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    Clinical Trial Results:
    An open-label, adaptive design study in patients with amyotrophic lateral sclerosis (ALS) to characterize safety, tolerability and brain microglia response, as measured by TSPO binding, following multiple doses of BLZ945 using positron emission tomography (PET) with the radioligand[11C]-PBR28

    Summary
    EudraCT number
    		 2019-000826-22
    Trial protocol
    		 SE   FI  
    Global end of trial date
    01 Feb 2024

    Results information
    Results version number
    		 v1
    This version publication date
    13 Feb 2025
    First version publication date
    13 Feb 2025
    Other versions
    		 v2

    Trial information

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    Trial identification
    Sponsor protocol code
    CBLZ945C12201
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04066244
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis Campus, Basel, Switzerland,
    Public contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Scientific contact
    Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@Novartis.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    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
    01 Feb 2024
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    01 Feb 2024
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    •Cohorts 1-4 and Cohort 5 (PET Sub-study): To evaluate brain microglial reduction, as measured by reduction in TSPO binding, following treatment with BLZ945 in ALS participants by using PET imaging with [11C]-PBR28 •Cohort 5: To assess safety-related effects on ECM accumulation under BLZ945 treatment
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Dec 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 States: 8
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Sweden: 12
    Worldwide total number of subjects
    28
    EEA total number of subjects
    20
    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)
    20
    From 65 to 84 years
    8
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 There was a screening and baseline period of up to 42 days for part 1 (Cohorts1-4) and of 6 weeks for part 2 (Cohort 5)

    Period 1
    Period 1 title
    Overall study (Part 1 + Part 2) (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 BLZ945 300mg - Cohort 1 (Part 1)
    Arm description
    		 BLZ945 300mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotuletinib
    Investigational medicinal product code
    BLZ945
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    300mg/day for 4 days

    Arm title
    		 BLZ945 600mg - Cohort 2 (Part 1)
    Arm description
    		 BLZ945 600mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotuletinib
    Investigational medicinal product code
    BLZ945
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    600mg/day for 4 days

    Arm title
    		 BLZ945 800mg - Cohort 4 (Part 1)
    Arm description
    		 BLZ945 800mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotuletinib
    Investigational medicinal product code
    BLZ945
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    800mg/day for 4 days

    Arm title
    		 BLZ945 1200mg - Cohort 3 (Part 1)
    Arm description
    		 BLZ945 1200mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotuletinib
    Investigational medicinal product code
    BLZ945
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    1200mg/day for 4 days

    Arm title
    		 BLZ945 800mg - Cohort 5 Arm #1 (Part 2)
    Arm description
    		 BLZ945 800mg (4 days on/10 days off)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotuletinib
    Investigational medicinal product code
    BLZ945
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use, Enteral use
    Dosage and administration details
    800mg in repeated cycles of 4 days on treatment followed by 10 days off for 12 weeks

    Arm title
    		 BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Arm description
    		 BLZ945 800mg (once weekly)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Sotuletinib
    Investigational medicinal product code
    BLZ945
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use, Enteral use
    Dosage and administration details
    800mg once weekly for 12 weeks

    Number of subjects in period 1
    		BLZ945 300mg - Cohort 1 (Part 1) BLZ945 600mg - Cohort 2 (Part 1) BLZ945 800mg - Cohort 4 (Part 1) BLZ945 1200mg - Cohort 3 (Part 1) BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Started
    4
    4
    4
    4
    6
    6
    Completed
    4
    4
    4
    4
    5
    2
    Not completed
    0
    0
    0
    0
    1
    4
         Consent withdrawn by subject
    -
    -
    -
    -
    1
    -
         Adverse Event
    -
    -
    -
    -
    -
    1
         Death
    -
    -
    -
    -
    -
    2
         Study terminated by sponsor
    -
    -
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    BLZ945 300mg - Cohort 1 (Part 1)
    Reporting group description
    		 BLZ945 300mg

    Reporting group title
    BLZ945 600mg - Cohort 2 (Part 1)
    Reporting group description
    		 BLZ945 600mg

    Reporting group title
    BLZ945 800mg - Cohort 4 (Part 1)
    Reporting group description
    		 BLZ945 800mg

    Reporting group title
    BLZ945 1200mg - Cohort 3 (Part 1)
    Reporting group description
    		 BLZ945 1200mg

