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    Clinical Trial Results:
    A randomized, double-blind, 104-weeks treatment study to evaluate the efficacy, safety, tolerability and pharmacokinetics of telbivudine oral solution and tablets in children and adolescents with compensated HBeAg-positive and negative chronic hepatitis B virus infection

    Summary
    EudraCT number
    		 2012-004942-14
    Trial protocol
    		 GB   GR   BG  
    Global end of trial date
    09 Jan 2019

    Results information
    Results version number
    		 v1
    This version publication date
    24 Jul 2019
    First version publication date
    24 Jul 2019
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    CLDT600A2306
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02058108
    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 613241111, Novartis.email@novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-000065-PIP01-07
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    09 Jan 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Jan 2019
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective was to demonstrate the antiviral efficacy of telbivudine compared to placebo in pediatric patients by determining the percentage of patients achieving serum HBV DNA level of <300 copies/mL (51 IU/mL) at Week 24.
    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
    31 Oct 2014
    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
    Bulgaria: 3
    Country: Number of subjects enrolled
    Greece: 1
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Korea, Republic of: 1
    Country: Number of subjects enrolled
    Romania: 18
    Country: Number of subjects enrolled
    Turkey: 17
    Country: Number of subjects enrolled
    Ukraine: 11
    Worldwide total number of subjects
    53
    EEA total number of subjects
    22
    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)
    29
    Adolescents (12-17 years)
    24
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted in 20 centers in 7 countries: Bulgaria (2), Greece (1), Israel (2), Republic of Korea (1), Romania (5), Turkey (4) and Ukraine (5 sites).

    Pre-assignment
    Screening details
    		 Patients were stratified by age group (2 to < 6 years, 6 to <12 years and 12 to <18 years) and HBV DNA level (low and high). At the baseline visit, eligible patients were randomized in a 24-week double blind period to telbivudine or placebo in a ratio 5:1. At Week 24 (visit 6), all patients were unblinded and HBV DNA level were assessed.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Telbivudine
    Arm description
    		 Patients of any age and weight< 30kg: telbivudine oral solution (20 mg/mL): 20 mg/kg up to 600 mg q.d corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight≥ 30kg: telbivudine oral solution (20mg/mL), 600 mg/day corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: telbivudine film-coated tablet, 600 mg/day, corresponding to 1 tablet p.o. once daily
    Arm type
    		 Experimental

    Investigational medicinal product name
    Telbivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Patients of any age and weight< 30kg: telbivudine oral solution (20 mg/mL): 20 mg/kg up to 600 mg q.d corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight≥ 30kg: telbivudine oral solution (20mg/mL), 600 mg/day corresponding to 30 mL p.o. once daily

    Investigational medicinal product name
    Telbivudine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients ≥ 12 years old and weight ≥ 30kg: telbivudine film-coated tablet, 600 mg/day, corresponding to 1 tablet p.o. once daily

    Arm title
    		 Placebo
    Arm description
    		 Patients of any age and weight < 30kg: placebo oral solution corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight ≥ 30kg: placebo oral solution corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: placebo tablet, corresponding to 1 tablet p.o. once daily. Placebo randomized patients were offered optional telbivudine administration at week 24.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo to match LDT600 20mg/mL oral solution

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo match to LDT600 600 mg film-coated tablets

    Number of subjects in period 1
    		Telbivudine Placebo
    Started
    43
    10
    Completed
    2
    0
    Not completed
    41
    10
         Consent withdrawn by subject
    1
    -
         Abnormal Laboratory Values
    -
    1
         Unsatisfactory therapeutic effect
    37
    4
         Administrative problems
    3
    3
         No longer requires study drug
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Telbivudine
    Reporting group description
    		 Patients of any age and weight< 30kg: telbivudine oral solution (20 mg/mL): 20 mg/kg up to 600 mg q.d corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight≥ 30kg: telbivudine oral solution (20mg/mL), 600 mg/day corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: telbivudine film-coated tablet, 600 mg/day, corresponding to 1 tablet p.o. once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Patients of any age and weight < 30kg: placebo oral solution corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight ≥ 30kg: placebo oral solution corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: placebo tablet, corresponding to 1 tablet p.o. once daily. Placebo randomized patients were offered optional telbivudine administration at week 24.

