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    Clinical Trial Results:
    Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety of BHV-3241 in Subjects with Multiple System Atrophy (M-STAR Study)

    Summary
    EudraCT number
    		 2019-001100-38
    Trial protocol
    		 FR   DE   GB   AT   IT  
    Global end of trial date
    30 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2023
    First version publication date
    13 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    BHV3241-301
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03952806
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Biohaven Pharmaceuticals, Inc
    Sponsor organisation address
    215 Church Street, New Haven, Connecticut, United States, 06510
    Public contact
    Chief Medical Officer, Biohaven Pharmaceuticals Inc, +1 203-404-0410, clinicaltrials@biohavenpharma.com
    Scientific contact
    Chief Medical Officer, Biohaven Pharmaceuticals Inc, +1 203-404-0410, clinicaltrials@biohavenpharma.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 Jul 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    29 Jul 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of verdiperstat (BHV-3241), compared to placebo, as measured by a change from baseline in a modified Unified Multiple System Atrophy (MSA) Rating Scale (UMSARS), consisting of a subset of items from Part I and Part II, at Week 48. To assess the safety and tolerability of verdiperstat relative to placebo in participants with MSA.
    Protection of trial subjects
    This study was conducted in accordance with Good Clinical Practice, as defined by the International Council on Harmonisation and in accordance with the ethical principles underlying European Union Directive 2001/20/EC, and the United States Code of Federal Regulations, Title 21, Part 50 (21CFR50).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    29 Jul 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    United States: 214
    Country: Number of subjects enrolled
    Austria: 9
    Country: Number of subjects enrolled
    France: 36
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Italy: 29
    Worldwide total number of subjects
    336
    EEA total number of subjects
    117
    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)
    227
    From 65 to 84 years
    109
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This Phase 3, randomized, double-blind, placebo-controlled study was conducted in participants with MSA at 48 centers.

    Pre-assignment
    Screening details
    		 This study consists of a screening period (up to 6 weeks) and double-blind treatment phase (48 weeks) followed by open-label extension (OLE) phase (48 weeks). A total of 336 participants were enrolled in this study.

    Period 1
    Period 1 title
    Randomization Phase (Weeks 1 Through 48)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Verdiperstat
    Arm description
    		 Randomization Phase (Randomization through Week 48): Participants received verdiperstat 300 milligrams (mg) tablet orally once daily for 1 week, followed by 300 mg twice daily for 1 week, and then 600 mg twice daily for the remaining 46 weeks of the double-blind phase.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Verdiperstat
    Investigational medicinal product code
    BHV­3241
    Other name
    AZD3241
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Verdiperstat 300 mg tablet administered orally once daily for 1 week, followed by 300 mg twice daily for 1 week, and then 600 mg twice daily for the remaining 46 weeks of the double-blind phase.

    Arm title
    		 Placebo
    Arm description
    		 Randomization Phase (Randomization through Week 48): Participants received placebo matching with verdiperstat for 48 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matching with verdiperstat administered orally once daily for 1 week, followed by twice daily for for the remaining 47 weeks of the double-blind phase.

    Number of subjects in period 1
    		Verdiperstat Placebo
    Started
    168
    168
    Completed
    127
    146
    Not completed
    41
    22
         Consent withdrawn by subject
    4
    2
         Disease progression
    5
    -
         Adverse event, non-fatal
    26
    15
         Participant request
    5
    5
         Unspecified
    1
    -
    Period 2
    Period 2 title
    OLE Phase (48 Weeks)
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Verdiperstat/Verdiperstat
    Arm description
    		 OLE phase (48 weeks): Participants who completed the double-blind phase were offered the opportunity to enroll in an OLE phase to continue verdiperstat 600 mg orally twice daily for 48 weeks.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Verdiperstat
    Investigational medicinal product code
    BHV­3241
    Other name
    AZD3241
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants continued verdiperstat 600 mg twice daily for 48 weeks in OLE phase.

    Arm title
    		 Placebo/Verdiperstat
    Arm description
    		 OLE phase (48 weeks): Participants who completed the double-blind phase were offered the opportunity to enroll in an OLE phase to receive verdiperstat 600 mg tablet orally twice daily for 48 weeks.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Verdiperstat
    Investigational medicinal product code
    BHV­3241
    Other name
    AZD3241
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants received verdiperstat 600 mg twice daily for 48 weeks in OLE phase.

