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    Clinical Trial Results:
    A Multicenter, Open-label, Randomized Phase 3 Clinical Study to Assess Efficacy and Safety of Bulevirtide in Patients with Chronic Hepatitis Delta

    Summary
    EudraCT number
    		 2019-001213-17
    Trial protocol
    		 SE   DE   IT  
    Global end of trial date
    08 Aug 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2025
    First version publication date
    21 Aug 2025
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MYR301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Clinicaltrials.gov: NCT03852719
    Sponsors
    Sponsor organisation name
    Gilead Sciences
    Sponsor organisation address
    333 Lakeside Drive, Foster City, CA, United States, 94404
    Public contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Scientific contact
    Gilead Clinical Study Information Center, Gilead Sciences, GileadClinicalTrials@gilead.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    08 Aug 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Aug 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of bulevirtide administered subcutaneously for 48 weeks at a dose of 2 mg or 10 mg once daily for treatment of chronic hepatitis delta in comparison to delayed treatment.
    Protection of trial subjects
    The protocol and consent/assent forms were submitted by each investigator to a duly constituted Independent Ethics Committee (IEC) or Institutional Review Board (IRB) for review and approval before study initiation. All revisions to the consent/assent forms (if applicable) after initial IEC/IRB approval were submitted by the investigator to the IEC/IRB for review and approval before implementation in accordance with regulatory requirements. This study was conducted in accordance with recognized international scientific and ethical standards, including but not limited to the International Conference on Harmonization guideline for Good Clinical Practice (ICH GCP) and the original principles embodied in the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Apr 2019
    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
    Sweden: 14
    Country: Number of subjects enrolled
    Germany: 27
    Country: Number of subjects enrolled
    Italy: 24
    Country: Number of subjects enrolled
    Russian Federation: 85
    Worldwide total number of subjects
    150
    EEA total number of subjects
    65
    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)
    150
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in Germany, Italy, Russia, and Sweden.

    Pre-assignment
    Screening details
    		 183 participants were screened.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Delayed Treatment/Bulevirtide 10 mg/Day
    Arm description
    		 After an observational period of 48 weeks, participants received bulevirtide 10 mg/day subcutaneous (SC) injection for 96 weeks and were followed for up to 96 weeks (Up to Week 240).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bulevirtide 10 mg
    Investigational medicinal product code
    Other name
    Myrcludex B, Hepcludex
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered via SC injections.

    Arm title
    		 Bulevirtide 2 mg/day
    Arm description
    		 Participants received bulevirtide 2 mg/day SC injection for 144 weeks and were followed for up to 96 weeks (Up to Week 240).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bulevirtide 2 mg
    Investigational medicinal product code
    Other name
    Myrcludex B, Hepcludex
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered via SC injections.

    Arm title
    		 Bulevirtide 10 mg/Day
    Arm description
    		 Participants received bulevirtide 10 mg/day SC injection for 144 weeks and were followed for up to 96 weeks (Up to Week 240).
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bulevirtide 10 mg
    Investigational medicinal product code
    Other name
    Myrcludex B, Hepcludex
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered via SC injections.

    Number of subjects in period 1
    		Delayed Treatment/Bulevirtide 10 mg/Day Bulevirtide 2 mg/day Bulevirtide 10 mg/Day
    Started
    51
    49
    50
    Completed
    28
    28
    30
    Not completed
    23
    21
    20
         Physician decision
    5
    4
    1
         Adverse Event
    2
    1
    4
         Death
    1
    -
    -
         Pregnancy
    2
    1
    -
         Withdrawal of consent
    8
    8
    9
         Progressive disease
    1
    4
    1
         Lost to follow-up
    1
    -
    -
         Reason not Specified
    3
    3
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Delayed Treatment/Bulevirtide 10 mg/Day
    Reporting group description
    		 After an observational period of 48 weeks, participants received bulevirtide 10 mg/day subcutaneous (SC) injection for 96 weeks and were followed for up to 96 weeks (Up to Week 240).

    Reporting group title
    Bulevirtide 2 mg/day
    Reporting group description
    		 Participants received bulevirtide 2 mg/day SC injection for 144 weeks and were followed for up to 96 weeks (Up to Week 240).

    Reporting group title
    Bulevirtide 10 mg/Day
    Reporting group description
    		 Participants received bulevirtide 10 mg/day SC injection for 144 weeks and were followed for up to 96 weeks (Up to Week 240).

    Reporting group values
    		 Delayed Treatment/Bulevirtide 10 mg/Day Bulevirtide 2 mg/day Bulevirtide 10 mg/Day Total
    Number of subjects
    		 51 49 50 150
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 51 49 50 150
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41 ( 7.5 ) 44 ( 9.0 ) 41 ( 8.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 25 19 20 64
        Male
    		 26 30 30 86
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0
        Asian
    		 11 8 6 25
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 0 0 1 1
        White
    		 40 41 43 124
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 0 0 0 0
    Liver stiffness
    Units: kPa
        arithmetic mean (standard deviation)
    		 15.3 ( 8.95 ) 14.0 ( 8.19 ) 14.8 ( 9.26 ) -
    Hepatitis Delta Virus (HDV) Ribonucleic Acid (RNA)
    Units: log10 IU/mL
        arithmetic mean (standard deviation)
    		 5.08 ( 1.358 ) 5.10 ( 1.194 ) 4.96 ( 1.461 ) -

    End points

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    End points reporting groups
    Reporting group title
    Delayed Treatment/Bulevirtide 10 mg/Day
    Reporting group description
    		 After an observational period of 48 weeks, participants received bulevirtide 10 mg/day subcutaneous (SC) injection for 96 weeks and were followed for up to 96 weeks (Up to Week 240).

    Reporting group title
    Bulevirtide 2 mg/day
    Reporting group description
    		 Participants received bulevirtide 2 mg/day SC injection for 144 weeks and were followed for up to 96 weeks (Up to Week 240).

    Reporting group title
    Bulevirtide 10 mg/Day
    Reporting group description
    		 Participants received bulevirtide 10 mg/day SC injection for 144 weeks and were followed for up to 96 weeks (Up to Week 240).

