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    Clinical Trial Results:
    OPTIMA: A randomized, open-label, 156-week treatment study to evaluate the efficacy and safety of telbivudine or tenofovir treatment in HBeAg-negative chronic hepatitis B patients based on the Roadmap concept

    Summary
    EudraCT number
    		 2007-000180-13
    Trial protocol
    		 AT   ES   DE   GR   BG   IT  
    Global end of trial date
    10 Dec 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    27 Dec 2016
    First version publication date
    27 Dec 2016
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    CLDT600A2409
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01379508
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharmaceuticals
    Sponsor organisation address
    CH - 4002,, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharmaceuticals, 41 613241111,
    Scientific contact
    Clinical Disclosure Office, Novartis Pharmaceuticals, 41 613241111,
    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
    10 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 Dec 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    10 Dec 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was to compare the efficacy of Roadmap-Concept-based telbivudine treatment versus Roadmap-Concept-based tenofovir treatment in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB) patients. The rate of patients achieving hepatitis B virus (HBV) deoxyribonucleic acid (DNA) < 300 copies/mL (51 IU/mL) at Week 52 was used for comparison of efficacy; the hypothesis being that the rate of patients achieving HBV DNA < 300 copies/mL (51 IU/mL) at Week 52 in the telbivudine arm (Arm 1) was non-inferior to that achieved in the tenofovir arm (Arm 2).
    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
    11 Mar 2011
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Austria: 7
    Country: Number of subjects enrolled
    Bulgaria: 125
    Country: Number of subjects enrolled
    Germany: 16
    Country: Number of subjects enrolled
    Greece: 10
    Country: Number of subjects enrolled
    Italy: 2
    Country: Number of subjects enrolled
    Russian Federation: 41
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Turkey: 35
    Worldwide total number of subjects
    241
    EEA total number of subjects
    165
    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)
    234
    From 65 to 84 years
    7
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There was a screening period of 6 weeks to assess eligibility and to taper disallowed medications. At the Baseline visit, eligible patients were randomly assigned according to a 1:1 ratio to either treatment arms (telbivudine 600 mg once daily or tenofovir disoproxil fumarate 300 mg once daily).

    Period 1
    Period 1 title
    Treatment to Week 104
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LdT Mono at Week 24
    Arm description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy of tenofovir.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Telbivudine
    Investigational medicinal product code
    LDT600
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg tablet orally (p.o.) taken once daily for up to 156 weeks. Dose adjustments were to be considered if CrCl decreased to 50 mL/min

    Arm title
    		 LdT+TDF at Week 24
    Arm description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily and additional 300 mg tenofovir after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.
    Arm type
    		 experimental plus active comparator

    Investigational medicinal product name
    tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg tablets taken as 300 mg once daily up to 156 weeks. Tenofovir dose adjustments were to be considered if estimated calculated serum CrCl by either Cockcroft-Gault or MDRD method < 50 mL/min, confirmed by 2 estimated calculations or laboratory serum phosphate < 1.5 mg/dL confirmed on retesting at the central laboratory

    Investigational medicinal product name
    telbivudine
    Investigational medicinal product code
    LDT600
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg tablet orally (p.o.) taken once daily for up to 156 weeks. Dose adjustments were to be considered if CrCl decreased to 50 mL/min

    Arm title
    		 TDF Mono at Week 24
    Arm description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy with telbivudine.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg tablets taken as 300 mg once daily up to 156 weeks. Tenofovir dose adjustments were to be considered if estimated calculated serum CrCl by either Cockcroft-Gault or MDRD method < 50 mL/min, confirmed by 2 estimated calculations or laboratory serum phosphate < 1.5 mg/dL confirmed on retesting at the central laboratory

    Arm title
    		 TDF + LdT at Week 24
    Arm description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir and additional 600 mg telbivudine after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.
    Arm type
    		 active comparator plus experimental add-on

    Investigational medicinal product name
    tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg tablets taken as 300 mg once daily up to 156 weeks. Tenofovir dose adjustments were to be considered if estimated calculated serum CrCl by either Cockcroft-Gault or MDRD method < 50 mL/min, confirmed by 2 estimated calculations or laboratory serum phosphate < 1.5 mg/dL confirmed on retesting at the central laboratory

    Investigational medicinal product name
    telbivudine
    Investigational medicinal product code
    LDT600
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg tablet orally (p.o.) taken once daily for up to 156 weeks. Dose adjustments were to be considered if CrCl decreased to 50 mL/min

    Number of subjects in period 1
    		LdT Mono at Week 24 LdT+TDF at Week 24 TDF Mono at Week 24 TDF + LdT at Week 24
    Started
    99
    22
    109
    11
    Completed Wk 24
    93
    22
    107
    11
    Treatment exposure ≥ 52 weeks
    91
    21
    105
    11
    Completed
    80
    19
    96
    11
    Not completed
    19
    3
    13
    0
         Consent withdrawn by subject
    6
    1
    4
    -
         Abnormal lab value
    1
    -
    -
    -
         Adverse event, non-fatal
    2
    -
    5
    -
         Administrative problems
    3
    1
    -
    -
         Lost to follow-up
    5
    -
    3
    -
         Abnormal test procedure result(s)
    1
    -
    -
    -
         Protocol deviation
    1
    1
    1
    -
    Period 2
    Period 2 title
    Extension Period Weeks 109-156
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 LdT Mono at Week 24
    Arm description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy of tenofovir
    Arm type
    		 Experimental

