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    Clinical Trial Results:
    A Multicenter, Open-label, Randomized Phase 2b Clinical Study to Assess Efficacy and Safety of Bulevirtide in Combination with Pegylated Interferon alfa-2a in Patients with Chronic Hepatitis Delta

    Summary
    EudraCT number
    		 2019-001485-15
    Trial protocol
    		 FR   RO  
    Global end of trial date
    28 Sep 2022

    Results information
    Results version number
    		 v2(current)
    This version publication date
    10 Oct 2024
    First version publication date
    10 Jul 2024
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Global Completion Date was updated.

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    MYR204
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03852433
    WHO universal trial number (UTN)
    		 -
    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
    28 Sep 2022
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of bulevirtide administered subcutaneously at a dose of 2 mg or 10 mg in combination with pegylated interferon alfa-2a once weekly relative to 10 mg bulevirtide monotherapy in participants with chronic hepatitis delta.
    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
    31 May 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
    France: 11
    Country: Number of subjects enrolled
    Romania: 41
    Country: Number of subjects enrolled
    Moldova, Republic of: 31
    Country: Number of subjects enrolled
    Russian Federation: 92
    Worldwide total number of subjects
    175
    EEA total number of subjects
    52
    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)
    174
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were enrolled at study sites in France, Moldova, Romania and Russia.

    Pre-assignment
    Screening details
    		 258 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
    		 Pegylated Interferon alfa-2a (PEG-IFN alfa)
    Arm description
    		 Participants received PEG-IFN alfa 180 microgram (mcg) once a week subcutaneously for 48 weeks with additional 48 weeks follow-up.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Pegylated Interferon alfa-2a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously.

    Arm title
    		 Bulevirtide 2 mg/day + PEG-IFN alfa
    Arm description
    		 Participants received bulevirtide 2 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 2 mg once a day for 48 weeks and additional 48 weeks follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bulevirtide 2 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously.

    Investigational medicinal product name
    Pegylated Interferon alfa-2a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously.

    Arm title
    		 Bulevirtide 10 mg/day + PEG-IFN alfa
    Arm description
    		 Participants received bulevirtide 10 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 10 mg once a day for 48 weeks and additional 48 weeks follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pegylated Interferon alfa-2a
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Administered subcutaneously.

    Investigational medicinal product name
    Bulevirtide 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Bulevertide 2*5 mg injection administered subcutaneously.

    Arm title
    		 Bulevirtide 10 mg/day
    Arm description
    		 Participants received bulevirtide 10 mg a once a day subcutaneously for 96 weeks with additional 48 weeks follow-up.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bulevirtide 5 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in vial
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    Bulevirtide 2*5 mg injection administered subcutaneously.

    Number of subjects in period 1
    		Pegylated Interferon alfa-2a (PEG-IFN alfa) Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Started
    25
    50
    50
    50
    Completed
    17
    38
    45
    45
    Not completed
    8
    12
    5
    5
         Physician decision
    1
    -
    -
    -
         Protocol violation
    -
    -
    1
    1
         Death
    -
    -
    1
    -
         Pregnancy
    -
    1
    1
    -
         Adverse event
    1
    1
    1
    1
         Non-compliance with study drug
    -
    -
    -
    1
         Withdrawal of consent
    5
    8
    1
    1
         Randomized but never treated
    1
    -
    -
    -
         Lost to follow-up
    -
    1
    -
    1
         Lack of efficacy
    -
    1
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pegylated Interferon alfa-2a (PEG-IFN alfa)
    Reporting group description
    		 Participants received PEG-IFN alfa 180 microgram (mcg) once a week subcutaneously for 48 weeks with additional 48 weeks follow-up.

    Reporting group title
    Bulevirtide 2 mg/day + PEG-IFN alfa
    Reporting group description
    		 Participants received bulevirtide 2 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 2 mg once a day for 48 weeks and additional 48 weeks follow-up.