    Subject analysis set title
    Delayed Treatment
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Observation period of 48 weeks.

    Subject analysis set title
    Bulevirtide 2 mg/Day
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received bulevirtide 2 mg/day SC injection for 48 weeks which continued up to 144 weeks and were followed for 96 weeks (Up to Week 240).

    Subject analysis set title
    Bulevirtide 10 mg/Day
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    Participants received bulevirtide 10 mg/day SC injection for 48 weeks which continued up to 144 weeks and were followed for 96 weeks (Up to Week 240).

    Subject analysis set title
    Delayed Treatment/Bulevirtide 10 mg/Day
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    After an observational period of 48 weeks, participants received bulevirtide 10 mg/day SC injection for 96 weeks and were followed for up to 96 weeks (Up to Week 240).

    Primary: Percentage of Participants With Combined Response at Week 48

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    End point title
    		 Percentage of Participants With Combined Response at Week 48
    End point description
    Combined response was defined as fulfilment of two conditions simultaneously: Undetectable (< lower limit of quantification (LLOQ, target not detected)) HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline; and ALT normalization. Analysis Population Description: The Full Analysis Set included participants randomized to delayed treatment arm or randomized to bulevirtide and received bulevirtide at least once after randomization. Participants were grouped according to randomized treatment. The arm titles and descriptions in this outcome measure are entered accordingly.
    End point type
    Primary
    End point timeframe
    Week 48
    End point values
    		 Delayed Treatment Bulevirtide 2 mg/Day Bulevirtide 10 mg/Day
    Number of subjects analysed
    51
    49
    50
    Units: percentage of participants
        number (confidence interval 95%)
    2.0 (0.0 to 10.4)
    44.9 (30.7 to 59.8)
    48.0 (33.7 to 62.6)
    Statistical analysis title
    		 Delayed Treatment V/s Bulevirtide 2 mg/Day
    Comparison groups
    Delayed Treatment v Bulevirtide 2 mg/Day
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [1]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    42.9
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 27
         upper limit
    		 58.5
    Notes
    [1] - Fisher's exact test was used for comparison of bulevirtide 2 mg versus Delayed Treatment using a significance level of 0.04 at Week 48.
    Statistical analysis title
    		 Delayed Treatment V/s Bulevirtide 10 mg/Day
    Comparison groups
    Delayed Treatment v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [2]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    46
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 30.5
         upper limit
    		 61.4
    Notes
    [2] - Fisher's exact test was used for comparison of bulevirtide 10 mg versus Delayed Treatment using a significance level of 0.04 at Week 48.

    Secondary: Percentage of Participants With Undetectable HDV RNA at Week 48

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    End point title
    		 Percentage of Participants With Undetectable HDV RNA at Week 48
    End point description
    Undetectable HDV RNA at Week 48 means undetectable (< LLOQ, target not detected) HDV RNA at Week 48. Analysis Population Description : Participants in the Full Analysis Set were analyzed. Participants were grouped according to randomized treatment. The arm titles and descriptions in this outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Delayed Treatment Bulevirtide 2 mg/Day Bulevirtide 10 mg/Day
    Number of subjects analysed
    51
    49
    50
    Units: percentage of participants
        number (confidence interval 95%)
    0 (0.0 to 7.0)
    12.2 (4.6 to 24.8)
    20.0 (10.0 to 33.7)
    Statistical analysis title
    		 Bulevirtide 2 mg/Day V/s Bulevirtide 10 mg/Day
    Comparison groups
    Bulevirtide 2 mg/Day v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.4139 [3]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    7.8
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 24.3
    Notes
    [3] - Fisher's exact test was used for the comparison of bulevirtide 10 mg versus bulevirtide 2 mg using a significance level of 0.04 at Week 48.

    Secondary: Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48

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    End point title
    		 Percentage of Participants With Alanine Aminotransferase (ALT) Normalization at Week 48
    End point description
    ALT normalization was defined as an ALT value within the normal range, based on the central laboratories [Russian sites: ≤ 31 U/L for females and ≤ 41 U/L for males; all other sites: ≤ 34 U/L for females and ≤ 49 U/L for males]). Analysis Population Description : Participants in the Full Analysis Set were analyzed. Participants were grouped according to randomized treatment. The arm titles and descriptions in this outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Delayed Treatment Bulevirtide 2 mg/Day Bulevirtide 10 mg/Day
    Number of subjects analysed
    51
    49
    50
    Units: percentage of participants
        number (confidence interval 95%)
    11.8 (4.4 to 23.9)
    51.0 (36.3 to 65.6)
    56.0 (41.3 to 70.0)
    Statistical analysis title
    		 Delayed Treatment V/s Bulevirtide 2 mg/Day
    Comparison groups
    Bulevirtide 2 mg/Day v Delayed Treatment
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [4]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    39.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 20
         upper limit
    		 55.8
    Notes
    [4] - Fisher's exact test was used for comparison of bulevirtide 2 mg versus Delayed treatment using a significance level of 0.05.
    Statistical analysis title
    		 Delayed Treatment V/s Bulevirtide 10 mg/Day
    Comparison groups
    Delayed Treatment v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    101
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.0001 [5]
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    44.2
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 25.8
         upper limit
    		 59.9
    Notes
    [5] - Fisher's exact test was used for comparison of bulevirtide 10 mg versus Delayed treatment using a significance level of 0.05.