    Investigational medicinal product name
    Telbivudine
    Investigational medicinal product code
    LDT600
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg tablet orally (p.o.) taken once daily for up to 156 weeks. Dose adjustments were to be considered if CrCl decreased to 50 mL/min

    Arm title
    		 LdT+TDF at Week 24
    Arm description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily and additional 300 mg tenofovir after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.
    Arm type
    		 telbivudine plus tenofovir add-on

    Investigational medicinal product name
    Telbivudine
    Investigational medicinal product code
    LDT600
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg tablet orally (p.o.) taken once daily for up to 156 weeks. Dose adjustments were to be considered if CrCl decreased to 50 mL/min

    Investigational medicinal product name
    tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg tablets taken as 300 mg once daily up to 156 weeks. Tenofovir dose adjustments were to be considered if estimated calculated serum CrCl by either Cockcroft-Gault or MDRD method < 50 mL/min, confirmed by 2 estimated calculations or laboratory serum phosphate < 1.5 mg/dL confirmed on retesting at the central laboratory

    Arm title
    		 TDF Mono at Week 24
    Arm description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy with telbivudine.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg tablets taken as 300 mg once daily up to 156 weeks. Tenofovir dose adjustments were to be considered if estimated calculated serum CrCl by either Cockcroft-Gault or MDRD method < 50 mL/min, confirmed by 2 estimated calculations or laboratory serum phosphate < 1.5 mg/dL confirmed on retesting at the central laboratory

    Arm title
    		 TDF + LdT at Week 24
    Arm description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir and additional 600 mg telbivudine after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.
    Arm type
    		 tenofovir plus telbivudine add-on

    Investigational medicinal product name
    tenofovir
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    300 mg tablets taken as 300 mg once daily up to 156 weeks. Tenofovir dose adjustments were to be considered if estimated calculated serum CrCl by either Cockcroft-Gault or MDRD method < 50 mL/min, confirmed by 2 estimated calculations or laboratory serum phosphate < 1.5 mg/dL confirmed on retesting at the central laboratory

    Investigational medicinal product name
    telbivudine
    Investigational medicinal product code
    LDT600
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    600 mg tablet orally (p.o.) taken once daily for up to 156 weeks. Dose adjustments were to be considered if CrCl decreased to 50 mL/min

    Number of subjects in period 2 [1]
    		LdT Mono at Week 24 LdT+TDF at Week 24 TDF Mono at Week 24 TDF + LdT at Week 24
    Started
    64
    17
    79
    10
    Completed
    45
    14
    65
    10
    Not completed
    19
    3
    14
    0
         Consent withdrawn by subject
    8
    1
    8
    -
         Administrative problems
    3
    -
    1
    -
         Lost to follow-up
    6
    1
    5
    -
         Protocol deviation
    2
    1
    -
    -
    Notes
    [1] - 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: Based on the following eligibility criteria for enrollment into the extension period, eligible patients were to be treated for 1 additional year up to Week 156: HBV DNA < 300 copies/mL at Weeks 92 and 104, and estimated serum CrCl ≥ 50 mL/min by Cockcroft-Gault, MDRD, or CKD-EPI at Weeks 92 and 104.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    LdT Mono at Week 24
    Reporting group description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy of tenofovir.

    Reporting group title
    LdT+TDF at Week 24
    Reporting group description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily and additional 300 mg tenofovir after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.

    Reporting group title
    TDF Mono at Week 24
    Reporting group description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy with telbivudine.

    Reporting group title
    TDF + LdT at Week 24
    Reporting group description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir and additional 600 mg telbivudine after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.

    Reporting group values
    		 LdT Mono at Week 24 LdT+TDF at Week 24 TDF Mono at Week 24 TDF + LdT at Week 24 Total
    Number of subjects
    		 99 22 109 11 241
    Age Categorical
    Units: Subjects
        < 30 years
    		 17 4 18 0 39
        Between 30 and 50 years
    		 56 13 59 7 135
        > 50 years
    		 26 5 32 4 67
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.3 ( 11.73 ) 41.3 ( 10.77 ) 43.2 ( 12.66 ) 44.9 ( 12.11 ) -
    Gender Categorical
    Units: Subjects
        Male
    		 71 15 75 7 168
        Female
    		 28 7 34 4 73
    Genotype
    Units: Subjects
        Genotype A
    		 5 1 2 0 8
        Genotype B
    		 1 0 0 0 1
        Genotype C
    		 0 0 1 0 1
        Genotype D
    		 84 20 99 11 214
        Genotype E
    		 0 0 0 0 0
        Genotype F
    		 0 0 0 0 0
        Genotype G
    		 1 0 0 0 1
        Other
    		 1 0 0 0 1
        Unknown
    		 7 1 7 0 15
    HBV DNA
    Units: Subjects
        < 7 log
    		 81 4 83 3 171
        ≥ 7 log
    		 18 18 26 8 70
    ALT - Multiples of ULN
    Units: Subjects
        ≤ 1 ×
    		 46 3 52 4 105
        > 1 × - < 2 ×
    		 35 7 27 5 74
        2 × - < 5 ×
    		 13 11 26 1 51
        5 × or more
    		 5 1 4 1 11
    AST - Multiples of ULN
    Units: Subjects
        ≤ 1 ×
    		 70 10 69 2 151
        > 1 × - < 2 ×
    		 14 7 23 7 51
        2 × - < 5 ×
    		 12 4 16 1 33
        5 × or more
    		 3 1 1 1 6
    Study Specific Characteristic HBV DNA
    Units: log10 copies/mL)
        arithmetic mean (standard deviation)
    		 5.887 ( 1.2862 ) 7.769 ( 1.2502 ) 5.838 ( 1.2464 ) 7.938 ( 1.0709 ) -

    End points

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    End points reporting groups
    Reporting group title
    LdT Mono at Week 24
    Reporting group description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy of tenofovir.