    Reporting group values
    		 Telbivudine Placebo Total
    Number of subjects
    		 43 10 53
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 23 6 29
        Adolescents (12-17 years)
    		 20 4 24
        Adults (18-64 years)
    		 0 0 0
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    		 10.2 ± 4.88 9.1 ± 4.89 -
    Sex: Female, Male
    Units: Subjects
        Female
    		 14 4 18
        Male
    		 29 6 35
    Race/Ethnicity, Customized
    Units: Subjects
        Caucasian
    		 40 10 50
        Black
    		 1 0 1
        Asian
    		 2 0 2
    Participants with alanine aminotransferase (ALT) - Multiples of upper limits of normal (ULN)
    Serum ALT normalization is an important clinically relevant efficacy endpoint. Elevated serum ALT levels are thought to reflect underlying hepatitis disease activity (i.e. active liver inflammation). Correspondingly, ALT normalization is an accepted therapeutic goal in hepatitis studies as it is thought to reflect a substantial reduction in hepatic disease activity. Measurement at baseline.
    Units: Subjects
        < 1 × ULN
    		 4 3 7
        >= 1 × - < 2 × ULN
    		 22 4 26
        2 × - < 5 × ULN
    		 16 2 18
        5 × or more ULN
    		 1 1 2
    Participants with aspartate aminotransferase (AST) - Multiples of upper limits of normal (ULN)
    Units: Subjects
        < 1 × ULN
    		 26 5 31
        >= 1 × - < 2 × ULN
    		 14 4 18
        2 × - < 5 × ULN
    		 2 0 2
        5 × or more ULN
    		 1 1 2
    HBV DNA
    Units: log10 copies/mL
        arithmetic mean (standard deviation)
    		 9.1 ± 1.14 8.2 ± 2.26 -

    End points

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    End points reporting groups
    Reporting group title
    Telbivudine
    Reporting group description
    		 Patients of any age and weight< 30kg: telbivudine oral solution (20 mg/mL): 20 mg/kg up to 600 mg q.d corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight≥ 30kg: telbivudine oral solution (20mg/mL), 600 mg/day corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: telbivudine film-coated tablet, 600 mg/day, corresponding to 1 tablet p.o. once daily

    Reporting group title
    Placebo
    Reporting group description
    		 Patients of any age and weight < 30kg: placebo oral solution corresponding to weight (kg) x1mL, p.o. once daily Patients < 12 years old and weight ≥ 30kg: placebo oral solution corresponding to 30 mL p.o. once daily Patients ≥ 12 years old and weight ≥ 30kg: placebo tablet, corresponding to 1 tablet p.o. once daily. Placebo randomized patients were offered optional telbivudine administration at week 24.

    Primary: Proportion of patients achieving serum HBV DNA level of <300 copies/mL (51 IU/mL) at Week 24

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    End point title
    		 Proportion of patients achieving serum HBV DNA level of <300 copies/mL (51 IU/mL) at Week 24
    End point description
    The primary objective of this study was to demonstrate the antiviral efficacy of telbivudine compared to placebo in pediatric patients (2- < 18 years) by determining the percentage of patients achieving serum HBV DNA level of <300 copies/mL (51 IU/mL) at Week 24.
    End point type
    Primary
    End point timeframe
    Week 24
    End point values
    		 Telbivudine Placebo
    Number of subjects analysed
    41
    8
    Units: Participants
        number (not applicable)
    5
    1
    Statistical analysis title
    		 HBV DNA level of <300 copies/mL at Week 24
    Statistical analysis description
    HBV DNA level of <300 copies/mL (51 IU/mL) at Week 24
    Comparison groups
    Telbivudine v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    		 [1]
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.03
         upper limit
    		 36.75
    Notes
    [1] - Missing assessment imputed using the closest available assessment

    Secondary: Proportion of patients achieving HBV DNA< 300 copies/mL (51 IU/mL) at Week 52 and Week 104