    Secondary: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 48

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    End point title
    		 Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 48
    End point description
    ANCOVA was used for analysis. Analysis Population Description : Participants in the Full Analysis Set with available data were analyzed. Data is reported separately for changes from Baseline at Week 48 for the Delayed Treatment arm and for Delayed Treatment/Bulevirtide 10 mg/day arm after 48 weeks of BLV 10 mg treatment. Participants were grouped according to randomized treatment and study design. The arm titles and descriptions in the outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline for Delayed Treatment/Bulevirtide 10 mg/day is reset at Week 48), Week 48
    End point values
    		 Delayed Treatment Bulevirtide 2 mg/Day Bulevirtide 10 mg/Day Delayed Treatment/Bulevirtide 10 mg/Day
    Number of subjects analysed
    46
    48
    42
    48
    Units: kPa
        least squares mean (confidence interval 95%)
    0.87 (-0.79 to 2.53)
    -3.06 (-4.67 to -1.45)
    -3.16 (-4.88 to -1.43)
    -3.36 (-4.60 to -2.12)
    Statistical analysis title
    		 Delayed Treatment V/s Bulevirtide 10 mg/Day
    Comparison groups
    Delayed Treatment v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 other [6]
    P-value
    		 = 0.001
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -4.02
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.39
         upper limit
    		 -1.65
    Notes
    [6] - Least squares (LS) means, standard errors (SE) and 95% CIs were from an analysis of covariance (ANCOVA) model for change from baseline at W48 in liver stiffness adjusted for treatment group, region, and presence of cirrhosis; with baseline liver stiffness as a covariate.
    Statistical analysis title
    		 Delayed Treatment V/s Bulevirtide 2 mg/Day
    Comparison groups
    Delayed Treatment v Bulevirtide 2 mg/Day
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [7]
    P-value
    		 = 0.0009
    Method
    		 ANCOVA
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -3.93
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.23
         upper limit
    		 -1.63
    Notes
    [7] - Least squares (LS) means, standard errors (SE) and 95% CIs were based on the mixed-effects model for repeated measurements (MMRM) model for change from baseline with treatment (BLV 2 mg, BLV 10 mg, and DT to BLV 10 mg group), region, presence of cirrhosis, visit and treatment by visit interaction as fixed effects, and baseline value as a covariate.

    Secondary: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 96

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    End point title
    		 Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 96
    End point description
    Mixed model for repeated measurements (MMRM) was used for analysis. Analysis Population Description : Participants from Full Analysis Set with available data were analyzed. Participants were grouped according to randomized treatment and study design. The arm titles and descriptions in the outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline for Delayed Treatment/Bulevirtide 10 mg/day is reset at Week 48), Week 96
    End point values
    		 Bulevirtide 2 mg/Day Bulevirtide 10 mg/Day Delayed Treatment/Bulevirtide 10 mg/Day
    Number of subjects analysed
    47
    47
    48
    Units: kPa
        least squares mean (confidence interval 95%)
    -4.31 (-5.54 to -3.08)
    -4.88 (-6.11 to -3.65)
    -4.20 (-5.41 to -2.98)
    Statistical analysis title
    		 Bulevirtide 2 mg/Day V/s Bulevirtide 10 mg/Day
    Comparison groups
    Bulevirtide 2 mg/Day v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 other [8]
    P-value
    		 = 0.5156
    Method
    		 MMRM
    Parameter type
    		 Difference in Least Square (LS) Mean
    Point estimate
    0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.16
         upper limit
    		 2.3
    Notes
    [8] - Least squares (LS) means, standard errors (SE) and 95% CIs were based on the mixed-effects model for repeated measurements (MMRM) model for change from baseline with treatment (BLV 2 mg, BLV 10 mg, and DT to BLV 10 mg group), region, presence of cirrhosis, visit and treatment by visit interaction as fixed effects, and baseline value as a covariate.

    Secondary: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 144

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    End point title
    		 Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 144 [9]
    End point description
    MMRM was used for analysis. Analysis Population Description : Participants from Full Analysis Set with available data were analyzed. Participants were grouped according to randomized treatment and study design. The arm titles and descriptions in the outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 144
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Bulevirtide 2 mg/day Bulevirtide 10 mg/Day
    Number of subjects analysed
    45
    43
    Units: kPa
        least squares mean (confidence interval 95%)
    -5.24 (-6.85 to -3.63)
    -4.03 (-5.67 to -2.40)
    Statistical analysis title
    		 Bulevirtide 2 mg/Day V/s Bulevirtide 10 mg/Day
    Comparison groups
    Bulevirtide 2 mg/day v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    88
    Analysis specification
    Pre-specified
    Analysis type
    		 other [10]
    P-value
    		 = 0.2977
    Method
    		 MMRM
    Parameter type
    		 Difference in Least Square (LS) Mean
    Point estimate
    -1.21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.5
         upper limit
    		 1.08
    Notes
    [10] - Least squares (LS) means, standard errors (SE) and 95% CIs were based on the mixed-effects model for repeated measurements (MMRM) model for change from baseline with treatment (BLV 2 mg, BLV 10 mg, and DT to BLV 10 mg group), region, presence of cirrhosis, visit and treatment by visit interaction as fixed effects, and baseline value as a covariate.

    Secondary: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 192

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    End point title
    		 Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 192 [11]
    End point description
    Participants from Full Analysis Set with available data were analyzed. Participants were grouped according to randomized treatment and study design. The arm titles and descriptions in the outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline for DT to BLV 10 mg was reset at Week 48), Week 192
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Bulevirtide 2 mg/day Bulevirtide 10 mg/Day Delayed Treatment/Bulevirtide 10 mg/Day
    Number of subjects analysed
    35
    34
    35
    Units: kPa
        least squares mean (confidence interval 95%)
    -3.74 (-5.28 to -2.20)
    -3.70 (-5.27 to -2.14)
    -1.91 (-3.49 to -0.34)
    Statistical analysis title
    		 Bulevirtide 2 mg/Day V/s Bulevirtide 10 mg/Day
    Comparison groups
    Bulevirtide 2 mg/day v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    69
    Analysis specification
    Pre-specified
    Analysis type
    		 other [12]
    P-value
    		 = 0.9719 [13]
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -0.04
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.23
         upper limit
    		 2.15
    Notes
    [12] - Least squares (LS) means, standard errors (SE) and 95% CIs were based on the mixed-effects model for repeated measurements (MMRM) model for change from baseline with treatment (BLV 2 mg, BLV 10 mg, and DT to BLV 10 mg group), region, presence of cirrhosis, visit and treatment by visit interaction as fixed effects, and baseline value as a covariate.
    [13] - P-value was based on the mixed-effects model for repeated measurements (MMRM) model.