    Reporting group title
    Bulevirtide 10 mg/day + PEG-IFN alfa
    Reporting group description
    		 Participants received bulevirtide 10 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 10 mg once a day for 48 weeks and additional 48 weeks follow-up.

    Reporting group title
    Bulevirtide 10 mg/day
    Reporting group description
    		 Participants received bulevirtide 10 mg a once a day subcutaneously for 96 weeks with additional 48 weeks follow-up.

    Reporting group values
    		 Pegylated Interferon alfa-2a (PEG-IFN alfa) Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day Total
    Number of subjects
    		 25 50 50 50 175
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 25 50 49 50 174
        Geriatrics (65 – 84 Years)
    		 0 0 1 0 1
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41 ( 8.2 ) 41 ( 9.3 ) 41 ( 8.6 ) 40 ( 8.5 ) -
    Gender categorical
    Units: Subjects
        Female
    		 6 17 15 12 50
        Male
    		 19 33 35 38 125
    Race
    Units: Subjects
        White
    		 21 44 43 44 152
        Asian
    		 4 3 4 4 15
        Black or African American
    		 0 3 2 2 7
        Other or More Than One Race
    		 0 0 1 0 1
    HDV RNA
    Units: log10 IU/mL)
        arithmetic mean (standard deviation)
    		 5.20 ( 1.064 ) 5.27 ( 1.355 ) 5.09 ( 1.343 ) 5.45 ( 1.098 ) -
    liver stiffness
    Units: kPa
        arithmetic mean (standard deviation)
    		 15.8 ( 11.57 ) 12.8 ( 6.43 ) 12.5 ( 7.60 ) 12.7 ( 6.65 ) -

    End points

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    End points reporting groups
    Reporting group title
    Pegylated Interferon alfa-2a (PEG-IFN alfa)
    Reporting group description
    		 Participants received PEG-IFN alfa 180 microgram (mcg) once a week subcutaneously for 48 weeks with additional 48 weeks follow-up.

    Reporting group title
    Bulevirtide 2 mg/day + PEG-IFN alfa
    Reporting group description
    		 Participants received bulevirtide 2 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 2 mg once a day for 48 weeks and additional 48 weeks follow-up.

    Reporting group title
    Bulevirtide 10 mg/day + PEG-IFN alfa
    Reporting group description
    		 Participants received bulevirtide 10 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 10 mg once a day for 48 weeks and additional 48 weeks follow-up.

    Reporting group title
    Bulevirtide 10 mg/day
    Reporting group description
    		 Participants received bulevirtide 10 mg a once a day subcutaneously for 96 weeks with additional 48 weeks follow-up.

    Primary: Percentage of Participants with Sustained Virological Response at Week 24 After the Scheduled End of Treatment (SVR24)

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    End point title
    		 Percentage of Participants with Sustained Virological Response at Week 24 After the Scheduled End of Treatment (SVR24)
    End point description
    SVR24 was defined as undetectable hepatitis delta virus (HDV) RNA (HDV RNA value < lower limit of quantitation [LLOQ] with target not detected) at 24 weeks after the scheduled end of treatment (EOT). Analysis Population Description: Full Analysis Set is defined as all randomized participants who received at least 1 dose of study drug (Peg-IFNα and/or BLV).
    End point type
    Primary
    End point timeframe
    24 weeks after EOT (Week 72 for Arm A and study Week 120 for Arms B, C, and D)
    End point values
    		 Pegylated Interferon alfa-2a (PEG-IFN alfa) Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Number of subjects analysed
    24
    50
    50
    50
    Units: percentage of participants
        number (confidence interval 95%)
    16.7 (4.7 to 37.4)
    32.0 (19.5 to 46.7)
    46.0 (31.8 to 60.7)
    12.0 (4.5 to 24.3)
    Statistical analysis title
    		 Statistical analysis of SVR24
    Comparison groups
    Bulevirtide 10 mg/day v Bulevirtide 10 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0003
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.6
         upper limit
    		 50.4
    Statistical analysis title
    		 Statistical analysis of SVR24
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Pegylated Interferon alfa-2a (PEG-IFN alfa)
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2631
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    15.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.2
         upper limit
    		 34.2
    Statistical analysis title
    		 Statistical analysis of SVR24
    Comparison groups
    Bulevirtide 10 mg/day + PEG-IFN alfa v Pegylated Interferon alfa-2a (PEG-IFN alfa)
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0197
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    29.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.8
         upper limit
    		 48.2
    Statistical analysis title
    		 Statistical analysis of SVR24
    Comparison groups
    Pegylated Interferon alfa-2a (PEG-IFN alfa) v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7186
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    -4.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -26.3
         upper limit
    		 11.8
    Statistical analysis title
    		 Statistical analysis of SVR24
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.2184
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.5
         upper limit
    		 32.7
    Statistical analysis title
    		 Statistical analysis of SVR24
    Comparison groups
    Bulevirtide 10 mg/day v Bulevirtide 2 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0283
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    -20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -36.1
         upper limit
    		 -3.5