    Reporting group title
    BLZ945 800mg - Cohort 5 Arm #1 (Part 2)
    Reporting group description
    		 BLZ945 800mg (4 days on/10 days off)

    Reporting group title
    BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Reporting group description
    		 BLZ945 800mg (once weekly)

    Reporting group values
    		 BLZ945 300mg - Cohort 1 (Part 1) BLZ945 600mg - Cohort 2 (Part 1) BLZ945 800mg - Cohort 4 (Part 1) BLZ945 1200mg - Cohort 3 (Part 1) BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2) Total
    Number of subjects
    		 4 4 4 4 6 6 28
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 4 3 2 1 5 5 20
        From 65-84 years
    		 0 1 2 3 1 1 8
        85 years and over
    		 0 0 0 0 0 0 0
    Age Continuous
    Units: years
        median (full range (min-max))
    		 50.5 (46 to 58) 59.5 (33 to 76) 65.5 (56 to 68) 64 (62 to 68) 55.5 (52 to 74) 62.5 (32 to 67) -
    Sex: Female, Male
    Units: Participants
        Female
    		 2 2 1 2 1 2 10
        Male
    		 2 2 3 2 5 4 18
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    		 0 0 0 0 0 0 0
        Asian
    		 0 0 0 0 0 0 0
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0 0 0 0
        Black or African American
    		 0 0 0 0 0 0 0
        White
    		 4 3 4 4 6 6 27
        More than one race
    		 0 0 0 0 0 0 0
        Unknown or Not Reported
    		 0 1 0 0 0 0 1

    End points

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    End points reporting groups
    Reporting group title
    BLZ945 300mg - Cohort 1 (Part 1)
    Reporting group description
    		 BLZ945 300mg

    Reporting group title
    BLZ945 600mg - Cohort 2 (Part 1)
    Reporting group description
    		 BLZ945 600mg

    Reporting group title
    BLZ945 800mg - Cohort 4 (Part 1)
    Reporting group description
    		 BLZ945 800mg

    Reporting group title
    BLZ945 1200mg - Cohort 3 (Part 1)
    Reporting group description
    		 BLZ945 1200mg

    Reporting group title
    BLZ945 800mg - Cohort 5 Arm #1 (Part 2)
    Reporting group description
    		 BLZ945 800mg (4 days on/10 days off)

    Reporting group title
    BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Reporting group description
    		 BLZ945 800mg (once weekly)

    Primary: Cohorts 1-4 : Change from baseline in volume of distribution (Vt) in different brain regions for [11C]-PBR28 PET scan

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    End point title
    		 Cohorts 1-4 : Change from baseline in volume of distribution (Vt) in different brain regions for [11C]-PBR28 PET scan [1] [2]
    End point description
    [11C]-PBR28 is a positron emission tomography (PET) radiotracer for the 18 kDa translocator protein (TSPO) that is used to image neuroinflammation in vivo. [11C]PBR28 imaging was used to measure microglial activation at baseline and after BLZ945 treatment in ALS participants. Relative % change from baseline in volume of distribution (Vt) of [11C]-PBR28 in different brain regions after BLZ945 treatment. No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Baseline, day 5
    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: No statistical analysis was planned for this primary outcome.
    [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 planned to be applicable only to cohorts 1-4
    End point values
    		 BLZ945 300mg - Cohort 1 (Part 1) BLZ945 600mg - Cohort 2 (Part 1) BLZ945 800mg - Cohort 4 (Part 1) BLZ945 1200mg - Cohort 3 (Part 1)
    Number of subjects analysed
    3
    3
    4
    2
    Units: Percent change from baseline
    arithmetic mean (standard deviation)
        Precentral gyrus - day 5
    0.67 ( 33.825 )
    -20.33 ( 16.458 )
    9.90 ( 31.570 )
    -9.63 ( 1.516 )
        Basal Ganglia - day 5
    -3.70 ( 22.729 )
    -15.18 ( 16.343 )
    13.27 ( 35.504 )
    -10.73 ( 5.872 )
        Brain Stem - day 5
    -7.10 ( 20.890 )
    -10.00 ( 13.464 )
    50.56 ( 100.838 )
    -16.69 ( 61.674 )
        Cerebellar White Matter - day 5
    -4.41 ( 20.678 )
    -14.11 ( 11.904 )
    27.65 ( 60.112 )
    -16.87 ( 4.874 )
        Cerebellum - day 5
    -3.53 ( 20.459 )
    -10.06 ( 8.365 )
    17.52 ( 44.628 )
    -11.78 ( 3.854 )
        Frontal Lobe - day 5
    1.33 ( 30.101 )
    -18.67 ( 15.881 )
    9.10 ( 29.745 )
    -9.70 ( 0.224 )
        Occipital Lobe - day 5
    -3.01 ( 23.217 )
    -11.50 ( 10.457 )
    14.18 ( 36.595 )
    -5.87 ( 0.292 )
        Thalamus - day 5
    -8.00 ( 22.581 )
    -14.85 ( 13.466 )
    13.89 ( 42.938 )
    -14.14 ( 3.521 )
        Whole Brain - day 5
    -0.95 ( 26.606 )
    -15.59 ( 14.716 )
    12.22 ( 34.922 )
    -7.72 ( 0.326 )
    No statistical analyses for this end point