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    End point title
    		 Proportion of patients achieving HBV DNA< 300 copies/mL (51 IU/mL) at Week 52 and Week 104
    End point description
    The antiviral efficacy at Weeks 52 and 104 was to be evaluated by: a) the proportion of patients achieving HBV DNA <300 copies/mL (51 IU/mL) at Week 52 and Week 104; b) the proportion of patients achieving HBV DNA < Lower Limit of Quantification (LLOQ), <1000 copies/ml (or 200 IU/mL), <10,000 copies/ml (or 2 000 IU/mL) and ≥10,000 copies/mL (or 2 000 IU/mL) at Week 24, 52 and 104; c) the proportion of patients achieving Serum HBV DNA reduction from baseline; d) the time to achieve HBV DNA <300 copies/mL (51 IU/mL); e) the proportion of patients with Primary non-response. Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), the long term efficacy endpoints for Week 52 and Week 104, were not analyzed.
    End point type
    Secondary
    End point timeframe
    Week 52, Week 104
    End point values
    		 Telbivudine Placebo
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: Participants
        number (not applicable)
    Notes
    [2] - Long term efficacy endpoints for Week 52 and Week 104 not analyzed (early terminated trial).
    [3] - Long term efficacy endpoints for Week 52 and Week 104 not analyzed (early terminated trial).
    No statistical analyses for this end point

    Secondary: Proportion of patients whose baseline ALTs were abnormal and subsequently normalized at Week 24, 52 and 104

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    End point title
    		 Proportion of patients whose baseline ALTs were abnormal and subsequently normalized at Week 24, 52 and 104
    End point description
    The biochemical response at Weeks 24, 52 and 104 was to be evaluated by the proportion of patients whose baseline ALTs were abnormal (defined as ALT >1 x Upper Limit of Normal [ULN]) and subsequently normalized. Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), the long term efficacy endpoints for Week 52 and Week 104, were not analyzed.
    End point type
    Secondary
    End point timeframe
    Week 24, Week 52, Week 104
    End point values
    		 Telbivudine Placebo
    Number of subjects analysed
    37
    5
    Units: Participants
    number (not applicable)
        Week 24
    12
    0
        Week 52
    0
    0
        Week 104
    0
    0
    Statistical analysis title
    		 ALT levels at Week 24
    Comparison groups
    Telbivudine v Placebo
    Number of subjects included in analysis
    42
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 0.2984
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    32.43
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -14.62
         upper limit
    		 74.6

    Secondary: Proportion of patients with HBeAg loss, HBeAg seroconversion at Week 24, 52 and 104

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    End point title
    		 Proportion of patients with HBeAg loss, HBeAg seroconversion at Week 24, 52 and 104
    End point description
    The serological response at Weeks 24, 52 and 104 was to be evaluated by: a) the proportion of HBeAg positive patients at baseline who subsequently have HBeAg loss and HBeAg seroconversion (defined as loss of HBeAg with detectable HBeAb); b) the proportion of HBsAg positive patients at baseline who subsequently have HBsAg loss and HBsAg seroconversion (defined as loss of HBsAg with detectable HBsAb). Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), the long term efficacy endpoints for Week 52 and Week 104, were not analyzed.
    End point type
    Secondary
    End point timeframe
    Week 24, Week 52, Week 104
    End point values
    		 Telbivudine Placebo
    Number of subjects analysed
    37
    4
    Units: Participants
    number (not applicable)
        HBeAg loss at Week 24
    1
    0
        HBeAg seroconversion at Week 24
    1
    0
    Statistical analysis title
    		 HBeAg loss at Week 24
    Comparison groups
    Telbivudine v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.7
         upper limit
    		 60.2
    Statistical analysis title
    		 HBeAg seroconversion at Week 24
    Comparison groups
    Telbivudine v Placebo
    Number of subjects included in analysis
    41
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -53.7
         upper limit
    		 60.2

    Secondary: Proportion of patients with HBsAg loss, HBsAg seroconversion at Week 24, 52 and 104

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    End point title
    		 Proportion of patients with HBsAg loss, HBsAg seroconversion at Week 24, 52 and 104
    End point description
    The serological response at Weeks 24, 52 and 104 was to be evaluated by: a) the proportion of HBeAg positive patients at baseline who subsequently have HBeAg loss and HBeAg seroconversion (defined as loss of HBeAg with detectable HBeAb); b) the proportion of HBsAg positive patients at baseline who subsequently have HBsAg loss and HBsAg seroconversion (defined as loss of HBsAg with detectable HBsAb). Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), the long term efficacy endpoints for Week 52 and Week 104, were not analyzed.
    End point type
    Secondary
    End point timeframe
    Week 24, Week 52, Week 104
    End point values
    		 Telbivudine Placebo
    Number of subjects analysed
    41
    7
    Units: Participants
    number (not applicable)
        HBsAg loss at Week 24
    1
    0
        HBsAg seroconversion at Week 24
    0
    0
    Statistical analysis title
    		 HBsAg loss at Week 24
    Comparison groups
    Telbivudine v Placebo
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.44
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.54
         upper limit
    		 42.17