    Secondary: Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 240

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    End point title
    		 Change From Baseline in Liver Stiffness, as Measured by Elastography at Week 240 [14]
    End point description
    MMRM was used for analysis. Analysis Population Description : Participants from Full Analysis Set with available data were analyzed. Participants were grouped according to randomized treatment and study design. The arm titles and descriptions in the outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Baseline (Baseline for DT to BLV 10 mg was reset at Week 48), Week 240
    Notes
    [14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Bulevirtide 2 mg/day Bulevirtide 10 mg/Day Delayed Treatment/Bulevirtide 10 mg/Day
    Number of subjects analysed
    28
    29
    28
    Units: kPa
        least squares mean (confidence interval 95%)
    -1.20 (-3.71 to 1.31)
    -3.31 (-5.78 to -0.84)
    -3.59 (-6.14 to -1.04)
    Statistical analysis title
    		 Bulevirtide 2 mg/Day V/s Bulevirtide 10 mg/Day
    Comparison groups
    Bulevirtide 2 mg/day v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    57
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [15]
    P-value
    		 = 0.2369 [16]
    Method
    		 MMRM
    Parameter type
    		 LS-Mean of Difference
    Point estimate
    2.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.41
         upper limit
    		 5.63
    Notes
    [15] - Least squares (LS) means, standard errors (SE), 95% CIs were based on the mixed-effects model for repeated measurements (MMRM) model for change from baseline
    [16] - P-value was based on the mixed-effects model for repeated measurements (MMRM) model.

    Secondary: Percentage of Participants With Undetectable HDV RNA 24 Weeks After Scheduled End of Treatment (Sustained Virological Response)

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    End point title
    		 Percentage of Participants With Undetectable HDV RNA 24 Weeks After Scheduled End of Treatment (Sustained Virological Response) [17]
    End point description
    Undetectable HDV RNA 24 Weeks after Scheduled End of Treatment means undetectable (< LLOQ, target not detected) HDV RNA at Week 168. Analysis Population Description : Participants in the Full Analysis Set were analyzed. Participants were grouped according to randomized treatment and study design. The arm titles and descriptions in the outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Week 168
    Notes
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Bulevirtide 2 mg/day Bulevirtide 10 mg/Day Delayed Treatment/Bulevirtide 10 mg/Day
    Number of subjects analysed
    49
    50
    50
    Units: percentage of participants
        number (confidence interval 95%)
    18.4 (8.8 to 32.0)
    26.0 (14.6 to 40.3)
    18.0 (8.6 to 31.4)
    Statistical analysis title
    		 Bulevirtide 2 mg/Day V/s Bulevirtide 10 mg/Day
    Comparison groups
    Bulevirtide 2 mg/day v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4695 [18]
    Method
    		 Fisher exact
    Parameter type
    		 Response Rate Difference
    Point estimate
    7.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.6
         upper limit
    		 24.4
    Notes
    [18] - P-value was based on Fisher's Exact Test.
    Statistical analysis title
    		 BLV 2 mg/Day V/s Delayed Treatment/BLV 10 mg/Day
    Comparison groups
    Bulevirtide 2 mg/day v Delayed Treatment/Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [19]
    Method
    		 Fisher exact
    Parameter type
    		 Response Rate Difference
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -16.3
         upper limit
    		 15.5
    Notes
    [19] - P-value was based on Fisher's Exact Test.

    Secondary: Percentage of Participants With Undetectable HDV RNA 48 Weeks After Scheduled End of Treatment (Sustained Virological Response)

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    End point title
    		 Percentage of Participants With Undetectable HDV RNA 48 Weeks After Scheduled End of Treatment (Sustained Virological Response) [20]
    End point description
    Undetectable HDV RNA 48 Weeks after Scheduled End of Treatment means undetectable (< LLOQ, target not detected) HDV RNA at Week 192. Analysis Population Description : Participants in the Full Analysis Set were analyzed. Participants were grouped according to randomized treatment and study design. The arm titles and descriptions in the outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Week 192
    Notes
    [20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Bulevirtide 2 mg/day Bulevirtide 10 mg/Day Delayed Treatment/Bulevirtide 10 mg/Day
    Number of subjects analysed
    49
    50
    50
    Units: percentage of participants
        number (confidence interval 95%)
    16.3 (7.3 to 29.7)
    24.0 (13.1 to 38.2)
    16.0 (7.2 to 29.1)
    Statistical analysis title
    		 Bulevirtide 2 mg/Day V/s Bulevirtide 10 mg/Day
    Comparison groups
    Bulevirtide 2 mg/day v Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4539 [21]
    Method
    		 Fisher exact
    Parameter type
    		 Response Rate Difference
    Point estimate
    7.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.8
         upper limit
    		 24
    Notes
    [21] - P-value was based on Fisher's Exact Test.
    Statistical analysis title
    		 BLV 2 mg/Day V/s DT/Bulevirtide 10 mg/Day
    Comparison groups
    Bulevirtide 2 mg/day v Delayed Treatment/Bulevirtide 10 mg/Day
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1 [22]
    Method
    		 Fisher exact
    Parameter type
    		 Response Rate Difference
    Point estimate
    -0.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -15.6
         upper limit
    		 15.5
    Notes
    [22] - P-value was based on Fisher's Exact Test.

    Secondary: Percentage of Participants Who Prematurely Discontinued Study Drug Due to an Adverse Event (AE) by Week 144

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    End point title
    		 Percentage of Participants Who Prematurely Discontinued Study Drug Due to an Adverse Event (AE) by Week 144 [23]
    End point description
    An AE was defined as any untoward medical occurrence in a participant administered study drug and which did not necessarily have a causal relationship with the study drug. An AE could therefore be any unfavourable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of study drug, whether or not related to the study drug. Analysis Population Description : Participants in the SAS were analyzed. The SAS included all participants who were randomized into the study and took at least 1 dose of BLV study drug, or who were randomized to the delayed treatment group. Participants were grouped according to actual treatment received for time points Week 0 to 144. The arm titles and descriptions in this outcome measure are entered accordingly.
    End point type
    Secondary
    End point timeframe
    Delayed Treatment/Bulevirtide 10 mg/day arm: Week 48 up to Week 144; Bulevirtide 2mg/day and 10 mg/day arms: First dose date up to Week 144
    Notes
    [23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical comparison was planned or performed.
    End point values
    		 Bulevirtide 2 mg/day Bulevirtide 10 mg/Day Delayed Treatment/Bulevirtide 10 mg/Day
    Number of subjects analysed
    49
    50
    50
    Units: percentage of participants
        number (not applicable)
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-Cause Mortality: Up to Week 240; Adverse Events: Week 0-48, Week 0-144, Week 48-144 and >Week 144 up to Week 240 per treatment description
    Adverse event reporting additional description
    Participants grouped according to treatment received for time points Week (Wk) 0 to 48, 0 to 144, 48 to 144 and last treatment received after Wk144, up to Wk240. Arm titles and descriptions were entered accordingly. Actual treatment= randomized treatment, unless actual treatment was different than randomized treatment for entire treatment duration.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.1
    Reporting groups
    Reporting group title
    Delayed Treatment (Baseline to Week 48)
    Reporting group description
    		 Observation for 48 weeks.