    Reporting group title
    LdT+TDF at Week 24
    Reporting group description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily and additional 300 mg tenofovir after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.

    Reporting group title
    TDF Mono at Week 24
    Reporting group description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy with telbivudine.

    Reporting group title
    TDF + LdT at Week 24
    Reporting group description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir and additional 600 mg telbivudine after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.
    Reporting group title
    LdT Mono at Week 24
    Reporting group description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy of tenofovir

    Reporting group title
    LdT+TDF at Week 24
    Reporting group description
    		 Patients who were initially treated with telbivudine and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 600 mg telbivudine daily and additional 300 mg tenofovir after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.

    Reporting group title
    TDF Mono at Week 24
    Reporting group description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid < 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir daily after Week 24. Patients who developed VB while on monotherapy received add-on therapy with telbivudine.

    Reporting group title
    TDF + LdT at Week 24
    Reporting group description
    		 Patients who were initially treated with tenofovir and had hepatitis B virus deoxyribonucleic acid > 300 copies/mL in their blood at Week 24 and continued to receive 300 mg tenofovir and additional 600 mg telbivudine after Week 24. If patients developed VB after Week 24 while on combination therapy already, study treatment was handled under the investigator’s discretion and the patient might have been discontinued.

    Subject analysis set title
    LdT Overall
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Total of LdT Mono and LdT + TDF

    Subject analysis set title
    TDF Overall
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Total of TDF and TDF = LdT

    Primary: Percentage of patients achieving HBV DNA < 300 copies/mL (51 IU/mL) at Week 52 (rITT population) -

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    End point title
    		 Percentage of patients achieving HBV DNA < 300 copies/mL (51 IU/mL) at Week 52 (rITT population) -
    End point description
    The primary objective was to compare the efficacy of Roadmap-Concept-based telbivudine vs tenofovir treatment in HBeAg-negative CHB patients.The Roadmap intent-to-treat (rITT) population consisted of ITT population who did not discontinue before Wk 24 and did not violate the protocol-defined rules of receiving add-on. rITT was used for all of the primary endpoint analysis. Mantel-Haenszel weighted estimates (stratified by HBV DNA level (< 7 log10 copies/mL or ≥7 log10 copies/mL) and ALT(< 3×ULN or ≥ 3×ULN) at baseline) was employed to assess the % of patients (response rate)who achieve HBV DNA < 300 copies/mL after 52 wks treatment in each treatment arm, as well as the difference in % (telbivudine – tenofovir arm) and the 95% CI of the difference. The hypothesis is that the aggregated rate of HBV DNA <300 copies/mL (51 IU/mL) at wk 52 of telbivudine is non-inferior to tenofovir (non-inferiority margin of 10%). All 4 analyses with different imputing methods utilize the above.
    End point type
    Primary
    End point timeframe
    week 52
    End point values
    		 LdT Overall TDF Overall
    Number of subjects analysed
    113
    117
    Units: Participants
    number (not applicable)
        Missing DNA data at Wk 52=failure (n=103,111)
    91
    95
        Imputing +/- 7 days DNA for Wk 52 (n=104,111)
    91.9
    95
        Imputing LOCF DNA for Wk 52(n=108,116)
    95.4
    99.2
        Imputing within +28d DNA for Wk 52 (n=105,111)
    92.7
    95
    Statistical analysis title
    		 Primary - Missing DNA data at Wk 52=failure
    Statistical analysis description
    For the Primary “treating missing as failure" analysis, patients who came for their primary endpoint Week 52 visit within the ± 7-day window but not on the exact designated day of the visit were treated as "missing data
    Comparison groups
    LdT Overall v TDF Overall
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [1]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -10.5
         upper limit
    		 2.5
    Notes
    [1] - Noninferiority was derived if the lower limit of two-sided 95% CI for the difference lied above the pre-determined non-inferiority margin (-10%).
    Statistical analysis title
    		 Imputing +/- 7 days DNA for Wk 52
    Statistical analysis description
    Imputing +/- 7 days DNA for Wk 52
    Comparison groups
    TDF Overall v LdT Overall
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [2]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -3.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.4
         upper limit
    		 3.1
    Notes
    [2] - Noninferiority was derived if the lower limit of two-sided 95% CI for the difference lied above the pre-determined non-inferiority margin (-10%).
    Statistical analysis title
    		 Imputing LOCF DNA for wk 52
    Statistical analysis description
    Imputing LOCF DNA for wk 52: d/c for non response prior to Wk 52: Treating missing as failure for patients who discontinued prior to Week 52 due to unsatisfactory therapeutic effect and imputing missing with LOCF for other patients.
    Comparison groups
    LdT Overall v TDF Overall
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [3]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -3.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.9
         upper limit
    		 0.4
    Notes
    [3] - Noninferiority was derived if the lower limit of two-sided 95% CI for the difference lied above the pre-determined non-inferiority margin (-10%).
    Statistical analysis title
    		 Imputing within +28d DNA for wk52
    Statistical analysis description
    Imputing within +28d DNA for wk52: d/c for non response <28 days from Wk 52:Treating missing as failure for patients who discontinued prior to Week 52 due to unsatisfactory therapeutic effect and imputing missing with the earliest available assessment within the 28-day window starting from the scheduled Week 52 date for other patients (if no such assessment is available, treated as failure)
    Comparison groups
    LdT Overall v TDF Overall
    Number of subjects included in analysis
    230
    Analysis specification
    Pre-specified
    Analysis type
    		 non-inferiority [4]
    Method
    Parameter type
    		 Difference in percentage
    Point estimate
    -2.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.3
         upper limit
    		 3.8
    Notes
    [4] - Noninferiority was derived if the lower limit of two-sided 95% CI for the difference lied above the pre-determined non-inferiority margin (-10%).