    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 from Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Pegylated Interferon alfa-2a (PEG-IFN alfa) Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Number of subjects analysed
    24
    50
    50
    50
    Units: percentage of participants
        number (confidence interval 95%)
    20.8 (7.1 to 42.2)
    40.0 (26.4 to 54.8)
    60.0 (45.2 to 73.6)
    10.0 (3.3 to 21.8)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Undetectable HDV RNA at Week 96 (Arms B, C, and D Only)

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    End point title
    		 Percentage of Participants With Undetectable HDV RNA at Week 96 (Arms B, C, and D Only) [1]
    End point description
    Undetectable HDV RNA at Week 96 means undetectable (< LLOQ, target not detected) HDV RNA at Week 96. Analysis Population Description: Participants from Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Week 96
    Notes
    [1] - 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: This endpoint was applicable for arms B, C, and D only.
    End point values
    		 Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Number of subjects analysed
    50
    50
    50
    Units: percentage of participants
        number (confidence interval 95%)
    44.0 (30.0 to 58.7)
    70.0 (55.4 to 82.1)
    22.0 (11.5 to 36.0)
    No statistical analyses for this end point

    Secondary: Percentage of Participants With Combined Response at Week 24 After the Scheduled End of Treatment

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    End point title
    		 Percentage of Participants With Combined Response at Week 24 After the Scheduled End of Treatment
    End point description
    Combined response was defined as fulfilment of 2 conditions simultaneously: 1) undetectable HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline, alanine aminotransferase (ALT) normalization, 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 from Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    24 weeks after EOT (Week 72 for Arm A and Week 120 for Arms B, C, and D)
    End point values
    		 Pegylated Interferon alfa-2a (PEG-IFN alfa) Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Number of subjects analysed
    24
    50
    50
    50
    Units: percentage of participants
        number (confidence interval 95%)
    20.8 (7.1 to 42.2)
    36.0 (22.9 to 50.8)
    52.0 (37.4 to 66.3)
    26.0 (14.6 to 40.3)
    Statistical analysis title
    		 Statistical analysis of Combined Response Week 24
    Comparison groups
    Bulevirtide 10 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0134
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    26
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6
         upper limit
    		 44

    Secondary: Percentage of Participants with Combined Response at Week 48 After the Scheduled End of Treatment

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    End point title
    		 Percentage of Participants with Combined Response at Week 48 After the Scheduled End of Treatment
    End point description
    Combined response is defined as fulfilment of 2 conditions simultaneously: 1) undetectable HDV RNA or decrease by ≥ 2 log10 IU/mL from baseline, ALT normalization, 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 from Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    48 weeks after EOT (Week 96 for Arm A and Week 144 for Arms B, C, and D)
    End point values
    		 Pegylated Interferon alfa-2a (PEG-IFN alfa) Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Number of subjects analysed
    24
    50
    50
    50
    Units: percentage of participants
        number (confidence interval 95%)
    33.3 (15.6 to 55.3)
    32.0 (19.5 to 46.7)
    46.0 (31.8 to 60.7)
    18.0 (8.6 to 31.4)
    Statistical analysis title
    		 Statistical analysis of Combined Response Week 48
    Comparison groups
    Bulevirtide 10 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0049
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    28
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 8.2
         upper limit
    		 45.1