    Reporting group title
    Bulevirtide 10 mg/Day (Baseline to Week 48)
    Reporting group description
    		 Bulevirtide 10 mg/day SC injection for 48 weeks.

    Reporting group title
    Bulevirtide 2 mg/Day (Baseline to Week 144)
    Reporting group description
    		 Participants received bulevirtide 2 mg/day SC injection for 144 weeks.

    Reporting group title
    DT/Bulevirtide 10 mg/Day (After EOT (>Week 144 up to Week 240)
    Reporting group description
    		 After 96 weeks of treatment (Up to Week 144) with bulevirtide 10 mg/day SC injection, participants were followed for up to 96 weeks (Up to Week 240).

    Reporting group title
    Delayed Treatment/Bulevirtide 10 mg/Day (Week 48 to Week 144)
    Reporting group description
    		 After an observational period of 48 weeks, participants received bulevirtide 10 mg/day SC injection for 96 weeks (Up to Week 144).

    Reporting group title
    Bulevirtide 2 mg/Day (After EOT (>Week 144 up to Week 240))
    Reporting group description
    		 After 144 weeks of treatment with bulevirtide 2 mg/day, participants were followed for up to 96 weeks (up to Week 240).

    Reporting group title
    Bulevirtide 10 mg/Day (After EOT (>Week 144 up to Week 240))
    Reporting group description
    		 After 144 weeks of treatment with bulevirtide 10 mg/day SC injection, participants were followed for up to 96 weeks (Up to Week 240).

    Reporting group title
    Bulevirtide 2 mg/Day (Baseline to Week 48)
    Reporting group description
    		 Bulevirtide 2 mg/day SC injection for 48 weeks.

    Reporting group title
    Bulevirtide 10 mg/Day (Baseline to Week 144)
    Reporting group description
    		 Participants received bulevirtide 10 mg/day SC injection for 144 weeks.

