    10 Aug 2012

    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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