    Secondary: Percentage of patients achieving secondary efficacy endpoints (rITT)

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    End point title
    		 Percentage of patients achieving secondary efficacy endpoints (rITT)
    End point description
    To assess the antiviral efficacy, as evaluated by the percentage of patients achieving HBV DNA <300 copies/mL (51 IU/mL), ALT normalization, HBsAg loss, HBsAg conversion, virologic breakthrough (VB) at study visit, cumulative VB by study defined study period, cumulative treatment-emergent resistance
    End point type
    Secondary
    End point timeframe
    week 24, 52, 104
    End point values
    		 LdT Mono at Week 24 LdT+TDF at Week 24 TDF Mono at Week 24 TDF + LdT at Week 24 LdT Overall TDF Overall
    Number of subjects analysed
    92
    21
    106
    11
    113
    117
    Units: Participants
    number (confidence interval 95%)
        HBV DNA<300 Week 24 (91,0,105,0,91,105)
    98.9 (94.1 to 100)
    0 (0 to 0)
    99.1 (94.9 to 100)
    0 (0 to 28.5)
    80.5 (72 to 87.4)
    89.7 (82.8 to 94.6)
        HBV DNA <300 Week 104 (n=64,16,79,9,80,88)
    69.6 (59.1 to 78.7)
    76.2 (52.8 to 91.8)
    74.5 (65.1 to 82.5)
    81.8 (48.2 to 97.7)
    70.8 (61.5 to 79)
    75.2 (66.4 to 82.7)
        HBV DNA <300 Week 24(n=92,0,106,0,,92,106) LOCF
    100 (96.1 to 100)
    0 (0 to 16.1)
    100 (96.6 to 100)
    0 (0 to 28.5)
    81.4 (73 to 88.1)
    90.6 (83.8 to 95.2)
        HBV DNA <300 Wk104(n=85,21,,105,11,106,116) LOCF
    92.4 (84.9 to 96.9)
    100 (83.9 to 100)
    99.1 (94.9 to 100)
    100 (71.5 to 100)
    93.8 (87.7 to 97.5)
    99.1 (95.3 to 100)
        ALT Normalization Week 52 (42,15,,47,6,57,53)
    84 (70.9 to 92.8)
    83.3 (58.6 to 96.4)
    82.5 (70.1 to 91.3)
    85.7 (42.1 to 99.6)
    83.8 (72.9 to 91.6)
    82.8 (71.3 to 91.1)
        ALT Normalization Week 104(35,13,,35,6,48,41)
    70 (55.4 to 82.1)
    72.2 (46.5 to 90.3)
    61.4 (47.6 to 74)
    85.7 (42.1 to 99.6)
    70.6 (58.3 to 81)
    64.1 (51.1 to 75.7)
        ALT Normalization Week 52 (44,15,,50,6,59,56) LOCF
    88 (75.7 to 95.5)
    83.3 (58.6 to 96.4)
    87.7 (76.3 to 94.9)
    85.7 (42.1 to 99.6)
    86.8 (76.4 to 93.8)
    87.5 (76.8 to 94.4)
        ALT Normalization Wk 104 (46,15,61,49,6,61,55)LOCF
    92 (80.8 to 97.8)
    83.3 (58.6 to 96.4)
    86 (74.2 to 93.7)
    85.7 (42.1 to 99.6)
    89.7 (79.9 to 95.8)
    85.9 (75 to 93.4)
        HBsAg loss Week 52 (0,0,0,0,0,0)
    0 (0 to 3.9)
    0 (0 to 16.1)
    0 (0 to 3.4)
    0 (0 to 28.5)
    0 (0 to 3.2)
    0 (0 to 3.1)
        HBsAg loss Week 104 (0,0,0,0,0,0)
    0 (0 to 3.9)
    0 (0 to 16.1)
    0 (0 to 3.4)
    0 (0 to 28.5)
    0 (0 to 3.2)
    0 (0 to 3.1)
        HBsAg conversion Week 52 (0,0,0,0,0,0)
    0 (0 to 3.9)
    0 (0 to 16.1)
    0 (0 to 3.4)
    0 (0 to 28.5)
    0 (0 to 3.2)
    0 (0 to 3.1)
        HBsAg conversion Week 104 (0,0,0,0,0,0)
    0 (0 to 3.9)
    0 (0 to 16.1)
    0 (0 to 3.4)
    0 (0 to 28.5)