    Secondary: Percentage of Participants With Sustained Virological Response 48 After the Scheduled End of Treatment (SVR48)

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    End point title
    		 Percentage of Participants With Sustained Virological Response 48 After the Scheduled End of Treatment (SVR48)
    End point description
    SVR48 is defined as undetectable hepatitis delta virus (HDV) RNA (HDV RNA value < lower limit of quantitation [LLOQ] with target not detected) at 48 weeks after the scheduled end of treatment. Analysis Population Description: Participants from Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    48 weeks after EOT (Week 96 for Arm A; Week 144 for Arms B, C, and D)
    End point values
    		 Pegylated Interferon alfa-2a (PEG-IFN alfa) Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Number of subjects analysed
    24
    50
    50
    50
    Units: percentage of participants
        number (confidence interval 95%)
    25.0 (9.8 to 46.7)
    26.0 (14.6 to 40.3)
    46.0 (31.8 to 60.7)
    12.0 (4.5 to 24.3)
    Statistical analysis title
    		 Statistical analysis for SVR48
    Comparison groups
    Bulevirtide 10 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0003
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 14.6
         upper limit
    		 50.4
    Statistical analysis title
    		 Statistical analysis for SVR48
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Pegylated Interferon alfa-2a (PEG-IFN alfa)
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 1
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -22.8
         upper limit
    		 21.4
    Statistical analysis title
    		 Statistical analysis for SVR48
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1247
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    -14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -29.9
         upper limit
    		 1.7
    Statistical analysis title
    		 Statistical analysis for SVR48
    Comparison groups
    Pegylated Interferon alfa-2a (PEG-IFN alfa) v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1863
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    -13
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -35.3
         upper limit
    		 5.4
    Statistical analysis title
    		 Statistical analysis for SVR48
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0601
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    20
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1
         upper limit
    		 38.2
    Statistical analysis title
    		 Statistical analysis for SVR48
    Comparison groups
    Pegylated Interferon alfa-2a (PEG-IFN alfa) v Bulevirtide 10 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    74
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1265
    Method
    		 Fisher exact
    Parameter type
    		 Difference in percentages
    Point estimate
    21
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.3
         upper limit
    		 42.2

    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
    The mixed-effects models for repeated measurements (MMRM) model was used for analysis. Analysis Population Description: Participants from Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 48
    End point values
    		 Pegylated Interferon alfa-2a (PEG-IFN alfa) Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Number of subjects analysed
    18
    45
    47
    48
    Units: kPa
        number (confidence interval 95%)
    -0.02 (-2.29 to 2.25)
    -1.85 (-3.42 to -0.28)
    -1.79 (-3.21 to -0.36)
    -3.34 (-4.84 to -1.85)
    Statistical analysis title
    		 Statistical analysis Liver Stiffness Week 48
    Comparison groups
    Bulevirtide 10 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    95
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0717
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.14
         upper limit
    		 3.26
    Statistical analysis title
    		 Statistical analysis Liver Stiffness Week 48
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0875
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -1.49
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.2
         upper limit
    		 0.22
    Statistical analysis title
    		 Statistical analysis Liver Stiffness Week 48
    Comparison groups
    Pegylated Interferon alfa-2a (PEG-IFN alfa) v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    66
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.0099
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -3.34
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.87
         upper limit
    		 -0.82
    Statistical analysis title
    		 Statistical analysis Liver Stiffness Week 48
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9384
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    0.07
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.67
         upper limit
    		 1.81
    Statistical analysis title
    		 Statistical analysis Liver Stiffness Week 48
    Comparison groups
    Pegylated Interferon alfa-2a (PEG-IFN alfa) v Bulevirtide 2 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    63
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1563
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -1.84
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.39
         upper limit
    		 0.71
    Statistical analysis title
    		 Statistical analysis Liver Stiffness Week 48
    Comparison groups
    Pegylated Interferon alfa-2a (PEG-IFN alfa) v Bulevirtide 10 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1626
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -1.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.33
         upper limit
    		 0.73