    Primary: Cohort 5 (PET sub-study): Change from baseline in volume of distribution (Vt) in different brain regions for [11C]-PBR28 PET scan

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    End point title
    		 Cohort 5 (PET sub-study): Change from baseline in volume of distribution (Vt) in different brain regions for [11C]-PBR28 PET scan [3] [4]
    End point description
    [11C]-PBR28 is a positron emission tomography (PET) radiotracer for the 18 kDa translocator protein (TSPO) that is used to image neuroinflammation in vivo. [11C]PBR28 imaging was used to measure microglial activation at baseline and after BLZ945 treatment in ALS participants. Relative % change from baseline in volume of distribution (Vt) of [11C]-PBR28 in different brain regions after BLZ945 treatment. No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Baseline, day 84
    Notes
    [3] - 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: No statistical analysis was planned for this primary outcome.
    [4] - 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 planned to be applicable only to cohort 5
    End point values
    		 BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    1
    0 [5]
    Units: Percent change from baseline
    arithmetic mean (standard deviation)
        Precentral gyrus - day 84
    -21.95 ( 999 )
    ( )
        Basal Ganglia - day 84
    -17.18 ( 999 )
    ( )
        Brain Stem - day 84
    -26.10 ( 999 )
    ( )
        Cerebellar White Matter - day 84
    -22.40 ( 999 )
    ( )
        Cerebellum - day 84
    -19.40 ( 999 )
    ( )
        Frontal Lobe - day 84
    -21.53 ( 999 )
    ( )
        Occipital Lobe - day 84
    -17.76 ( 999 )
    ( )
        Thalamus - day 84
    -29.39 ( 999 )
    ( )
        Whole Brain - day 84
    -20.51 ( 999 )
    ( )
    Notes
    [5] - 0 participants with a valid assessment of the outcome measure.
    No statistical analyses for this end point

    Primary: Cohort 5: Change from baseline in esophageal wall thickness

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    End point title
    		 Cohort 5: Change from baseline in esophageal wall thickness [6] [7]
    End point description
    Mean change from baseline in esophageal wall thickness measured in mm. No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Day 84
    Notes
    [6] - 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: No statistical analysis was planned for this primary outcome.
    [7] - 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 planned to be applicable only to cohort 5
    End point values
    		 BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    4
    2
    Units: mm
    arithmetic mean (standard deviation)
        Wall thickness average
    0.258 ( 0.7990 )
    0.758 ( 2.1708 )
        Lower third Wall Thickness
    0.040 ( 0.9475 )
    -1.400 ( 2.9981 )
        Middle third Wall Thickness
    0.235 ( 0.0212 )
    2.795 ( 2.6234 )
        Upper third Wall Thickness
    0.500 ( 1.4284 )
    0.880 ( 0.8910 )
    No statistical analyses for this end point