    Number of subjects in period 2 [1]
    		Verdiperstat/Verdiperstat Placebo/Verdiperstat
    Started
    123
    140
    Completed
    44
    46
    Not completed
    79
    94
         Consent withdrawn by subject
    4
    5
         Disease progression
    6
    9
         Adverse event, non-fatal
    18
    29
         Participant request to discontinue
    35
    38
         Unspecified
    16
    13
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Participants who continued into the extension phase.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Verdiperstat
    Reporting group description
    		 Randomization Phase (Randomization through Week 48): Participants received verdiperstat 300 milligrams (mg) tablet orally once daily for 1 week, followed by 300 mg twice daily for 1 week, and then 600 mg twice daily for the remaining 46 weeks of the double-blind phase.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomization Phase (Randomization through Week 48): Participants received placebo matching with verdiperstat for 48 weeks.

    Reporting group values
    		 Verdiperstat Placebo Total
    Number of subjects
    		 168 168 336
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.4 ( 7.12 ) 60.1 ( 6.68 ) -
    Gender categorical
    Units: Subjects
        Female
    		 83 83 166
        Male
    		 85 85 170
    Ethnicity
    Units: Subjects
        Hispanic or Latino
    		 5 5 10
        Not Hispanic or Latino
    		 163 163 326
        Unknown or Not Reported
    		 0 0 0
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 3 1 4
        Asian
    		 5 7 12
        Native Hawaiian or Other Pacific Islander
    		 1 0 1
        Black or African American
    		 3 2 5
        White
    		 155 156 311
        More than one race
    		 0 0 0
        Unknown or Not Reported
    		 1 2 3
    UMSARS Modified Score
    Units: unit on a scale
        arithmetic mean (standard deviation)
    		 6.1 ( 4.24 ) 5.8 ( 3.74 ) -

    End points

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    End points reporting groups
    Reporting group title
    Verdiperstat
    Reporting group description
    		 Randomization Phase (Randomization through Week 48): Participants received verdiperstat 300 milligrams (mg) tablet orally once daily for 1 week, followed by 300 mg twice daily for 1 week, and then 600 mg twice daily for the remaining 46 weeks of the double-blind phase.

    Reporting group title
    Placebo
    Reporting group description
    		 Randomization Phase (Randomization through Week 48): Participants received placebo matching with verdiperstat for 48 weeks.
    Reporting group title
    Verdiperstat/Verdiperstat
    Reporting group description
    		 OLE phase (48 weeks): Participants who completed the double-blind phase were offered the opportunity to enroll in an OLE phase to continue verdiperstat 600 mg orally twice daily for 48 weeks.

    Reporting group title
    Placebo/Verdiperstat
    Reporting group description
    		 OLE phase (48 weeks): Participants who completed the double-blind phase were offered the opportunity to enroll in an OLE phase to receive verdiperstat 600 mg tablet orally twice daily for 48 weeks.

    Primary: Change From Baseline in the Modified UMSARS Score at Week 48

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    End point title
    		 Change From Baseline in the Modified UMSARS Score at Week 48
    End point description
    The UMSARS is a clinician-rated 5-point scale of items graded 0 (no impairment) to 4 (complete impairment) comprised of 4 parts: Part I, Historical Review, is an assessment of functioning across various areas. Part II is a Motor Examination. Part III is an Autonomic Examination and includes supine and standing vital signs, orthostatic change, and orthostatic symptoms. Part IV is a Global Disability Scale. The primary outcome variable for the study was the Modified UMSARS, which is composed of a subset of 9 items from UMSARS Part I and Part II. The Modified UMSARS Part I and Part II responses are measured on a 4-point scale ranging from 0 to 3, where, 0=no/mild impairment, 1=moderate impairment, 2=severe impairment, and 3=complete impairment. Higher scores indicate greater impairment. Modified Intent to Treat (mITT) population included randomized participants who received at least 1 dose of blinded study therapy and provided a baseline and at least 1 post-baseline efficacy assessment.
    End point type
    Primary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Verdiperstat Placebo
    Number of subjects analysed
    125
    140
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    5.20 (4.52 to 5.89)
    4.85 (4.19 to 5.51)
    Statistical analysis title
    		 Treatment difference in modified UMSARS score
    Comparison groups
    Verdiperstat v Placebo
    Number of subjects included in analysis
    265
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4656
    Method
    		 Mixed models analysis
    Parameter type
    		 Least Square mean difference
    Point estimate
    0.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.6
         upper limit
    		 1.3
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.48