    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 [2]
    End point description
    The MMRM model was used for analysis. Participants from Full Analysis Set with available data were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 96
    Notes
    [2] - 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: This endpoint was applicable for arms B, C, and D only.
    End point values
    		 Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Number of subjects analysed
    43
    47
    46
    Units: kPa
        number (confidence interval 95%)
    -3.37 (-4.94 to -1.80)
    -3.70 (-5.11 to -2.29)
    -3.85 (-5.35 to -2.35)
    Statistical analysis title
    		 Statistical analysis Liver Stiffness Week 96
    Comparison groups
    Bulevirtide 10 mg/day v Bulevirtide 10 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    93
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.8645
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    0.15
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.54
         upper limit
    		 1.83
    Statistical analysis title
    		 Statistical analysis Liver Stiffness Week 96
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    89
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.5806
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -0.48
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.18
         upper limit
    		 1.23
    Statistical analysis title
    		 Statistical analysis Liver Stiffness Week 96
    Comparison groups
    Bulevirtide 10 mg/day + PEG-IFN alfa v Bulevirtide 2 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    90
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7033
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -0.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.06
         upper limit
    		 1.39

    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
    End point description
    The MMRM model was used for analysis. Analysis Population Description: Participants from Full Analysis Set were analyzed.
    End point type
    Secondary
    End point timeframe
    Baseline, 48 weeks after EOT (Week 96 for Arm A and study Week 144 for Arms B, C, and D)
    End point values
    		 Pegylated Interferon alfa-2a (PEG-IFN alfa) Bulevirtide 2 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day + PEG-IFN alfa Bulevirtide 10 mg/day
    Number of subjects analysed
    16
    32
    40
    40
    Units: kPa
        number (confidence interval 95%)
    -0.31 (-2.75 to 2.12)
    -2.35 (-4.20 to -0.50)
    -2.47 (-4.12 to -0.83)
    -0.79 (-2.53 to 0.93)
    Statistical analysis title
    		 Statistical analysis of Liver Stiffness Week 144
    Comparison groups
    Bulevirtide 10 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    80
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1103
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -1.68
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.75
         upper limit
    		 0.39
    Statistical analysis title
    		 Statistical analysis of Liver Stiffness Week 144
    Comparison groups
    Pegylated Interferon alfa-2a (PEG-IFN alfa) v Bulevirtide 2 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    48
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1533
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -2.05
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.88
         upper limit
    		 0.77
    Statistical analysis title
    		 Statistical analysis of Liver Stiffness Week 144
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1526
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    1.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 3.7
    Statistical analysis title
    		 Statistical analysis of Liver Stiffness Week 144
    Comparison groups
    Pegylated Interferon alfa-2a (PEG-IFN alfa) v Bulevirtide 10 mg/day
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.6753
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -0.58
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.34
         upper limit
    		 2.17
    Statistical analysis title
    		 Statistical analysis of Liver Stiffness Week 144
    Comparison groups
    Bulevirtide 2 mg/day + PEG-IFN alfa v Bulevirtide 10 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.9124
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.28
         upper limit
    		 2.04
    Statistical analysis title
    		 Statistical analysis of Liver Stiffness Week 144
    Comparison groups
    Pegylated Interferon alfa-2a (PEG-IFN alfa) v Bulevirtide 10 mg/day + PEG-IFN alfa
    Number of subjects included in analysis
    56
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.1129
    Method
    		 MMRM
    Parameter type
    		 Difference in LS Mean
    Point estimate
    -2.22
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.98
         upper limit
    		 0.53