    0 (0 to 3.2)
    0 (0 to 3.1)
        Cum virol break BaseL to Wk 24 (n=0,1,0,0,1,0)
    0 (0 to 0)
    4.8 (0.1 to 23.8)
    0 (0 to 3.4)
    0 (0 to 28.5)
    0.9 (0 to 4.8)
    0 (0 to 3.1)
        Cum virol break Wk 24 to Wk 52 (n=3,0,,0,0,3,0)
    3.3 (0.7 to 9.2)
    0 (0 to 16.1)
    0 (0 to 3.4)
    0 (0 to 28.5)
    2.7 (0.6 to 7.6)
    0 (0 to 3.1)
        Cum virol break Wk 52 to Wk 104 (n=11,0,2,0,11,2)
    12 (6.1 to 20.4)
    0 (0 to 16.1)
    1.9 (0.2 to 6.6)
    0 (0 to 28.5)
    9.7 (5 to 16.8)
    1.7 (0.2 to 6)
        Cum virol break BaseLto Wk 104 (n=13,1,2,0,14,2)
    14.1 (7.7 to 23)
    4.8 (0.1 to 23.8)
    1.9 (0.2 to 6.6)
    0 (0 to 28.5)
    12.4 (6.9 to 19.9)
    1.7 (0.2 to 6)
        Cum vir break BL to Wk24 (n=0,1,0,0,1,0) LOCF
    0 (0 to 3.9)
    4.8 (0.1 to 23.8)
    0 (0 to 3.4)
    0 (0 to 28.5)
    0.9 (0 to 4.8)
    0 (0 to 3.1)
        Cum virol break Wk 24 to Wk 52(n=3,0,0,0,3,0) LOCF
    3.3 (0.7 to 9.2)
    0 (0 to 16.1)
    0 (0 to 3.4)
    0 (0 to 28.5)
    2.7 (0.6 to 7.6)
    0 (0 to 3.1)
        Cum virol break Wk52-Wk104(n=11,0,2,0,11,2) LOCF
    12 (6.1 to 20.4)
    0 (0 to 16.1)
    1.9 (0.2 to 6.6)
    0 (0 to 28.5)
    9.7 (5 to 16.8)
    1.7 (0.2 to 6)
        Cum virol break BLto Wk 104(n=13,1,,2,0,14,2) LOCF
    14.1 (7.7 to 23)
    4.8 (0.1 to 23.8)
    1.9 (0.2 to 6.6)
    0 (0 to 28.5)
    12.4 (6.6 to 19.9)
    1.7 (0.2 to 6)
        Cum tx emergent resistance Wk 52 (n=3,0,0,0,3,0)
    3.3 (0.7 to 9.2)
    0 (0 to 16.1)
    0 (0 to 3.4)
    0 (0 to 28.5)
    2.7 (0.6 to 7.6)
    0 (0 to 3.1)
        Ccum tx emergent resistance Wk 104 (n=8,0,0,0,8,0)
    9.2 (4.1 to 17.3)
    0 (0 to 16.1)
    0 (0 to 3.5)
    0 (0 to 28.5)
    7.4 (3.3 to 14.1)
    0 (0 to 3.1)
        Cum tx emergent resist Wk52 (n=3,0,0,0,3,0)LOCF
    3.3 (0.7 to 9.2)
    0 (0 to 16.1)
    0 (0 to 3.4)
    0 (0 to 28.5)
    2.7 (0.6 to 7.6)
    0 (0 to 3.1)
        Cum tx emergent resist Wk 104 (n=8,0,0,0,8,0) LOCF
    9.2 (4.1 to 17.3)
    0 (0 to 16.1)
    0 (0 to 3.5)
    0 (0 to 28.5)
    7.4 (3.3 to 14.1)
    0 (0 to 3.1)
        <7 log at BL HBV DNA <300 Wk52(n=71,3,,76,3,74,79)
    93.4 (85.3 to 97.8)
    75 (19.4 to 99.4)
    95 (87.7 to 98.6)
    100 (29.2 to 100)
    92.5 (84.4 to 97.2)
    95.2 (88.1 to 98.7)
        <7 log HBV DNA <300 Wk104 (n=52,2,61,2,54,63)
    68.4 (56.7 to 78.6)
    50 (6.8 to 93.2)
    76.3 (65.4 to 85.1)
    66.7 (9.4 to 99.2)
    67.5 (56.1 to 77.6)
    75.9 (65.3 to 84.6)
        <7 log HBV DNA <300 Wk52 (n=74,4,80,3,78,83)LOCF
    97.4 (90.8 to 99.7)
    100 (39.8 to 100)
    100 (95.5 to 100)
    100 (29.2 to 100)
    97.5 (91.3 to 99.7)
    100 (95.7 to 100)
        <7 log HBV DNA <300 Wk104 (n=70,4,79,3,74,82)LOCF
    92.1 (83.6 to 97)
    100 (39.8 to 100)
    98.8 (93.2 to 100)
    100 (29.2 to 100)
    92.5 (84.4 to 97.2)
    98.8 (93.5 to 100)
    No statistical analyses for this end point

    Secondary: Percentage of patients achieving secondary efficacy endpoints at Week 156 (mITT)