    Primary: Cohort 5: Cardiac valve thickness at day 84 compared to baseline

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    End point title
    		 Cohort 5: Cardiac valve thickness at day 84 compared to baseline [8] [9]
    End point description
    Cardiac valve thickness on a three point ordinal scale. Categorized by imaging vendor into three semiquantitative (normal, mild-moderate and severe) categories. Cardiac valves evaluated are aortic valve (AV), mitral valve (MV), Pulmonary valve (PV) and Tricuspid valve (TV). No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Day 84
    Notes
    [8] - 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: No statistical analysis was planned for this primary outcome.
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this primary outcome.
    End point values
    		 BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    6
    6
    Units: Participants
        Baseline AV thickness - Normal
    6
    6
        Day 84 AV thickness - Normal (n=2)
    2
    2
        Baseline MV thickness - Normal
    6
    5
        Baseline MV thickness - Mild-Moderate
    0
    1
        Day 84 MV thickness - Normal (n=2)
    2
    2
        Baseline PV thickness - Normal
    6
    6
        Day 84 PV thickness - Normal (n=2)
    2
    2
        Baseline TV thickness - Normal
    6
    6
        Day 84 TV thickness - Normal (n=2)
    2
    2
    No statistical analyses for this end point

    Primary: Cohort 5: Cardiac valve stenosis at day 84 compared to baseline

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    End point title
    		 Cohort 5: Cardiac valve stenosis at day 84 compared to baseline [10] [11]
    End point description
    Cardiac valve stenosis on a four point ordinal scale. Categorized by imaging vendor into four semiquantitative (normal, mild, moderate and severe) categories. ardiac valves evaluated are aortic valve (AV), mitral valve (MV), Pulmonary valve (PV) and Tricuspid valve (TV). No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Day 84
    Notes
    [10] - 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: No statistical analysis was planned for this primary outcome.
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this primary outcome.
    End point values
    		 BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    6
    6
    Units: Participants
        Baseline AV stenosis - Normal
    6
    6
        Day 84 AV stenosis - Normal (n=2)
    2
    2
        Baseline MV stenosis - Normal
    6
    6
        Day 84 MV stenosis - Normal (n=2)
    2
    2
        Baseline PV stenosis - Normal
    6
    6
        Day 84 PV stenosis - Normal (n=2)
    2
    2
        Baseline TV stenosis - Normal
    6
    6
        Day 84 TV stenosis - Normal (n=2)
    2
    2
    No statistical analyses for this end point

    Primary: Cohort 5: Cardiac valve regurgitation severity at day 84 compared to baseline

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    End point title
    		 Cohort 5: Cardiac valve regurgitation severity at day 84 compared to baseline [12] [13]
    End point description
    Cardiac valve regurgitation severity on a four point ordinal scale. Categorized by imaging vendor into four semiquantitative (normal, mild, moderate and severe) categories. ardiac valves evaluated are aortic valve (AV), mitral valve (MV), Pulmonary valve (PV) and Tricuspid valve (TV). No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Baseline, Day 84
    Notes
    [12] - 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: No statistical analysis was planned for this primary outcome.
    [13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: No statistical analysis was planned for this primary outcome.
    End point values
    		 BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    6
    6
    Units: Participants
        Baseline AV regurgitation - Normal
    5
    6
        Baseline AV regurgitation - Mild
    1
    0
        Day 84 AV regurgitation - Normal
    2
    2
        Day 84 AV regurgitation - Mild
    0
    0
        Baseline MV regurgitation - Normal
    3
    3
        Baseline MV regurgitation - mild
    3
    3
        Day 84 MV regurgitation - Normal
    0
    1
        Day 84 MV regurgitation - Mild
    2
    1
        Baseline PV regurgitation - Normal
    3
    4
        Baseline PV regurgitation - Mild
    3
    2
        Day 84 PV regurgitation - Normal
    2
    1
        Day 84 PV regurgitation - Mild
    0
    1
        Baseline TV regurgitation - Normal
    3
    2
        Baseline TV regurgitation - Mild
    3
    4
        Day 84 TV regurgitation - Normal
    1
    1
        Day 84 TV regurgitation - Mild
    1
    1
    No statistical analyses for this end point

    Primary: Cohort 5: Change from baseline in Left Ventricular Ejection Fraction (LVEF).