    Primary: Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs

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    End point title
    		 Number of Participants With Treatment-Emergent Adverse Events (TEAEs) and Serious TEAEs [1]
    End point description
    An adverse event (AE) is defined as any new untoward medical occurrence or worsening of a pre-existing medical condition in participants or clinical investigation participants administered an investigational (medicinal) product and that does not necessarily have a causal relationship with this treatment. A serious AE (SAE) is defined as any event that met any of the following criteria at any dose: death; life-threatening; inpatient hospitalization or prolongation of existing hospitalization; persistent or significant disability/incapacity; congenital anomaly/birth defect in the offspring of a participant who received study drug; other important medical events that may not have resulted in death, be life-threatening, or required hospitalization, or, based upon appropriate medical judgment, they may have jeopardized the participant and may have required medical or surgical intervention to prevent one of the other serious outcomes. Treated population.
    End point type
    Primary
    End point timeframe
    Up to 100 weeks
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive statistical analysis was performed for the primary end point.
    End point values
    		 Verdiperstat Placebo Verdiperstat/Verdiperstat Placebo/Verdiperstat
    Number of subjects analysed
    168
    168
    123
    140
    Units: participants
        TEAE
    160
    156
    95
    112
        Serious TEAE
    44
    29
    30
    27
    No statistical analyses for this end point

    Secondary: Clinical Global Impression of Improvement (CGI-I) Score at Week 48

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    End point title
    		 Clinical Global Impression of Improvement (CGI-I) Score at Week 48
    End point description
    The CGI-I is a clinician-rated scale measuring the change in the participant’s clinical status from a specific point in time. It is scored on a 7- point scale, ranging from 1 (very much improved) to 7 (very much worse), with a score of 4 indicating no change. Higher scores indicate greater impairment. mITT population.
    End point type
    Secondary
    End point timeframe
    Week 48
    End point values
    		 Verdiperstat Placebo
    Number of subjects analysed
    126
    142
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    5.07 (4.92 to 5.21)
    5.14 (5.00 to 5.27)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Motor Subscale at Week 48

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    End point title
    		 Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Motor Subscale at Week 48
    End point description
    The MSA-QoL is a participant-rated scale that was designed to measure health-related quality of life specifically in MSA. It assesses activities of daily living and has subscales for motor, nonmotor, and emotional/social domains. The MSA-QoL includes 40 items and has three subscales: (1) motor (14 items), (2) nonmotor (12 items), and (3) emotional/social (14 items). Scores on each of the subscales are derived by summing the respective items with higher scores on each scale indicating a higher impact of the disease on the aspect measured by each subscale. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Verdiperstat Placebo
    Number of subjects analysed
    114
    130
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    13.83 (10.97 to 16.69)
    13.45 (10.72 to 16.18)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Non-motor Subscale at Week 48

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    End point title
    		 Change From Baseline in Multiple System Atrophy Quality of Life (MSA-QoL) Non-motor Subscale at Week 48
    End point description
    The MSA-QoL is a participant-rated scale that was designed to measure health-related quality of life specifically in MSA. It assesses activities of daily living and has subscales for motor, nonmotor, and emotional/social domains. The MSA-QoL includes 40 items and has three subscales: (1) motor (14 items), (2) nonmotor (12 items), and (3) emotional/social (14 items). Scores on each of the subscales are derived by summing the respective items with higher scores on each scale indicating a higher impact of the disease on the aspect measured by each subscale. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Verdiperstat Placebo
    Number of subjects analysed
    116
    128
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    7.52 (4.93 to 10.11)
    5.56 (3.07 to 8.04)
    No statistical analyses for this end point

    Secondary: Change From Baseline in UMSARS Part I and Part II Total Score at Week 48