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    End point title
    		 Percentage of patients achieving secondary efficacy endpoints at Week 156 (mITT)
    End point description
    The modified intent-to-treat (mITT) population consisted of all patients in the ITT population who were eligible and enrolled into the extension period beyond Week 104. Objectives were to assess the antiviral efficacy and present the percentage of patients achieving HBV DNA <300 copies/mL (51 IU/mL) at Week156, ALT normalization, HBsAg loss, development of HBsAg conversion , cumulative tx emergent resistance, HBV DNA <300 copies/mL with HBV DNA <7 log at Baseline.
    End point type
    Secondary
    End point timeframe
    156 weeks
    End point values
    		 LdT Mono at Week 24 LdT+TDF at Week 24 TDF Mono at Week 24 TDF + LdT at Week 24 LdT Overall TDF Overall
    Number of subjects analysed
    62
    17
    79
    10
    79
    89
    Units: Participants
    number (confidence interval 95%)
        HBV DNA < 300 Week 156 (n=11,2,11,2,13,13)
    17.7 (9.2 to 29.5)
    11.8 (1.5 to 36.4)
    13.9 (7.2 to 23.5)
    20 (2.5 to 55.6)
    16.5 (9.1 to 26.5)
    14.6 (8 to 23.7)
        HBV DNA < 300 Wk156 (n=55,17,79,10,72,89) LOCF
    88.7 (78.1 to 95.3)
    100 (80.5 to 100)
    100 (95.4 to 100)
    100 (69.2 to 100)
    91.1 (82.6 to 96.4)
    100 (95.9 to 100)
        ALT normalization Wk 156 (n=5,1,4,2,6,6)
    14.3 (4.8 to 30.3)
    6.7 (0.2 to 31.9)
    10.5 (2.9 to 24.8)
    28.6 (3.7 to 71)
    12 (4.5 to 24.3)
    13.3 (5.1 to 26.8)
        ALT normalization Wk 156 (n=30,14,33,6,44,39) LOCF
    85.7 (69.7 to 95.2)
    93.3 (68.1 to 99.8)
    86.8 (71.9 to 95.6)
    85.7 (42.1 to 99.6)
    88 (75.7 to 95.5)
    86.7 (73.2 to 94.9)
        HBSAg loss/ seroconversion (n=0)
    0 (0 to 7)
    0 (0 to 70.8)
    0 (0 to 6.6)
    0 (0 to 70.8)
    0 (0 to 6.6)
    0 (0 to 6.6)
        Cum VB Wk104-156 LOCF (n=10,0,1,0,10,1)
    16.1 (8 to 27.7)
    0 (0 to 19.5)
    1.3 (0 to 6.9)
    0 (0 to 30.8)
    12.7 (6.2 to 22)
    1.1 (0 to 6.1)
        Cum VB BL to Wk 156 LOCF (13,0,1,0,13,1)
    21 (11.7 to 33.2)
    0 (0 to 19.5)
    1.3 (0 to 6.9)
    0 (0 to 30.8)
    16.5 (9.1 to 26.5)
    1.1 (0 to 6.1)
        Cum tx emerg resist Week 156 LOCF (n=8,0,0,0,8,0)
    14 (6.3 to 25.8)
    0 (0 to 19.5)
    0 (0 to 4.6)
    0 (0 to 30.8)
    10.8 (4.8 to 20.2)
    0 (0 to 4.1)
        HBV DNA < 300 Wk156 <7 log at BL(n=9,0,7,1,9,8)
    17.6 (8.4 to 30.9)
    0 (0 to 70.8)
    11.7 (4.8 to 22.6)
    50 (1.3 to 98.7)
    16.7 (7.9 to 29.3)
    12.9 (5.7 to 23.9)
        HBV DNA <300 Wk156 <7 log (n=45,3,60,2,48,62) LOCF
    88.2 (76.1 to 95.6)
    100 (29.2 to 100)
    100 (94 to 100)
    100 (15.8 to 100)
    88.9 (77.4 to 95.8)
    100 (94.2 to 100)
        Cumtx-emerg resist Wk156 <7log(n=4,0,0,0,4,0) LOCF
    8.7 (2.4 to 20.8)
    0 (0 to 70.8)
    0 (0 to 6)
    0 (0 to 84.2)
    8.2 (2.3 to 19.6)
    0 (0 to 5.8)
    No statistical analyses for this end point

    Secondary: eGFR change from baseline in telbivudine arm vs tenofovir arm over the course of the study