    Secondary: Proportion of patients achieving a composite endpoints (HBV DNA < 300 copies/mL (51 IU/mL), ALT normalization and HBeAg seroconversion) at Week 52 and 104

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    End point title
    		 Proportion of patients achieving a composite endpoints (HBV DNA < 300 copies/mL (51 IU/mL), ALT normalization and HBeAg seroconversion) at Week 52 and 104
    End point description
    The proportion of patients achieving composite endpoints at Week 52 and 104 was to be evaluated by the proportion of patients achieving: a) HBV DNA <300 copies/mL (51 IU/mL); b) ALT normalization and HBeAg seroconversion for HBeAg positive patients only; c) HBV DNA <300 copies/mL (51 IU/mL) and ALT normalization for HBeAg negative patients. Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), the long term efficacy endpoints for Week 52 and Week 104, were not analyzed.
    End point type
    Secondary
    End point timeframe
    Week 52, Week 104
    End point values
    		 Telbivudine Placebo
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: Participants
        number (not applicable)
    Notes
    [4] - Long term efficacy endpoints for Week 52 and Week 104 not analyzed (early terminated trial).
    [5] - Long term efficacy endpoints for Week 52 and Week 104 not analyzed (early terminated trial).
    No statistical analyses for this end point

    Secondary: The cumulative rate of virological breakthrough (VB) at Week 52 and 104

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    End point title
    		 The cumulative rate of virological breakthrough (VB) at Week 52 and 104
    End point description
    The assessment of virological breakthrough (VB) was to be evaluated by: a) the cumulative rate of patients with confirmed VB at Week 52 and Week 104; b) the time to VB. Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), the long term efficacy endpoints for Week 52 and Week 104, were not analyzed.
    End point type
    Secondary
    End point timeframe
    Week 52, Week 104
    End point values
    		 Telbivudine Placebo
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Participants
        number (not applicable)
    Notes
    [6] - Long term efficacy endpoints for Week 52 and Week 104 not analyzed (early terminated trial).
    [7] - Long term efficacy endpoints for Week 52 and Week 104 not analyzed (early terminated trial).
    No statistical analyses for this end point

    Secondary: Presence of treatment emergent genotypic resistance associated with VB, or in patients with HBV DNA≥300 copies/mL (51 IU/mL) at Week 24 and discontinued from the study

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    End point title
    		 Presence of treatment emergent genotypic resistance associated with VB, or in patients with HBV DNA≥300 copies/mL (51 IU/mL) at Week 24 and discontinued from the study
    End point description
    Assessment of the presence of treatment emergent genotypic resistance (confirmed by genotypic sequencing) associated with virological breakthrough over the study period, or in patients with HBV DNA≥300 copies/mL (51 IU/mL) at Week 24 and discontinued from the study treatment (or at discontinuation if prior to Week 24 for subjects with at least 16 weeks of LDT treatment)
    End point type
    Secondary
    End point timeframe
    Week 24
    End point values
    		 Telbivudine Placebo
    Number of subjects analysed
    41
    8
    Units: Participants
    number (not applicable)
        Cumulative virological breakthrough
    0
    0
        Cumulative treatment emergent genotypic resistance
    1
    0
    Statistical analysis title
    		 Treatment emergent genotypic resistance at Week 24
    Comparison groups
    Telbivudine v Placebo
    Number of subjects included in analysis
    49
    Analysis specification
    Pre-specified
    Analysis type
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Mean difference (net)
    Point estimate
    2.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -37.05
         upper limit
    		 41.83