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    End point title
    		 Change From Baseline in UMSARS Part I and Part II Total Score at Week 48
    End point description
    The UMSARS is a clinician-rated 5-point scale of items graded 0 (no impairment) to 4 (complete impairment) comprised of 4 parts: Part I, Historical Review, is an assessment of functioning across various areas. Part II is a Motor Examination. The UMSARS Part I and Part II responses are measured on a 4-point scale ranging from 0 to 3, where, 0 = no/mild impairment, 1 = moderate impairment, 2 = severe impairment, and 3 = complete impairment. Higher scores indicate greater impairment. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Verdiperstat Placebo
    Number of subjects analysed
    125
    139
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    12.00 (10.37 to 13.63)
    11.34 (9.77 to 12.90)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Patient Global Impression of Severity (PGI-S) at Week 48

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    End point title
    		 Change From Baseline in Patient Global Impression of Severity (PGI-S) at Week 48
    End point description
    The PGI-S is a participant-rated scale which measures how participants perceive the severity of their illness. The PGI-S is a 1- item questionnaire on a 4-point scale ranging from 1 to 4, where, 1 = normal, 2 = mild, 3 = moderate, 4 = severe. Higher scores indicate greater impairment. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Verdiperstat Placebo
    Number of subjects analysed
    125
    142
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    0.33 (0.23 to 0.42)
    0.27 (0.18 to 0.36)
    No statistical analyses for this end point

    Secondary: Change From Baseline in Clinical Global Impression of Severity (CGI-S) at Week 48

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    End point title
    		 Change From Baseline in Clinical Global Impression of Severity (CGI-S) at Week 48
    End point description
    The CGI-S is a clinician-rated scale measuring the severity of the participant’s illness. It is scored on a 7- point scale ranging from 1 (normal, not ill at all) to 7 (among the most extremely ill participants). Higher scores indicate greater impairment. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Verdiperstat Placebo
    Number of subjects analysed
    126
    142
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    0.79 (0.66 to 0.92)
    0.78 (0.66 to 0.90)
    No statistical analyses for this end point

    Secondary: Change From Baseline in UMSARS Part III at Week 48

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    End point title
    		 Change From Baseline in UMSARS Part III at Week 48
    End point description
    The UMSARS is a clinician-rated 5-point scale of items graded 0 (no impairment) to 4 (complete impairment) comprised of 4 parts: Part III is an Autonomic Examination, and includes supine and standing vital signs, orthostatic change, and orthostatic symptoms. mITT population. Here, n= number of participants analyzed for each parameter.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Verdiperstat Placebo
    Number of subjects analysed
    119
    132
    Units: unit on a scale
    least squares mean (confidence interval 95%)
        Systolic blood pressure (BP) (n=118, 132)
    -2.18 (-5.90 to 1.55)
    -3.09 (-6.63 to 0.44)
        Diastolic BP (n=118, 131)
    -2.87 (-5.13 to -0.61)
    -2.54 (-4.70 to -0.38)
        Heart rate (n=119, 132)
    0.20 (-1.48 to 1.87)
    -0.68 (-2.27 to 0.91)
    No statistical analyses for this end point

    Secondary: Change From Baseline in UMSARS Part IV at Week 48

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    End point title
    		 Change From Baseline in UMSARS Part IV at Week 48
    End point description
    The UMSARS is a clinician-rated 5-point scale of items graded 0 (no impairment) to 4 (complete impairment) comprised of 4 parts: Part IV is a Global Disability Scale. The UMSARS Part IV measured on a 5-point scale ranging from 0 to 4, where, 0 = Completely independent, 1 = Not completely independent, 2 = More dependent, 3 = Very dependent, and 4 = Totally dependent and helpless. Higher scores indicate greater impairment. mITT population.
    End point type
    Secondary
    End point timeframe
    Baseline and Week 48
    End point values
    		 Verdiperstat Placebo
    Number of subjects analysed
    126
    140
    Units: unit on a scale
        least squares mean (confidence interval 95%)
    0.82 (0.69 to 0.96)
    0.85 (0.72 to 0.99)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    TEAEs were reported from first dose of study drug and prior to 30 days after the last dose of study drug, maximum of 100 weeks.
    Adverse event reporting additional description
    Treated population included enrolled participants who received at least 1 dose of blinded study therapy (verdiperstat or placebo).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Verdiperstat - Randomization Phase
    Reporting group description
    		 Participants received verdiperstat 300 mg tablet orally once daily for 1 week, followed by 300 mg twice daily for 1 week, and then 600 mg twice daily for the remaining 46 weeks of the double-blind phase.