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    End point title
    		 eGFR change from baseline in telbivudine arm vs tenofovir arm over the course of the study
    End point description
    eGFR changes from baseline to Week52, Week104 and Week156 for the overall population.
    End point type
    Secondary
    End point timeframe
    52 weeks, 104 weeks, 156 weeks
    End point values
    		 LdT Mono at Week 24 LdT+TDF at Week 24 TDF Mono at Week 24 TDF + LdT at Week 24 LdT Overall TDF Overall
    Number of subjects analysed
    98
    22
    109
    11
    120
    120
    Units: mL/min/1.73 m2
    arithmetic mean (standard deviation)
        Week 24 Change (n=97,22,108,11,119,119)
    1.43 ( 12.815 )
    -12.06 ( 14.394 )
    -2.41 ( 14.885 )
    -7.17 ( 15.368 )
    -1.07 ( 14.076 )
    -2.85 ( 14.928 )
        Week 52 change(n=97,22,108,11,119,119)
    5.18 ( 18.842 )
    -6.8 ( 17.229 )
    -2.7 ( 18.636 )
    -8.39 ( 10.479 )
    2.96 ( 19.064 )
    -3.22 ( 18.082 )
        Week 104 change(n=97,22,108,11,119,119)
    5.19 ( 16.583 )
    -5.77 ( 15.943 )
    -3.83 ( 15.157 )
    -8.69 ( 15.632 )
    3.16 ( 16.947 )
    -4.28 ( 15.2 )
        Week 156 change(n=62,17,79,10,79,89)
    8.07 ( 16.777 )
    -10.89 ( 14.993 )
    -5.34 ( 13.393 )
    -6.67 ( 11.905 )
    3.99 ( 18.104 )
    -5.49 ( 13.178 )
        Baseline actual (98,22,109,11,120,120)
    94.71 ( 16.422 )
    109.79 ( 19.56 )
    95.91 ( 16.396 )
    94.5 ( 17.558 )
    97.47 ( 17.936 )
    95.78 ( 16.433 )
        Week 24 actual (n=97,22,108,11,119,119)
    96.43 ( 16.434 )
    97.73 ( 17.69 )
    93.61 ( 18.5 )
    87.33 ( 16.854 )
    96.67 ( 16.603 )
    93.03 ( 18.378 )
        Week 52 actual (n=97,22,108,11,119,119)
    100.18 ( 20.257 )
    102.99 ( 19.425 )
    93.32 ( 18.88 )
    86.12 ( 14.233 )
    100.7 ( 20.054 )
    92.66 ( 18.569 )
        Week 104 actual (n=97,22,108,11,119,119)
    100.2 ( 16.287 )
    104.02 ( 18.201 )
    92.19 ( 18.24 )
    85.81 ( 13.099 )
    100.7 ( 20.054 )
    92.66 ( 18.569 )
        Week 156 actual (n=62,17,79,10,79,89)
    101.33 ( 18.505 )
    100.7 ( 20.029 )
    88.83 ( 13.28 )
    87.93 ( 13.28 )
    100.9 ( 16.643 )
    91.6 ( 17.879 )
    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 are reported in this record from First Patient First Treatment until Last Patient Last Visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    LdT Mono at Week 24
    Reporting group description
    		 LdT Mono at Week 24

    Reporting group title
    LdT+TDF at Week 24
    Reporting group description
    		 LdT+TDF at Week 24

    Reporting group title
    TDF Mono at Week 24
    Reporting group description
    		 TDF Mono at Week 24

    Reporting group title
    TDF+LdT at Week 24
    Reporting group description
    		 TDF+LdT at Week 24