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All-cause mortality: Up to approximately 144 weeks; Adverse events: Pegylated Interferon Alfa-2a (PEG-IFN Alfa): Up to Week 48 plus 30 days; for all other arms: Up to 96 weeks plus 30 days
    Adverse event reporting additional description
    All-cause mortality: Participants from All Randomized Set with available data were analyzed. Adverse events: Safety Analysis Set included all participants who took at least 1 dose of study drug.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Pegylated Interferon alfa-2a (PEGIFN alfa)
    Reporting group description
    		 Participants received PEG-IFN alfa 180 microgram (mcg) once a week subcutaneously for 48 weeks with additional 48 weeks follow-up.

    Reporting group title
    Bulevirtide 10 mg/Day
    Reporting group description
    		 Participants received bulevirtide 10 mg once day subcutaneously for 96 weeks with additional 48 weeks follow-up.

    Reporting group title
    Bulevirtide 10 mg/Day + PEG-IFN alfa
    Reporting group description
    		 Participants received bulevirtide 10 mg once day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 10 mg once a day for 48 weeks and additional 48 weeks follow-up.

    Reporting group title
    Bulevirtide 2 mg/Day + PEG-IFN alfa
    Reporting group description
    		 Participants received bulevirtide 2 mg once a day subcutaneously in combination with PEG-IFN alfa 180 mcg once a week subcutaneously for 48 weeks followed by bulevirtide 2 mg once day for 48 weeks and additional 48 weeks follow-up.