    Reporting group title
    Placebo - Randomization Phase
    Reporting group description
    		 Participants received placebo matching with verdiperstat for 48 weeks.

    Reporting group title
    Verdiperstat - Randomization Phase/ Verdiperstat - OLE Phase
    Reporting group description
    		 Participants who completed the double-blind phase were offered the opportunity to enroll in an OLE phase to continue verdiperstat 600 mg orally twice daily for 48 weeks.

    Reporting group title
    Placebo - Randomization Phase/ Verdiperstat - OLE Phase
    Reporting group description
    		 Participants who completed the double-blind phase were offered the opportunity to enroll in an OLE phase to receive verdiperstat 600 mg tablet orally twice daily for 48 weeks.

    Serious adverse events
    		 Verdiperstat - Randomization Phase Placebo - Randomization Phase Verdiperstat - Randomization Phase/ Verdiperstat - OLE Phase Placebo - Randomization Phase/ Verdiperstat - OLE Phase
    Total subjects affected by serious adverse events
         subjects affected / exposed
    44 / 168 (26.19%)
    29 / 168 (17.26%)
    30 / 123 (24.39%)
    27 / 140 (19.29%)
         number of deaths (all causes)
    11
    5
    12
    10
         number of deaths resulting from adverse events
    1
    1
    0
    1
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial adenocarcinoma
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Arteriosclerosis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Deep vein thrombosis
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 168 (1.19%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypertensive urgency
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         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
    Orthostatic hypotension
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Disease progression
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Fatigue
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (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
    General physical health deterioration
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Multiple organ dysfunction syndrome
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         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
    Oedema peripheral
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Pyrexia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Sudden death
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Vulva cyst
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Chronic obstructive pulmonary disease
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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 respiratory failure
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         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
    1 / 1
    Hypoxia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         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
    Increased bronchial secretion
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (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
    Pneumonitis aspiration
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    3 / 168 (1.79%)
    1 / 168 (0.60%)
    1 / 123 (0.81%)
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    1 / 3
    1 / 1
    0 / 1
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Respiratory failure
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    3 / 123 (2.44%)
    2 / 140 (1.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 3
    0 / 2
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Suicide attempt
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Product issues
    Device occlusion
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Investigations
    Blood creatine phosphokinase abnormal
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (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
    Weight decreased
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (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
    Injury, poisoning and procedural complications
    Ankle fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (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
    Clavicle fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 168 (1.19%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 168 (0.60%)
    2 / 168 (1.19%)
    2 / 123 (1.63%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 2
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femoral neck fracture
         subjects affected / exposed
    2 / 168 (1.19%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Femur fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Head injury
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    2 / 123 (1.63%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Hip fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 168 (0.60%)
    1 / 123 (0.81%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Overdose
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius fracture
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Rib fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin laceration
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (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
    Subdural haematoma
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (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
    Thoracic vertebral fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (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
    Upper limb fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (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
    Wrist fracture
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Acute myocardial infarction
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac arrest
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 168 (0.60%)
    2 / 123 (1.63%)
    3 / 140 (2.14%)
         occurrences causally related to treatment / all
    0 / 1
    1 / 1
    0 / 2
    0 / 3
         deaths causally related to treatment / all
    0 / 1
    1 / 1
    0 / 2
    0 / 2