    Serious adverse events
    		 LdT Mono at Week 24 LdT+TDF at Week 24 TDF Mono at Week 24 TDF+LdT at Week 24
    Total subjects affected by serious adverse events
         subjects affected / exposed
    6 / 98 (6.12%)
    5 / 22 (22.73%)
    11 / 109 (10.09%)
    2 / 11 (18.18%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder cancer
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    0 / 11 (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
    Breast cancer
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Hepatocellular carcinoma
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 22 (0.00%)
    3 / 109 (2.75%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metastases to abdominal wall
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Metastasis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Vascular disorders
    Arterial occlusive disease
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 22 (4.55%)
    0 / 109 (0.00%)
    0 / 11 (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
    Thrombophlebitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    0 / 11 (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
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         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
    Respiratory, thoracic and mediastinal disorders
    Pneumothorax spontaneous
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 22 (4.55%)
    0 / 109 (0.00%)
    0 / 11 (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
    Psychiatric disorders
    Psychogenic pain disorder
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Investigations
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         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
    Nervous system disorders
    Carpal tunnel syndrome
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 22 (4.55%)
    0 / 109 (0.00%)
    0 / 11 (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
    Diabetic neuropathy
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    2 / 109 (1.83%)
    0 / 11 (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
    Gastroduodenitis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Cholecystitis acute
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    0 / 11 (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
    Hepatic cirrhosis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    3 / 109 (2.75%)
    0 / 11 (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
    Jaundice cholestatic
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Calculus ureteric
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 22 (4.55%)
    1 / 109 (0.92%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hydronephrosis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 22 (4.55%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Osteonecrosis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    0 / 11 (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
    Spinal column stenosis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         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
    Abdominal abscess
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Anal abscess
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Appendicitis
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 22 (4.55%)
    0 / 109 (0.00%)
    0 / 11 (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
    Metabolism and nutrition disorders
    Type 1 diabetes mellitus
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    0 / 11 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LdT Mono at Week 24 LdT+TDF at Week 24 TDF Mono at Week 24 TDF+LdT at Week 24
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 98 (61.22%)
    15 / 22 (68.18%)
    56 / 109 (51.38%)
    8 / 11 (72.73%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    7 / 98 (7.14%)
    4 / 22 (18.18%)
    5 / 109 (4.59%)
    0 / 11 (0.00%)
         occurrences all number
    7
    4
    5
    0
    Hypotension
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    5 / 98 (5.10%)
    1 / 22 (4.55%)
    0 / 109 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    5
    2
    0
    4
    Fatigue
         subjects affected / exposed
    5 / 98 (5.10%)
    1 / 22 (4.55%)
    8 / 109 (7.34%)
    0 / 11 (0.00%)
         occurrences all number
    6
    1
    8
    0
    Influenza like illness
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    2
    Oedema peripheral
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    2 / 11 (18.18%)
         occurrences all number
    2
    0
    1
    2
    Pyrexia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    2 / 11 (18.18%)
         occurrences all number
    0
    0
    1
    2
    Insomnia
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    5 / 98 (5.10%)
    0 / 22 (0.00%)
    5 / 109 (4.59%)
    1 / 11 (9.09%)
         occurrences all number
    5
    0
    5
    1
    Amylase increased
         subjects affected / exposed
    1 / 98 (1.02%)
    2 / 22 (9.09%)
    0 / 109 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    7 / 98 (7.14%)
    1 / 22 (4.55%)
    4 / 109 (3.67%)
    0 / 11 (0.00%)
         occurrences all number
    7
    1
    5
    0
    Blood creatine phosphokinase increased
         subjects affected / exposed
    24 / 98 (24.49%)
    10 / 22 (45.45%)
    17 / 109 (15.60%)
    2 / 11 (18.18%)
         occurrences all number
    48
    15
    42
    7
    Blood phosphorus increased
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    1
    1
    Injury, poisoning and procedural complications
    Epicondylitis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Laceration
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    1
    1
    Nervous system disorders
    Ataxia
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Headache
         subjects affected / exposed
    17 / 98 (17.35%)
    3 / 22 (13.64%)
    16 / 109 (14.68%)
    2 / 11 (18.18%)
         occurrences all number
    29
    15
    35
    10
    Paraesthesia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    0
    2
    Leukopenia
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 22 (0.00%)
    6 / 109 (5.50%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    6
    0
    Thrombocytopenia
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Visual impairment
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    0 / 98 (0.00%)
    1 / 22 (4.55%)
    2 / 109 (1.83%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    2
    2
    Abdominal pain upper
         subjects affected / exposed
    6 / 98 (6.12%)
    0 / 22 (0.00%)
    5 / 109 (4.59%)
    3 / 11 (27.27%)
         occurrences all number
    6
    0
    7
    4
    Diarrhoea
         subjects affected / exposed
    8 / 98 (8.16%)
    0 / 22 (0.00%)
    5 / 109 (4.59%)
    0 / 11 (0.00%)
         occurrences all number
    9
    0
    5
    0
    Dyspepsia
         subjects affected / exposed
    3 / 98 (3.06%)
    0 / 22 (0.00%)
    5 / 109 (4.59%)
    1 / 11 (9.09%)
         occurrences all number
    3
    0
    5
    1
    Gastritis
         subjects affected / exposed
    6 / 98 (6.12%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    6
    0
    1
    2
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Nausea
         subjects affected / exposed
    10 / 98 (10.20%)
    3 / 22 (13.64%)
    2 / 109 (1.83%)
    3 / 11 (27.27%)
         occurrences all number
    11
    3
    2
    3
    Toothache
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Alopecia
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    1
    Rash
         subjects affected / exposed
    2 / 98 (2.04%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    2
    0
    0
    1
    Seborrhoeic dermatitis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    2
    Renal and urinary disorders
    Crystalluria
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    Haematuria
         subjects affected / exposed
    1 / 98 (1.02%)
    5 / 22 (22.73%)
    1 / 109 (0.92%)
    0 / 11 (0.00%)
         occurrences all number
    1
    6
    1
    0
    Nephroptosis
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    3 / 98 (3.06%)
    3 / 22 (13.64%)
    8 / 109 (7.34%)
    2 / 11 (18.18%)
         occurrences all number
    5
    4
    9
    2
    Groin pain
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    1
    Myalgia
         subjects affected / exposed
    10 / 98 (10.20%)
    2 / 22 (9.09%)
    2 / 109 (1.83%)
    1 / 11 (9.09%)
         occurrences all number
    14
    6
    4
    1
    Neck pain
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Osteoarthritis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Pain in extremity
         subjects affected / exposed
    4 / 98 (4.08%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    2 / 11 (18.18%)
         occurrences all number
    4
    0
    2
    2
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    1 / 98 (1.02%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    1
    1
    Ear infection
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Influenza
         subjects affected / exposed
    8 / 98 (8.16%)
    2 / 22 (9.09%)
    8 / 109 (7.34%)
    2 / 11 (18.18%)
         occurrences all number
    12
    2
    11
    11
    Nasopharyngitis
         subjects affected / exposed
    7 / 98 (7.14%)
    2 / 22 (9.09%)
    8 / 109 (7.34%)
    1 / 11 (9.09%)
         occurrences all number
    14
    5
    9
    1
    Respiratory tract infection
         subjects affected / exposed
    3 / 98 (3.06%)
    0 / 22 (0.00%)
    1 / 109 (0.92%)
    1 / 11 (9.09%)
         occurrences all number
    5
    0
    1
    1
    Rhinitis
         subjects affected / exposed
    5 / 98 (5.10%)
    2 / 22 (9.09%)
    0 / 109 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    5
    2
    0
    0
    Metabolism and nutrition disorders
    Hyperglycaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    3
    Hypoalbuminaemia
         subjects affected / exposed
    0 / 98 (0.00%)
    0 / 22 (0.00%)
    0 / 109 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Oct 2011
    The main purposes of this amendment were to: -align inclusion criteria to current guidelines and update to clinical practice - introduce the following key exploratory objectives to evaluate liver fibrosis and further -investigate renal function under nucleos(t)ide analogues: -- Explore changes of exploratory liver fibrosis biomarkers over the course of the study  --Explore renal function using urine-kidney biomarkers -Provide further clarification for patient management in case of VB
    08 Apr 2013
    The rationale of this amendment was to extend the prospective 2-year study for an additional 1 year of treatment/follow-up (a total of 156 weeks), to assess the long-term benefits of telbivudine treatment on renal function (as assessed by eGFR), and to assess the long-term cumulative resistance rate in CHB patients. Also included in Amendment 2 was the introduction of the secondary objectives presented in the endpoints.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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