    Secondary: Safety and tolerability of Telbivudine

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    End point title
    		 Safety and tolerability of Telbivudine
    End point description
    Evaluation of the safety and tolerability of Telbivudine defined by AEs, SAEs, adverse events of special interest (AESI) (including muscle related events) and death; laboratory evaluations specifically on-treatment and post-treatment ALT flares, incidence and clinical significance of CK elevations; growth and development (linear growth and sexual maturation); development of liver decompensation and/or HCC. Only descriptive analysis performed.
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment to 30 days after last dose of study treatment, up to 112 weeks
    End point values
    		 Telbivudine Placebo
    Number of subjects analysed
    43
    10
    Units: Participants
    number (not applicable)
        On-treatment Adverse Event (AEs)
    20
    4
        On-treatment Serious Adverse Event (SAEs)
    0
    0
        On-treatment Deaths
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events and serious adverse events were collected for the maximum actual duration of treatment exposure and follow up for a participant per the protocol for approximately 112 weeks.
    Adverse event reporting additional description
    AEs occurring in patients in the Initial Placebo group were assigned to either Placebo or Telbivudine (LdT) treatment based on their onset date: - Placebo: AEs with onset before the first date of LdT treatment after switching+patients who did not switch to LdT - LdT: AEs with onset date on or after the first date of LdT treatment after switching
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.1
    Reporting groups
    Reporting group title
    Initial Ldt
    Reporting group description
    		 Initial Ldt

    Reporting group title
    On Placebo
    Reporting group description
    		 On Placebo

    Reporting group title
    On Ldt
    Reporting group description
    		 On Ldt

    Reporting group title
    All Ldt
    Reporting group description
    		 All Ldt

    Serious adverse events
    		 Initial Ldt On Placebo On Ldt All Ldt
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    0 / 48 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Initial Ldt On Placebo On Ldt All Ldt
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    20 / 43 (46.51%)
    4 / 10 (40.00%)
    1 / 5 (20.00%)
    21 / 48 (43.75%)
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    2
    0
    0
    2
    Surgical and medical procedures
    Antibiotic prophylaxis
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Headache
         subjects affected / exposed
    6 / 43 (13.95%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    6 / 48 (12.50%)
         occurrences all number
    7
    1
    0
    7
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Conjunctival hyperaemia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Abdominal pain upper
         subjects affected / exposed
    5 / 43 (11.63%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    5 / 48 (10.42%)
         occurrences all number
    6
    0
    0
    6
    Diarrhoea
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    2
    0
    0
    2
    Nausea
         subjects affected / exposed
    0 / 43 (0.00%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Vomiting
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Epistaxis
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    2
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Myalgia
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Infections and infestations
    Exanthema subitum
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Gastroenteritis
         subjects affected / exposed
    2 / 43 (4.65%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    2 / 48 (4.17%)
         occurrences all number
    2
    0
    0
    2
    Laryngitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 10 (0.00%)
    1 / 5 (20.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    1
    1
    Otitis media
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Pharyngitis
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Tonsillitis
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    0
    1
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 10 (10.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    1
    0
    1
    Varicella
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Viral infection
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    1
    0
    0
    1
    Viral upper respiratory tract infection
         subjects affected / exposed
    3 / 43 (6.98%)
    0 / 10 (0.00%)
    0 / 5 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    3
    0
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Mar 2015
    Amendment 1 was issued after the inclusion of 35.3% of patients and introduced the following changes: • Update inclusion criteria for children enrolled in the Republic of South Korea by specified age groups to align with the availability of alternative treatments for CHB infection for the specified age groups (which eliminated children 12 years of age or older from study participation in South Korea). • Clarify serum ALT criteria for study inclusion. Eliminate the inclusion criterion for patients with normal ALT levels to substantiate moderate to severe hepatic inflammation by histology report or FibroScan. • Eliminate acute infection with herpes simplex virus (HSV) as exclusion criteria. • Eliminate duplication of list of viral causes of infectious hepatitis (Exclusion Criteria 7 and 12). • Clarify the management of patient discontinuation and premature patient withdrawal. • Remove the Serum ALT requirements for eligibility criteria for placebo treated patients to start telbivudine treatment at Week 28. • Reduce the number of assays to rule out other viral infections with a potential to cause hepatitis in order to align the protocol with current diagnostic practices and to reduce required blood volume for diagnostic tests. • Extend screening period up to 10 weeks in cases of operational or administrative issues.
    22 Nov 2016
    Amendment 2 was issued at that time enrolment was already placed on temporary halt. It added clarifications on the role of Data Monitoring Committee (DMC) and add clarifying wording for the timing of interim analyses. Amendment stated while planned DMC convened regularly to review safety analyses, committee could also request and review additional safety and /or efficacy analyses where appropriate.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to early termination of the study and limited number of enrolled patients on track to complete 52 weeks of participation (8 patients overall), the long term efficacy endpoints for Week 52 and Week 104, were not analyzed.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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