    Cardiac failure
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (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 / 1
    0 / 0
    0 / 0
    Cardio-respiratory arrest
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         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
    Coronary artery disease
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    3 / 123 (2.44%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 2
    0 / 0
    Pericarditis constrictive
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Nervous system disorders
    Bradykinesia
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (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
    Brain oedema
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cerebrovascular accident
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dorsal ramus syndrome
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Facial paresis
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (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
    Hypoaesthesia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Ischaemic stroke
         subjects affected / exposed
    0 / 168 (0.00%)
    2 / 168 (1.19%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Loss of consciousness
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Multiple system atrophy
         subjects affected / exposed
    3 / 168 (1.79%)
    2 / 168 (1.19%)
    1 / 123 (0.81%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 2
    1 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 0
    Oromandibular dystonia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (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
    Paralysis recurrent laryngeal nerve
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (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
    Presyncope
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Syncope
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Vocal cord paralysis
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (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
    Neutropenia
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         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
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Constipation
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dysphagia
         subjects affected / exposed
    2 / 168 (1.19%)
    1 / 168 (0.60%)
    1 / 123 (0.81%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Haemorrhoids
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (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
    Intestinal obstruction
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Volvulus
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Decubitus ulcer
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    0 / 140 (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 reaction with eosinophilia and systemic symptoms
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         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
    Renal and urinary disorders
    Acute kidney injury
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Bladder pain
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Renal pain
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Urinary retention
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    1 / 123 (0.81%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Infections and infestations
    Bronchitis
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         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
    1 / 168 (0.60%)
    1 / 168 (0.60%)
    1 / 123 (0.81%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
    0 / 1
    COVID-19 pneumonia
         subjects affected / exposed
    1 / 168 (0.60%)
    4 / 168 (2.38%)
    1 / 123 (0.81%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 4
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Clostridial sepsis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    Clostridium difficile colitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Herpes zoster
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Infected skin ulcer
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Infection
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (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
    Localised infection
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Pneumococcal sepsis
         subjects affected / exposed
    0 / 168 (0.00%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    5 / 168 (2.98%)
    2 / 168 (1.19%)
    1 / 123 (0.81%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    Pneumonia aspiration
         subjects affected / exposed
    2 / 168 (1.19%)
    2 / 168 (1.19%)
    1 / 123 (0.81%)
    3 / 140 (2.14%)
         occurrences causally related to treatment / all
    0 / 2
    1 / 4
    0 / 1
    0 / 3
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 1
    Pyelonephritis acute
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Sepsis
         subjects affected / exposed
    3 / 168 (1.79%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    3 / 140 (2.14%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    Urinary tract infection
         subjects affected / exposed
    7 / 168 (4.17%)
    1 / 168 (0.60%)
    4 / 123 (3.25%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 11
    0 / 1
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Urosepsis
         subjects affected / exposed
    4 / 168 (2.38%)
    2 / 168 (1.19%)
    1 / 123 (0.81%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 3
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 168 (0.00%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    1 / 140 (0.71%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 168 (0.60%)
    1 / 168 (0.60%)
    0 / 123 (0.00%)
    0 / 140 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hypokalaemia
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Malnutrition
         subjects affected / exposed
    1 / 168 (0.60%)
    0 / 168 (0.00%)
    0 / 123 (0.00%)