    Serious adverse events
    		 Pegylated Interferon alfa-2a (PEGIFN alfa) Bulevirtide 10 mg/Day Bulevirtide 10 mg/Day + PEG-IFN alfa Bulevirtide 2 mg/Day + PEG-IFN alfa
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 50 (4.00%)
    8 / 50 (16.00%)
    3 / 50 (6.00%)
         number of deaths (all causes)
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Anaplastic astrocytoma
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         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 / 1
    Hepatocellular carcinoma
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (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
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Eye disorders
    Retinal detachment
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (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
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (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
    Cholecystitis acute
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (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
    Drug-induced liver injury
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cholecystitis chronic
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (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
    Osteoarthritis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (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
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (0.00%)
    0 / 50 (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
    Appendicitis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (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
    Chronic sinusitis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         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
    Hepatitis B reactivation
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (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
    Injection site cellulitis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         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
    Covid-19
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
    0 / 50 (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
    Covid-19 pneumonia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    0 / 50 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pegylated Interferon alfa-2a (PEGIFN alfa) Bulevirtide 10 mg/Day Bulevirtide 10 mg/Day + PEG-IFN alfa Bulevirtide 2 mg/Day + PEG-IFN alfa
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    22 / 24 (91.67%)
    37 / 50 (74.00%)
    50 / 50 (100.00%)
    49 / 50 (98.00%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    2 / 50 (4.00%)
         occurrences all number
    1
    0
    3
    5
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    5 / 24 (20.83%)
    0 / 50 (0.00%)
    13 / 50 (26.00%)
    8 / 50 (16.00%)
         occurrences all number
    5
    0
    19
    34
    Asthenia
         subjects affected / exposed
    3 / 24 (12.50%)
    4 / 50 (8.00%)
    6 / 50 (12.00%)
    7 / 50 (14.00%)
         occurrences all number
    4
    9
    10
    7
    Injection site erythema
         subjects affected / exposed
    0 / 24 (0.00%)
    4 / 50 (8.00%)
    4 / 50 (8.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    5
    4
    68
    Influenza like illness
         subjects affected / exposed
    10 / 24 (41.67%)
    2 / 50 (4.00%)
    20 / 50 (40.00%)
    22 / 50 (44.00%)
         occurrences all number
    12
    2
    25
    31
    Chills
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
    4 / 50 (8.00%)
         occurrences all number
    0
    2
    0
    10
    Injection site reaction
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    4 / 50 (8.00%)
    5 / 50 (10.00%)
         occurrences all number
    0
    0
    4
    28
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    0
    1
    1
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 50 (2.00%)
    4 / 50 (8.00%)
    2 / 50 (4.00%)
         occurrences all number
    2
    1
    4
    2
    Anxiety
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    4 / 50 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    8 / 24 (33.33%)
    5 / 50 (10.00%)
    12 / 50 (24.00%)
    5 / 50 (10.00%)
         occurrences all number
    10
    6
    14
    5
    Weight decreased
         subjects affected / exposed
    3 / 24 (12.50%)
    2 / 50 (4.00%)
    4 / 50 (8.00%)
    3 / 50 (6.00%)
         occurrences all number
    3
    4
    4
    3
    Activated partial thromboplastin time prolonged
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 50 (2.00%)
    5 / 50 (10.00%)
    6 / 50 (12.00%)
         occurrences all number
    3
    1
    6
    6
    Aspartate aminotransferase increased
         subjects affected / exposed
    8 / 24 (33.33%)
    3 / 50 (6.00%)
    10 / 50 (20.00%)
    6 / 50 (12.00%)
         occurrences all number
    9
    4
    11
    6
    Neutrophil count decreased
         subjects affected / exposed
    3 / 24 (12.50%)
    1 / 50 (2.00%)
    12 / 50 (24.00%)
    11 / 50 (22.00%)
         occurrences all number
    5
    3
    19
    14
    White blood cell count decreased
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 50 (2.00%)
    8 / 50 (16.00%)
    10 / 50 (20.00%)
         occurrences all number
    3
    3
    13
    10
    Platelet count decreased
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 50 (2.00%)
    7 / 50 (14.00%)
    9 / 50 (18.00%)
         occurrences all number
    3
    1
    10
    11
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    6 / 24 (25.00%)
    3 / 50 (6.00%)
    7 / 50 (14.00%)
    2 / 50 (4.00%)
         occurrences all number
    8
    4
    9
    2
    Bile acids increased
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 50 (2.00%)
    4 / 50 (8.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    5
    1
    Amylase increased
         subjects affected / exposed
    0 / 24 (0.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    3
    0
    1