    Serious adverse events
    		 Delayed Treatment (Baseline to Week 48) Bulevirtide 10 mg/Day (Baseline to Week 48) Bulevirtide 2 mg/Day (Baseline to Week 144) DT/Bulevirtide 10 mg/Day (After EOT (>Week 144 up to Week 240) Delayed Treatment/Bulevirtide 10 mg/Day (Week 48 to Week 144) Bulevirtide 2 mg/Day (After EOT (>Week 144 up to Week 240)) Bulevirtide 10 mg/Day (After EOT (>Week 144 up to Week 240)) Bulevirtide 2 mg/Day (Baseline to Week 48) Bulevirtide 10 mg/Day (Baseline to Week 144)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    3 / 49 (6.12%)
    8 / 49 (16.33%)
    3 / 50 (6.00%)
    7 / 46 (15.22%)
    7 / 47 (14.89%)
    2 / 49 (4.08%)
    6 / 50 (12.00%)
         number of deaths (all causes)
    0
    0
    0
    1
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Alanine aminotransferase ~ increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transaminases increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Plasma cell myeloma
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Phyllodes tumour
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Foot fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Lumbar vertebral fracture
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hemiparesis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paralysis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Varices oesophageal
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Oesophageal varices haemorrhage
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic fibrosis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatic function abnormal
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Liver injury
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis acute
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Urinary retention
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Hepatitis D
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
    0 / 50 (0.00%)
    4 / 46 (8.70%)
    4 / 47 (8.51%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 0
    0 / 4
    0 / 4
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic hepatitis B
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Covid-19 pneumonia
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Coronavirus pneumonia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatitis E
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Yersinia infection
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Delayed Treatment (Baseline to Week 48) Bulevirtide 10 mg/Day (Baseline to Week 48) Bulevirtide 2 mg/Day (Baseline to Week 144) DT/Bulevirtide 10 mg/Day (After EOT (>Week 144 up to Week 240) Delayed Treatment/Bulevirtide 10 mg/Day (Week 48 to Week 144) Bulevirtide 2 mg/Day (After EOT (>Week 144 up to Week 240)) Bulevirtide 10 mg/Day (After EOT (>Week 144 up to Week 240)) Bulevirtide 2 mg/Day (Baseline to Week 48) Bulevirtide 10 mg/Day (Baseline to Week 144)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    30 / 51 (58.82%)
    41 / 50 (82.00%)
    44 / 49 (89.80%)
    34 / 49 (69.39%)
    41 / 50 (82.00%)
    31 / 46 (67.39%)
    33 / 47 (70.21%)
    35 / 49 (71.43%)
    46 / 50 (92.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    2 / 50 (4.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 49 (2.04%)
    4 / 50 (8.00%)
         occurrences all number
    0
    3
    3
    1
    2
    0
    0
    1
    4
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    2 / 49 (4.08%)
    4 / 49 (8.16%)
    1 / 50 (2.00%)
    3 / 46 (6.52%)
    4 / 47 (8.51%)
    1 / 49 (2.04%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    2
    4
    1
    3
    4
    1
    3
    Injection site erythema
         subjects affected / exposed
    0 / 51 (0.00%)
    5 / 50 (10.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    2 / 49 (4.08%)
    5 / 50 (10.00%)
         occurrences all number
    0
    5
    13
    0
    6
    0
    0
    2
    5
    Fatigue
         subjects affected / exposed
    1 / 51 (1.96%)
    7 / 50 (14.00%)
    7 / 49 (14.29%)
    4 / 49 (8.16%)
    3 / 50 (6.00%)
    0 / 46 (0.00%)
    5 / 47 (10.64%)
    5 / 49 (10.20%)
    9 / 50 (18.00%)
         occurrences all number
    1
    18
    12
    4
    3
    0
    6
    8
    22
    Injection site reaction
         subjects affected / exposed
    0 / 51 (0.00%)
    5 / 50 (10.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    3 / 49 (6.12%)
    6 / 50 (12.00%)
         occurrences all number
    0
    7
    3
    0
    4
    0
    0
    3
    8
    Pyrexia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    1 / 46 (2.17%)
    2 / 47 (4.26%)
    1 / 49 (2.04%)
    4 / 50 (8.00%)
         occurrences all number
    0
    2
    3
    0
    1
    1
    2
    1
    6
    Injection site pruritus
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    2 / 49 (4.08%)
    3 / 50 (6.00%)
         occurrences all number
    0
    6
    2
    0
    3
    0
    0
    2
    6
    Injection site swelling
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 49 (2.04%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    0
    1
    3
    Oedema peripheral
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    2
    0
    0
    0
    0
    1
    0
    3
    Psychiatric disorders
    Sleep disorder
         subjects affected / exposed
    1 / 51 (1.96%)
    3 / 50 (6.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    2 / 47 (4.26%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    1
    8
    0
    0
    0
    0
    2
    0
    8
    Investigations
    Blood bilirubin increased
         subjects affected / exposed
    0 / 51 (0.00%)
    1 / 50 (2.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
    2 / 49 (4.08%)
    1 / 50 (2.00%)
         occurrences all number
    0
    1
    6
    1
    0
    2
    1
    3
    2
    Transaminases increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    2 / 49 (4.08%)
    0 / 50 (0.00%)
    2 / 46 (4.35%)
    7 / 47 (14.89%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    0
    0
    2
    0
    2
    7
    0
    1
    Bilirubin conjugated increased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    4 / 46 (8.70%)
    1 / 47 (2.13%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    4
    1
    0
    0
    Lipase increased
         subjects affected / exposed
    1 / 51 (1.96%)
    1 / 50 (2.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    1 / 46 (2.17%)
    2 / 47 (4.26%)
    2 / 49 (4.08%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    8
    0
    2
    1
    2
    3
    5
    Alpha-2 macroglobulin increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    4 / 49 (8.16%)
    6 / 49 (12.24%)
    2 / 50 (4.00%)
    2 / 46 (4.35%)
    3 / 47 (6.38%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    1
    0
    4
    6
    2
    2
    3
    0
    3
    Aspartate aminotransferase increased
         subjects affected / exposed
    3 / 51 (5.88%)
    1 / 50 (2.00%)
    2 / 49 (4.08%)
    15 / 49 (30.61%)
    1 / 50 (2.00%)
    17 / 46 (36.96%)
    11 / 47 (23.40%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
         occurrences all number
    4
    1
    2
    21
    2
    18
    11
    1
    1
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 50 (4.00%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    2 / 50 (4.00%)
    8 / 46 (17.39%)
    4 / 47 (8.51%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    1
    4
    1
    4
    3
    8
    5
    0
    6
    Alanine aminotransferase increased
         subjects affected / exposed
    4 / 51 (7.84%)
    3 / 50 (6.00%)
    5 / 49 (10.20%)
    18 / 49 (36.73%)
    0 / 50 (0.00%)
    19 / 46 (41.30%)
    11 / 47 (23.40%)
    2 / 49 (4.08%)
    4 / 50 (8.00%)
         occurrences all number
    4
    3
    6
    23
    0
    21
    11
    2
    4
    Amylase increased
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences all number
    2
    0
    4
    0
    1
    0
    1
    1
    0
    Activated partial thromboplastin time ~ prolonged
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    2 / 50 (4.00%)
    2 / 46 (4.35%)
    3 / 47 (6.38%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    1
    0
    2
    2
    2
    3
    0
    1
    Hepatitis D RNA positive
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    4 / 47 (8.51%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    4