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    End point title
    		 Cohort 5: Change from baseline in Left Ventricular Ejection Fraction (LVEF). [14] [15]
    End point description
    Mean change from baseline in Left Ventricular Ejection Fraction. LVEF is defined as the percentage of blood volume ejected from the left ventricle during systole (contraction phase) relative to the total volume of blood present in the ventricle at the end of diastole (relaxation phase). No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Baseline, day 84
    Notes
    [14] - 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: No statistical analysis was planned for this primary outcome.
    [15] - 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 planned to be applicable only to cohort 5
    End point values
    		 BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    2
    2
    Units: Change from baseline
        arithmetic mean (standard deviation)
    1.533 ( 2.9713 )
    5.021 ( 2.0796 )
    No statistical analyses for this end point

    Primary: Cohort 5: Adverse events related to Extracellular matrix (ECM) accumulation

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    End point title
    		 Cohort 5: Adverse events related to Extracellular matrix (ECM) accumulation [16] [17]
    End point description
    Number of patients with adverse events related to ECM accumulation. No statistical analysis was planned for this primary outcome.
    End point type
    Primary
    End point timeframe
    Up to Day 84
    Notes
    [16] - 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: No statistical analysis was planned for this primary outcome.
    [17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint was planned to be applicable only to cohort 5
    End point values
    		 BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    6
    6
    Units: Participants
    2
    2
    No statistical analyses for this end point

    Secondary: Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax

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    End point title
    		 Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Cmax
    End point description
    Measured by Cmax - The maximum plasma concentration of BLZ945
    End point type
    Secondary
    End point timeframe
    Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4. Cohort 5: pre-dose, 1, 2 and 4 hours after BLZ945 dosing on Day 1 (Arm#2 only) and Day 4 (Arm#1 only)
    End point values
    		 BLZ945 300mg - Cohort 1 (Part 1) BLZ945 600mg - Cohort 2 (Part 1) BLZ945 800mg - Cohort 4 (Part 1) BLZ945 1200mg - Cohort 3 (Part 1) BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    4
    4
    4
    3
    4 [18]
    6 [19]
    Units: ng/mL of BLZ945
    arithmetic mean (standard deviation)
        Day 1
    6850 ( 780 )
    16000 ( 2510 )
    21100 ( 5630 )
    25900 ( 2630 )
    999 ( 999 )
    19900 ( 5990 )
        Day 4
    12100 ( 2300 )
    25900 ( 3440 )
    30700 ( 7800 )
    37600 ( 4270 )
    22400 ( 3120 )
    999 ( 999 )
    Notes
    [18] - 0 participants analyzed at day 1
    [19] - 0 participants analyzed at day 4
    No statistical analyses for this end point

    Secondary: Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax

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    End point title
    		 Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - Tmax
    End point description
    Measured by Tmax - Time to Reach the Maximum Concentration After Drug Administration of BLZ945. Actual recorded sampling times were taken into consideration for the calculation of PK parameters.
    End point type
    Secondary
    End point timeframe
    Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4. Cohort 5: pre-dose, 1, 2 and 4 hours after BLZ945 dosing on Day 1 (Arm#2 only) and Day 4 (Arm#1 only)
    End point values
    		 BLZ945 300mg - Cohort 1 (Part 1) BLZ945 600mg - Cohort 2 (Part 1) BLZ945 800mg - Cohort 4 (Part 1) BLZ945 1200mg - Cohort 3 (Part 1) BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    4
    4
    4
    3
    4 [20]
    6 [21]
    Units: hours
    median (full range (min-max))
        Day 1
    1.02 (1.00 to 1.07)
    2.01 (1.00 to 2.08)
    2.01 (1.00 to 7.00)
    1.00 (1.00 to 1.00)
    999 (999 to 999)
    2.00 (1.00 to 4.17)
        Day 4
    1.01 (0.500 to 1.03)
    1.50 (1.00 to 4.00)
    3.00 (1.00 to 6.08)
    2.02 (1.00 to 4.00)
    1.49 (0.817 to 2.00)
    999 (999 to 999)
    Notes
    [20] - 0 participants analyzed at day 1
    [21] - 0 participants analyzed at day 4
    No statistical analyses for this end point