    0 / 140 (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
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Verdiperstat - Randomization Phase Placebo - Randomization Phase Verdiperstat - Randomization Phase/ Verdiperstat - OLE Phase Placebo - Randomization Phase/ Verdiperstat - OLE Phase
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    125 / 168 (74.40%)
    130 / 168 (77.38%)
    55 / 123 (44.72%)
    71 / 140 (50.71%)
    Investigations
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    9 / 168 (5.36%)
    1 / 168 (0.60%)
    6 / 123 (4.88%)
    7 / 140 (5.00%)
         occurrences all number
    13
    1
    6
    7
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    37 / 168 (22.02%)
    39 / 168 (23.21%)
    21 / 123 (17.07%)
    21 / 140 (15.00%)
         occurrences all number
    66
    53
    27
    38
    Vascular disorders
    Hypertension
         subjects affected / exposed
    3 / 168 (1.79%)
    9 / 168 (5.36%)
    1 / 123 (0.81%)
    3 / 140 (2.14%)
         occurrences all number
    3
    9
    1
    3
    Orthostatic hypotension
         subjects affected / exposed
    7 / 168 (4.17%)
    11 / 168 (6.55%)
    4 / 123 (3.25%)
    4 / 140 (2.86%)
         occurrences all number
    7
    12
    4
    4
    Nervous system disorders
    Balance disorder
         subjects affected / exposed
    17 / 168 (10.12%)
    14 / 168 (8.33%)
    3 / 123 (2.44%)
    4 / 140 (2.86%)
         occurrences all number
    20
    15
    4
    5
    Dizziness
         subjects affected / exposed
    13 / 168 (7.74%)
    22 / 168 (13.10%)
    3 / 123 (2.44%)
    5 / 140 (3.57%)
         occurrences all number
    16
    22
    3
    6
    Headache
         subjects affected / exposed
    21 / 168 (12.50%)
    23 / 168 (13.69%)
    3 / 123 (2.44%)
    11 / 140 (7.86%)
         occurrences all number
    25
    28
    4
    12
    Syncope
         subjects affected / exposed
    3 / 168 (1.79%)
    9 / 168 (5.36%)
    2 / 123 (1.63%)
    8 / 140 (5.71%)
         occurrences all number
    4
    11
    5
    8
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    7 / 168 (4.17%)
    6 / 168 (3.57%)
    5 / 123 (4.07%)
    7 / 140 (5.00%)
         occurrences all number
    7
    7
    5
    8
    Fatigue
         subjects affected / exposed
    15 / 168 (8.93%)
    14 / 168 (8.33%)
    6 / 123 (4.88%)
    4 / 140 (2.86%)
         occurrences all number
    15
    17
    6
    4
    Gait disturbance
         subjects affected / exposed
    12 / 168 (7.14%)
    12 / 168 (7.14%)
    2 / 123 (1.63%)
    2 / 140 (1.43%)
         occurrences all number
    12
    12
    2
    2
    Oedema peripheral
         subjects affected / exposed
    12 / 168 (7.14%)
    7 / 168 (4.17%)
    6 / 123 (4.88%)
    4 / 140 (2.86%)
         occurrences all number
    12
    8
    6
    4
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    19 / 168 (11.31%)
    12 / 168 (7.14%)
    7 / 123 (5.69%)
    4 / 140 (2.86%)
         occurrences all number
    21
    13
    7
    6
    Nausea
         subjects affected / exposed
    17 / 168 (10.12%)
    8 / 168 (4.76%)
    1 / 123 (0.81%)
    8 / 140 (5.71%)
         occurrences all number
    19
    8
    1
    9
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    9 / 168 (5.36%)
    4 / 168 (2.38%)
    1 / 123 (0.81%)
    4 / 140 (2.86%)
         occurrences all number
    12
    5
    1
    5
    Psychiatric disorders
    Depression
         subjects affected / exposed
    10 / 168 (5.95%)
    7 / 168 (4.17%)
    3 / 123 (2.44%)
    2 / 140 (1.43%)
         occurrences all number
    11
    7
    3
    2
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 168 (3.57%)
    9 / 168 (5.36%)
    3 / 123 (2.44%)
    2 / 140 (1.43%)
         occurrences all number
    6
    9
    3
    2
    Back pain
         subjects affected / exposed
    7 / 168 (4.17%)
    9 / 168 (5.36%)
    3 / 123 (2.44%)
    3 / 140 (2.14%)
         occurrences all number
    7
    10
    3
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 168 (1.19%)
    11 / 168 (6.55%)
    3 / 123 (2.44%)
    5 / 140 (3.57%)
         occurrences all number
    2
    11
    3
    5
    Urinary tract infection
         subjects affected / exposed
    44 / 168 (26.19%)
    54 / 168 (32.14%)
    26 / 123 (21.14%)
    29 / 140 (20.71%)
         occurrences all number
    71
    77
    38
    40

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    31 Jan 2020
    Modification of UMSARS analysis, refinement of eligibility criteria and clarification of prohibited/restricted concomitant medications /timing of required washout for prohibited medications to address limitations in this rare disease population of very ill participants with multiple comorbidities, specification of option to Rescreen participants, incorporation of Administrative Letters 1, 2 and 3 to update ICON medical monitor information and clarify IP storage temperature and excursion reporting, and administrative clarifications/updates.
    16 Jul 2020
    Due to restrictions intended to minimize COVID-19 public health emergency resurgence potential hazards to study participants, that impact conduct of study assessments and visits, provisions were added/implemented to allow alternatives to in-person study visits if needed, including remote safety visits and expansion of window for Week 48 visit to proactively account for any visits that may be delayed. In addition, sample size was increased to proactively account for potential loss of subjects due to COVID-19 and to increase the power to 90%. Addition of Open-Label Extension to provide participants who complete the double-blind portion of the study with access to treatment with open-label BHV-3241.
    20 Jan 2021
    Addition of exploratory objectives and clarification of eligibility criteria related to Open Label Extension phase of study and correction of typographical error in Section 4.5.2 to correspond to text correctly presented in Table 2 Schedule of Assessments and Events – Open Label Phase, Footnote 1.

    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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