    0
    0
    Weight decreased
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    3 / 46 (6.52%)
    1 / 47 (2.13%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    3
    1
    0
    0
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    4 / 50 (8.00%)
    1 / 46 (2.17%)
    2 / 47 (4.26%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    1
    0
    2
    0
    6
    2
    2
    0
    4
    Bradycardia
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    1
    0
    0
    0
    0
    0
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 51 (0.00%)
    10 / 50 (20.00%)
    10 / 49 (20.41%)
    1 / 49 (2.04%)
    7 / 50 (14.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    9 / 49 (18.37%)
    12 / 50 (24.00%)
         occurrences all number
    0
    21
    33
    1
    12
    0
    1
    25
    49
    Dizziness
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    2 / 49 (4.08%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    2 / 49 (4.08%)
    4 / 50 (8.00%)
         occurrences all number
    0
    3
    2
    1
    1
    0
    0
    2
    4
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    8 / 51 (15.69%)
    5 / 50 (10.00%)
    10 / 49 (20.41%)
    7 / 49 (14.29%)
    7 / 50 (14.00%)
    6 / 46 (13.04%)
    5 / 47 (10.64%)
    5 / 49 (10.20%)
    8 / 50 (16.00%)
         occurrences all number
    10
    6
    14
    9
    10
    6
    6
    6
    17
    Neutropenia
         subjects affected / exposed
    3 / 51 (5.88%)
    5 / 50 (10.00%)
    8 / 49 (16.33%)
    3 / 49 (6.12%)
    3 / 50 (6.00%)
    3 / 46 (6.52%)
    4 / 47 (8.51%)
    2 / 49 (4.08%)
    10 / 50 (20.00%)
         occurrences all number
    5
    5
    12
    3
    6
    4
    5
    3
    17
    Leukopenia
         subjects affected / exposed
    10 / 51 (19.61%)
    5 / 50 (10.00%)
    10 / 49 (20.41%)
    5 / 49 (10.20%)
    7 / 50 (14.00%)
    2 / 46 (4.35%)
    4 / 47 (8.51%)
    7 / 49 (14.29%)
    9 / 50 (18.00%)
         occurrences all number
    12
    6
    23
    6
    9
    2
    5
    9
    20
    Eosinophilia
         subjects affected / exposed
    0 / 51 (0.00%)
    5 / 50 (10.00%)
    5 / 49 (10.20%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    5 / 49 (10.20%)
    5 / 50 (10.00%)
         occurrences all number
    0
    5
    5
    0
    1
    0
    0
    5
    5
    Lymphopenia
         subjects affected / exposed
    4 / 51 (7.84%)
    4 / 50 (8.00%)
    8 / 49 (16.33%)
    7 / 49 (14.29%)
    5 / 50 (10.00%)
    3 / 46 (6.52%)
    4 / 47 (8.51%)
    4 / 49 (8.16%)
    6 / 50 (12.00%)
         occurrences all number
    8
    5
    22
    10
    9
    3
    5
    5
    16
    Anaemia
         subjects affected / exposed
    3 / 51 (5.88%)
    2 / 50 (4.00%)
    5 / 49 (10.20%)
    5 / 49 (10.20%)
    3 / 50 (6.00%)
    1 / 46 (2.17%)
    1 / 47 (2.13%)
    3 / 49 (6.12%)
    3 / 50 (6.00%)
         occurrences all number
    4
    2
    5
    5
    5
    1
    1
    3
    7
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    1 / 51 (1.96%)
    5 / 50 (10.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 49 (0.00%)
    5 / 50 (10.00%)
         occurrences all number
    1
    13
    2
    0
    2
    0
    1
    0
    13
    Nausea
         subjects affected / exposed
    2 / 51 (3.92%)
    4 / 50 (8.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    3 / 49 (6.12%)
    6 / 50 (12.00%)
         occurrences all number
    2
    6
    9
    1
    1
    0
    0
    9
    9
    Diarrhoea
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    9
    0
    0
    1
    0
    1
    0
    10
    Abdominal pain
         subjects affected / exposed
    1 / 51 (1.96%)
    4 / 50 (8.00%)
    2 / 49 (4.08%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    1 / 49 (2.04%)
    4 / 50 (8.00%)
         occurrences all number
    1
    9
    3
    0
    2
    0
    1
    1
    11
    Gastritis
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    0 / 49 (0.00%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    1 / 47 (2.13%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    0
    0
    0
    0
    1
    0
    3
    Hepatobiliary disorders
    Hepatic fibrosis
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    1 / 49 (2.04%)
    3 / 49 (6.12%)
    2 / 50 (4.00%)
    5 / 46 (10.87%)
    4 / 47 (8.51%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    1
    3
    2
    5
    4
    0
    0
    Hyperbilirubinaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    4 / 49 (8.16%)
    1 / 49 (2.04%)
    3 / 50 (6.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    2 / 49 (4.08%)
    2 / 50 (4.00%)
         occurrences all number
    0
    2
    6
    2
    5
    1
    0
    2
    5
    Skin and subcutaneous tissue disorders
    Pruritus
         subjects affected / exposed
    0 / 51 (0.00%)
    7 / 50 (14.00%)
    6 / 49 (12.24%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    3 / 47 (6.38%)
    6 / 49 (12.24%)
    8 / 50 (16.00%)
         occurrences all number
    0
    10
    7
    1
    0
    1
    3
    7
    11
    Alopecia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    2 / 49 (4.08%)
    3 / 50 (6.00%)
         occurrences all number
    0
    2
    3
    0
    0
    0
    0
    2
    3
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    2 / 51 (3.92%)
    1 / 50 (2.00%)
    4 / 49 (8.16%)
    0 / 49 (0.00%)
    2 / 50 (4.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    3 / 49 (6.12%)
    3 / 50 (6.00%)
         occurrences all number
    3
    1
    10
    0
    2
    0
    0
    4
    4
    Musculoskeletal and connective tissue disorders
    Neck pain
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    3 / 49 (6.12%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    1 / 49 (2.04%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    3
    1
    0
    0
    0
    1
    0
    Osteopenia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 50 (0.00%)
    3 / 49 (6.12%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    2 / 49 (4.08%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    3
    0
    1
    0
    0
    2
    0
    Myalgia
         subjects affected / exposed
    0 / 51 (0.00%)
    2 / 50 (4.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    1 / 50 (2.00%)
    0 / 46 (0.00%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    1
    0
    1
    0
    0
    0
    4
    Muscle spasms
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 50 (6.00%)
    1 / 49 (2.04%)
    0 / 49 (0.00%)
    0 / 50 (0.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    3
    4
    0
    0
    1
    0
    0
    3
    Arthralgia
         subjects affected / exposed
    0 / 51 (0.00%)
    4 / 50 (8.00%)
    6 / 49 (12.24%)
    1 / 49 (2.04%)
    1 / 50 (2.00%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
    3 / 49 (6.12%)
    8 / 50 (16.00%)
         occurrences all number
    0
    4
    7
    1
    2
    2
    1
    4
    8
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 50 (0.00%)
    5 / 49 (10.20%)
    0 / 49 (0.00%)
    3 / 50 (6.00%)
    2 / 46 (4.35%)
    1 / 47 (2.13%)
    4 / 49 (8.16%)
    2 / 50 (4.00%)
         occurrences all number
    2
    0
    9
    0
    3
    2
    1
    7
    2
    Covid-19
         subjects affected / exposed
    1 / 51 (1.96%)
    0 / 50 (0.00%)
    5 / 49 (10.20%)
    2 / 49 (4.08%)
    5 / 50 (10.00%)
    1 / 46 (2.17%)
    0 / 47 (0.00%)
    1 / 49 (2.04%)
    8 / 50 (16.00%)
         occurrences all number
    1
    0
    6
    3
    5
    1
    0
    1
    9
    Urinary tract infection
         subjects affected / exposed
    1 / 51 (1.96%)
    2 / 50 (4.00%)
    2 / 49 (4.08%)
    1 / 49 (2.04%)
    2 / 50 (4.00%)
    1 / 46 (2.17%)
    2 / 47 (4.26%)
    1 / 49 (2.04%)
    6 / 50 (12.00%)
         occurrences all number
    3
    2
    5
    1
    4
    1
    3
    1
    8
    Metabolism and nutrition disorders
    Vitamin D deficiency
         subjects affected / exposed
    13 / 51 (25.49%)
    7 / 50 (14.00%)
    22 / 49 (44.90%)
    7 / 49 (14.29%)
    14 / 50 (28.00%)
    6 / 46 (13.04%)
    7 / 47 (14.89%)
    7 / 49 (14.29%)
    19 / 50 (38.00%)
         occurrences all number
    13
    7
    31
    7
    16
    6
    8
    7
    26