    Prothrombin level decreased
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    3
    1
    Alpha-2 macroglobulin increased
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 50 (4.00%)
    3 / 50 (6.00%)
    1 / 50 (2.00%)
         occurrences all number
    0
    2
    3
    1
    Lipase increased
         subjects affected / exposed
    1 / 24 (4.17%)
    4 / 50 (8.00%)
    2 / 50 (4.00%)
    4 / 50 (8.00%)
         occurrences all number
    1
    8
    2
    5
    Cardiac disorders
    Sinus bradycardia
         subjects affected / exposed
    0 / 24 (0.00%)
    4 / 50 (8.00%)
    2 / 50 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    5
    3
    4
    Angina pectoris
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    0
    2
    1
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    1 / 24 (4.17%)
    5 / 50 (10.00%)
    2 / 50 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    1
    9
    2
    4
    Headache
         subjects affected / exposed
    2 / 24 (8.33%)
    7 / 50 (14.00%)
    7 / 50 (14.00%)
    7 / 50 (14.00%)
         occurrences all number
    2
    20
    8
    30
    Blood and lymphatic system disorders
    Thrombocytopenia
         subjects affected / exposed
    14 / 24 (58.33%)
    8 / 50 (16.00%)
    24 / 50 (48.00%)
    23 / 50 (46.00%)
         occurrences all number
    18
    11
    35
    30
    Leukopenia
         subjects affected / exposed
    13 / 24 (54.17%)
    8 / 50 (16.00%)
    27 / 50 (54.00%)
    26 / 50 (52.00%)
         occurrences all number
    17
    15
    46
    35
    Neutropenia
         subjects affected / exposed
    12 / 24 (50.00%)
    6 / 50 (12.00%)
    28 / 50 (56.00%)
    23 / 50 (46.00%)
         occurrences all number
    19
    8
    45
    37
    Anaemia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 50 (2.00%)
    6 / 50 (12.00%)
    4 / 50 (8.00%)
         occurrences all number
    1
    1
    8
    6
    Lymphopenia
         subjects affected / exposed
    7 / 24 (29.17%)
    5 / 50 (10.00%)
    15 / 50 (30.00%)
    12 / 50 (24.00%)
         occurrences all number
    7
    6
    28
    24
    Eye disorders
    Presbyopia
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    0
    0
    1
    Retinal vascular disorder
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 50 (0.00%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
         occurrences all number
    1
    0
    0
    3
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 24 (0.00%)
    4 / 50 (8.00%)
    4 / 50 (8.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    5
    6
    0
    Dyspepsia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    1
    2
    3
    Abdominal pain
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 50 (4.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    2
    1
    3
    Dry mouth
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 50 (2.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    1
    3
    0
    Nausea
         subjects affected / exposed
    2 / 24 (8.33%)
    3 / 50 (6.00%)
    4 / 50 (8.00%)
    1 / 50 (2.00%)
         occurrences all number
    2
    3
    4
    1
    Gingival bleeding
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    6
    0
    Hepatobiliary disorders
    Hepatic fibrosis
         subjects affected / exposed
    1 / 24 (4.17%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    3
    0
    1
    Hyperbilirubinaemia
         subjects affected / exposed
    3 / 24 (12.50%)
    4 / 50 (8.00%)
    2 / 50 (4.00%)
    0 / 50 (0.00%)
         occurrences all number
    4
    4
    2
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 50 (0.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    0
    4
    0
    Pruritus
         subjects affected / exposed
    0 / 24 (0.00%)
    3 / 50 (6.00%)
    5 / 50 (10.00%)
    2 / 50 (4.00%)
         occurrences all number
    0
    3
    5
    2
    Renal and urinary disorders
    Proteinuria
         subjects affected / exposed
    1 / 24 (4.17%)
    4 / 50 (8.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
         occurrences all number
    1
    6
    4
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 50 (4.00%)
    3 / 50 (6.00%)
    0 / 50 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Myalgia
         subjects affected / exposed
    2 / 24 (8.33%)
    2 / 50 (4.00%)
    4 / 50 (8.00%)
    3 / 50 (6.00%)
         occurrences all number
    2
    2
    4
    10
    Arthralgia
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 50 (2.00%)
    4 / 50 (8.00%)
    1 / 50 (2.00%)
         occurrences all number
    1
    1
    17
    1
    Infections and infestations
    Covid-19
         subjects affected / exposed
    0 / 24 (0.00%)
    2 / 50 (4.00%)
    5 / 50 (10.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    2
    5
    3
    Urinary tract infection
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 50 (0.00%)
    2 / 50 (4.00%)
    3 / 50 (6.00%)
         occurrences all number
    0
    0
    2
    3
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 50 (2.00%)
    2 / 50 (4.00%)
    2 / 50 (4.00%)
         occurrences all number
    3
    2
    2
    2
    Vitamin D deficiency
         subjects affected / exposed
    3 / 24 (12.50%)
    13 / 50 (26.00%)
    13 / 50 (26.00%)
    9 / 50 (18.00%)
         occurrences all number
    3
    15
    14
    10

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Sep 2021
    The protocol has been amended primarily to transfer sponsorship from MYR GmbH to Gilead Sciences, Inc and to update safety reporting procedures accordingly. Global changes made throughout protocol include: • Sponsor changed from MYR GmbH to Gilead Sciences, Inc. • Contact details have been updated, including changes to safety reporting.
    08 Feb 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.

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/34482769
    http://www.ncbi.nlm.nih.gov/pubmed/36712949
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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