    Secondary: Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC

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    End point title
    		 Cohorts 1-5: Plasma Pharmacokinetics (PK) of BLZ945 - AUC
    End point description
    Measured by AUC - Area under the curve of BLZ945 AUC0-24h is the AUC calculated from time zero to 24 hours after dosing (end of a dosing interval). AUClast is the AUC from time zero to the last measurable concentration sampling time.
    End point type
    Secondary
    End point timeframe
    Day 1; Day 4
    End point values
    		 BLZ945 300mg - Cohort 1 (Part 1) BLZ945 600mg - Cohort 2 (Part 1) BLZ945 800mg - Cohort 4 (Part 1) BLZ945 1200mg - Cohort 3 (Part 1) BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    4
    4
    4
    3
    4 [22]
    6 [23]
    Units: hour * ng/mL
    arithmetic mean (standard deviation)
        AUC 0-24h - Day 1
    93000 ( 2510 )
    204000 ( 28000 )
    278000 ( 49600 )
    391000 ( 10600 )
    999 ( 999 )
    999 ( 999 )
        AUC 0-24h - Day 4
    175000 ( 14100 )
    401000 ( 88700 )
    535000 ( 157000 )
    680000 ( 48300 )
    999 ( 999 )
    999 ( 999 )
        AUClast - Day 1
    92600 ( 2750 )
    203000 ( 26800 )
    277000 ( 99500 )
    34100 ( 91100 )
    999 ( 999 )
    56900 ( 21400 )
        AUClast - Day 4
    170000 ( 20300 )
    399000 ( 87800 )
    533000 ( 158000 )
    671000 ( 43400 )
    73400 ( 7710 )
    999 ( 999 )
    Notes
    [22] - 0 participants analyzed at day 1
    [23] - 0 participants analyzed at day 4
    No statistical analyses for this end point

    Secondary: Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2

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    End point title
    		 Cohorts 1-4: Plasma Pharmacokinetics (PK) of BLZ945 - T1/2 [24]
    End point description
    Measured by T1/2 - The elimination half-life of BLZ945
    End point type
    Secondary
    End point timeframe
    Cohort 1-4: Pre-dose, 0.5, 1, 2, 4, 6, 8, 12 and 24 hours after BLZ945 dosing on Day 1 and Day 4.
    Notes
    [24] - 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 planned to be applicable only to cohorts 1-4
    End point values
    		 BLZ945 300mg - Cohort 1 (Part 1) BLZ945 600mg - Cohort 2 (Part 1) BLZ945 800mg - Cohort 4 (Part 1) BLZ945 1200mg - Cohort 3 (Part 1)
    Number of subjects analysed
    4
    4
    3
    4
    Units: Hours
    arithmetic mean (standard deviation)
        Day 1
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
        Day 4
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Cohorts 1-4: Renal Clearance (CLR) of BLZ945

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    End point title
    		 Cohorts 1-4: Renal Clearance (CLR) of BLZ945 [25]
    End point description
    Urine renal clearance (CLR) of BLZ945
    End point type
    Secondary
    End point timeframe
    pre-dose, 0-4, 4-8, 8-12 and 12-24 hours after BLZ945 dosing on Day 1 and Day 4
    Notes
    [25] - 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 planned to be applicable only to cohorts 1-4
    End point values
    		 BLZ945 300mg - Cohort 1 (Part 1) BLZ945 600mg - Cohort 2 (Part 1) BLZ945 800mg - Cohort 4 (Part 1) BLZ945 1200mg - Cohort 3 (Part 1)
    Number of subjects analysed
    4
    4
    4
    3
    Units: liter/hour (L/hr)
    arithmetic mean (standard deviation)
        Day 1
    0.00597 ( 0.00184 )
    0.00844 ( 0.00675 )
    0.00466 ( 0.00312 )
    0.0213 ( 0.0258 )
        Day 4
    0.00667 ( 0.00127 )
    0.00410 ( 0.00205 )
    0.00362 ( 0.00262 )
    0.00550 ( 0.00129 )
    No statistical analyses for this end point

    Secondary: Cohorts 1-5: Number of patients with adverse events (AEs) and serious adverse events (SAEs)