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Feb 2019
    Protocol Amendment 1 Summary: Administrative: Sponsor address updated; EudraCT number added. Abbreviations: Added for EQ-5O, FSS, HQLQ™, Local Reactions assessment, Treatment Compliance, and Quality of Life questionnaires. Synopsis: Tenofovir provision clarified: Sponsor provides if unavailable via routine medical care. Patient Rationale: Aligned with updated Exclusion Criteria. Eligibility: Plasma HOV RNA can now confirm patient eligibility. Exclusion Criteria Updates: Child-Pugh hepatic insufficiency >7 (uncomplicated esophageal varices allowed; exclude current/history of bleeding/ligation within 2 yrs). HCV/uncontrolled HIV coinfection: HCV Ab+ OK if HCV RNA negative. HIV+ OK if CD4 >500/mL & HIV RNA undetectable >12 mos. Uncontrolled arterial hypertension within 3 months pre-study (SBP >150 or DBP >100 mmHg despite treatment) allowed post-Study Medical Monitor confirmation. Current/previous (within last 2 yrs) decompensated liver disease (incl. coagulopathy, hepatic encephalopathy, esophageal varices hemorrhage). History of regular systemic glucocorticosteroid use (inhalative allowed). Participation in other investigational drug studies within 30 days pre-randomization. Prior bulevirtide receipt (incl. clinical trials). New/Revised Sections: Treatment Compliance section added. Prohibited treatments: Confirmed inhalative glucocorticosteroids allowed. Physical Examination: Added assessment of local injection site reactions (per Table 1; record in eCRF; AE if clinically significant). New section on Local bulevirtide injection site reactions. Pregnancy Reporting: Male subjects' pregnant partners require Information Sheet & ICF for pregnancy outcome data collection.
    17 Mar 2021
    New abbreviation is added (INR), ·'Lower Limit of Detection" is changed to "Limit of Detection" The list o f countries is corrected - Sweden was added It is added that tenofovir in tablets wi ll be provided by Sponsor and in patients in whom tenofovir is contraindicated, entecavir (tablets) will be provided. Primary Efficacy Endpoint: It is corrected that Undetectable HOV RNA is <LoD Exploratory endpoints: "Clinical events (decompensation, liver related death)" is changed to "Liver related clinical events (cirrhosis development; development or worsening jaundice, coagulopathy, ascites, hepatic encephalopathy; bleeding from esophageal varices; Hepatocellular carcinoma development; liver transplantation; liver related hospitalization: amount of hospitalizations and duration of each period of hospitalization; liver related death) at all postbaseline assessments" Other variables: "HBeAg and HBeAg antibodies status at all postbaseline assessments (for patients with positive HBeAg at SCR)" is added. Primary Efficacy Endpoint: It is corrected that Undetectable HOV RNA is <LoD Exploratory endpoints: "Clinical events (decompensation, liver related death) is changed to "Liver related clinical events (cirrhosis development; development or worsening jaundice, coagulopathy, ascites, hepatic encephalopathy; bleeding from esophageal varices; Hepatocellular carcinoma development; liver transplantation; liver related hospitalization: amount of hospitalizations and duration of each period of hospitalization; liver related death) at all postbaseline assessments" Other variables: "HBeAg and HBeAg antibodies status at all postbaseline assessments (for patients with positive HBeAg at SCR)" is added. The list of countries is corrected - Sweden was added The following is added: "The study will be considered to have started when the first patient has provided signed informed consent, and will be considered to have finished after the last patient has completed the last follow-up
    16 Sep 2021
    The major update(s) to the protocol and related rationale are as follows: An additional Phase 2 treatment arm was added that includes zimberelimab to allow the assessment of the efficacy and safety of magrolimab in combination with pembrolizumab +platinum + 5-FU (Cohort 1 Arm A) versus pembrolizumab + platinum + 5-FU (Cohort 1 Arm B) versus zimberelimab + platinum + 5-FU (Cohort 1 Arm C). Arm C was added to provide a comparison of zimberelimab with pembrolizumab in combination with magrolimab and chemotherapeutics in the treatment of head and neck squamous cell carcinoma (HNSCC).
    25 Apr 2022
    The primary reasons for this amendment are to: (1) update the regulatory and clinical development status of bulevirtide, (2) give instructions for operational changes in sample collection, and (3) specify changes to the statistical analyses.
    19 Oct 2022
    The primary reason for this amendment is to update the definition of viral breakthrough and nonresponders used for virologic resistance analysis and clarify the criteria for selection of the samples that will be tested for resistance.
    25 Jan 2023
    A Week 180 visit was added with additional assessments to allow a more standardized approach for study investigators to monitor and manage posttreatment hepatitis exacerbation. Updated the definition of hepatitis delta virus (HDV) ribonucleic acid (RNA) undetectable” to “< lower limit of quantification (LLOQ), target not detected.” To identify and monitor participants at risk of developing a hepatitis flare, specific procedures were added for the management of posttreatment exacerbation of hepatitis, ie, if laboratory results indicated alanine aminotransferase (ALT) elevations. An optional third liver biopsy was added to the list of assessments. The timing of an exploratory analysis was changed from Week 168 to Week 192. Clarified details of adverse event (AE)/serious AE reporting procedures period and liver-related clinical events. Addition of Appendix 2 (Monitoring Study Participants for Posttreatment ALT Elevation: Flowchart) and Appendix 3 (Unscheduled Visit for Management of posttreatment ALT Elevations). Definition of Per Protocol Analysis Set was updated Updated the word ‘Subject’ to ‘Participants’ and other style-related changes included where possible.

    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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    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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