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    End point title
    		 Cohorts 1-5: Number of patients with adverse events (AEs) and serious adverse events (SAEs)
    End point description
    Incidence and severity of AEs and SAEs by treatment group. AE grades to characterize the severity of the AEs were based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5. For CTCAE, Grade 1 = mild; Grade 2 = moderate; Grade 3 = severe; Grade 4 = life-threatening; Grade 5 = death related to AE
    End point type
    Secondary
    End point timeframe
    From first dose of study treatment up to 32 days after last dose (Day 36) for Cohorts 1-4 and up to 4 weeks after last dose (Day 330) for Cohort 5. *Maxim duration of exposure in Cohort 5 was 302 days. 302 + 28 days of FU=330 days
    End point values
    		 BLZ945 300mg - Cohort 1 (Part 1) BLZ945 600mg - Cohort 2 (Part 1) BLZ945 800mg - Cohort 4 (Part 1) BLZ945 1200mg - Cohort 3 (Part 1) BLZ945 800mg - Cohort 5 Arm #1 (Part 2) BLZ945 800mg - Cohort 5 Arm #2 (Part 2)
    Number of subjects analysed
    4
    4
    4
    4
    6
    6
    Units: Participants
        Total AEs
    2
    2
    4
    4
    6
    6
        AE of grade 1
    2
    2
    4
    4
    5
    6
        AE of grade 2
    2
    1
    3
    2
    5
    5
        AE of grade 3
    0
    0
    2
    0
    1
    5
        AE of grade 4
    0
    0
    0
    0
    0
    1
        AE of grade 5
    0
    0
    0
    0
    0
    2
        Study drug-related AEs
    2
    2
    3
    2
    5
    5
        Serious AEs
    0
    0
    1
    0
    0
    4
        AEs leading to discontinuation of study treatment
    0
    0
    0
    0
    0
    4
        BLZ945 related AEs causing drug discontinuation
    0
    0
    0
    0
    0
    3
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From first dose of study treatment up to 32 days after last dose (Day 36) for Cohorts 1-4 and up to 4 weeks after last dose (Day 330) for Cohort 5. *Maxim duration of exposure in Cohort 5 was 302 days. 302 + 28 days of FU=330 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    27.0
    Reporting groups
    Reporting group title
    BLZ945 300mg
    Reporting group description
    		 BLZ945 300mg

    Reporting group title
    BLZ945 600mg
    Reporting group description
    		 BLZ945 600mg

    Reporting group title
    BLZ945 800mg
    Reporting group description
    		 BLZ945 800mg

    Reporting group title
    BLZ945 1200mg
    Reporting group description
    		 BLZ945 1200mg

    Reporting group title
    Arm 1 (4/10)
    Reporting group description
    		 Arm 1 (4/10)

    Reporting group title
    Arm 2 (4/10) QW
    Reporting group description
    		 Arm 2 (4/10) QW

    Reporting group title
    Total
    Reporting group description
    		 Total

    Serious adverse events
    		 BLZ945 300mg BLZ945 600mg BLZ945 800mg BLZ945 1200mg Arm 1 (4/10) Arm 2 (4/10) QW Total
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    4 / 6 (66.67%)
    5 / 28 (17.86%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    2
    2
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    0
    Investigations
    Transaminases increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory failure
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
    Infections and infestations
    Pneumonia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 1
    Pneumonia aspiration
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 BLZ945 300mg BLZ945 600mg BLZ945 800mg BLZ945 1200mg Arm 1 (4/10) Arm 2 (4/10) QW Total
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    4 / 4 (100.00%)
    4 / 4 (100.00%)
    6 / 6 (100.00%)
    6 / 6 (100.00%)
    24 / 28 (85.71%)
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Flushing
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Hypertension
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    4
    0
    4
    Swelling face
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Peripheral swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Fatigue
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    8 / 28 (28.57%)
         occurrences all number
    1
    0
    0
    2
    4
    2
    9
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Seasonal allergy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Respiratory, thoracic and mediastinal disorders
    Atelectasis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Dyspnoea
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 6 (33.33%)
    0 / 6 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    Pleurisy
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Pulmonary oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Stridor
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Psychiatric disorders
    Panic attack
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Anxiety
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    1
    0
    0
    1
    2
    Product issues
    Device dislocation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    2 / 6 (33.33%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    2
    Aspartate aminotransferase increased
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    2 / 6 (33.33%)
    4 / 28 (14.29%)
         occurrences all number
    1
    0
    0
    0
    1
    2
    4
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Blood bilirubin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    2
    0
    0
    2
    Blood urine present
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Electrocardiogram T wave inversion
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Faecal volume decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Hepatic enzyme increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Transaminases increased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Weight decreased
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Troponin increased
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 6 (33.33%)
    2 / 6 (33.33%)
    5 / 28 (17.86%)
         occurrences all number
    0
    0
    0
    1
    2
    3
    6
    Contusion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    1
    0
    2
    3
    Epicondylitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Rib fracture
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Wound
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Nervous system disorders
    Brain fog
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    1
    0
    1
    2
    Amyotrophic lateral sclerosis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Paraesthesia
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    2
    Muscle contractions involuntary
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    3
    Migraine
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    2
    0
    0
    0
    1
    0
    3
    Hypogeusia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Headache
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    3 / 4 (75.00%)
    3 / 6 (50.00%)
    2 / 6 (33.33%)
    10 / 28 (35.71%)
         occurrences all number
    2
    0
    0
    3
    4
    2
    11
    Dizziness
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    7 / 28 (25.00%)
         occurrences all number
    2
    0
    2
    1
    6
    4
    15
    Somnolence
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    2 / 28 (7.14%)
         occurrences all number
    1
    0
    0
    0
    0
    1
    2
    Tremor
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    1
    0
    0
    0
    1
    Syncope
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    2
    Ear and labyrinth disorders
    Vertigo positional
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    1
    0
    0
    0
    0
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    2
    Eye disorders
    Eye swelling
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    2
    3
    Eye pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Eye irritation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Periorbital oedema
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Abdominal pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    1
    2
    0
    3
    Vomiting
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    3 / 28 (10.71%)
         occurrences all number
    1
    0
    1
    1
    0
    0
    3
    Salivary hypersecretion
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Nausea
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    3 / 4 (75.00%)
    3 / 6 (50.00%)
    1 / 6 (16.67%)
    9 / 28 (32.14%)
         occurrences all number
    1
    0
    2
    3
    5
    1
    12
    Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    1
    1
    2
    Diarrhoea
         subjects affected / exposed
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    4 / 28 (14.29%)
         occurrences all number
    1
    1
    1
    0
    0
    1
    4
    Constipation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Hepatobiliary disorders
    Ocular icterus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Skin and subcutaneous tissue disorders
    Rash maculo-papular
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Rash
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Pruritus
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    2
    Renal and urinary disorders
    Chromaturia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Urine abnormality
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    2
    0
    0
    0
    2
    Musculoskeletal and connective tissue disorders
    Groin pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Arthralgia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Muscle fatigue
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    1 / 6 (16.67%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    0
    0
    2
    1
    3
    Muscular weakness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    0
    0
    1
    1
    0
    0
    2
    Myokymia
         subjects affected / exposed
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    1
    0
    0
    0
    0
    1
    Infections and infestations
    Mucosal infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    2 / 28 (7.14%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    2
    Sinusitis
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Wound infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    1
    0
    1
    Urinary tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Tooth infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 6 (0.00%)
    1 / 6 (16.67%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    1
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 6 (0.00%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    1
    0
    0
    1
    Decreased appetite
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 6 (16.67%)
    0 / 6 (0.00%)
    1 / 28 (3.57%)
         occurrences all number
    0
    0
    0
    0
    2
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    09 Jul 2019
    The original version of the protocol was amended before submission to competent authorities/Ethics committee to incorporate input from investigators on the use of alternatives types of pet scanning.
    19 Sep 2019
    The trial protocol was amended to address comments from health authorities by adding discontinuation rules related to QT prolongation, aligning stopping rules with dole limiting toxicities, adding ALS diagnostic criteria and including IUD, IUS, and hormonal contraception methods.
    03 Sep 2020
    Protocol was amended to remove age limitations, incorporate home nursing as an option for study procedures and add flexibility around PET and MRI imaging
    04 May 2021
    The primary purpose of this amendment was to address the potential for additional pharmacokinetic drug-drug interactions.
    13 Jul 2022
    The protocol was amended to evaluate the safety and preliminary efficacy of repeated cycles of BLZ945 using two dosing regimens in Cohort 5. Additional safety monitoring assessments, as well as new clinical and pharmacodynamic outcome measures were added in Cohort 5. Amendment 5 introduced a new study structure and an extension of the recruitment numbers
    20 Jan 2023
    The main purpose of this amendment was to ensure a continuation of treatment in participants already enrolled in the study, to continue to assess long term safety, tolerability, and pharmacokinetic and pharmacodynamic data beyond 12 weeks of treatment.
    05 Oct 2023
    The main purpose of this amendment was to update the BLZ945 dose in both treatment arms of Cohort 5

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    Due to EudraCT system limitations, which EMA is aware of, data using 999 as data points in this record are not an accurate representation of the clinical trial results. Please use https://www.novctrd.com/#/
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