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    Clinical Trial Results:
    A Randomized, Double-Blind, Placebo-Controlled Dose Range Finding Study with Open-Label Extension to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of LMI070/branaplam when Administered as Weekly Oral Doses in Participants with Early Manifest Huntington’s Disease

    Summary
    EudraCT number
    		 2020-000105-92
    Trial protocol
    		 DE   HU   ES   FR   IT   BE   LT  
    Global end of trial date
    23 Oct 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Sep 2024
    First version publication date
    12 Sep 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLMI070C12203
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05111249
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Novartis Pharma AG
    Sponsor organisation address
    Novartis campus, Basel, Switzerland, CH-4056
    Public contact
    Clinical Disclosure Office, Novartis Pharma AS, 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
    27 Oct 2023
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    23 Oct 2023
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objectives of the trial were: • To assess the dose response relationship of branaplam administered over 16 weeks on mutant Huntingtin (mHTT) protein change from baseline in cerebrospinal fluid (CSF) • To evaluate the safety and tolerability of branaplam when administered for 16 weeks or longer in participants with Huntington’s disease (HD)
    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
    08 Dec 2021
    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
    Canada: 3
    Country: Number of subjects enrolled
    France: 3
    Country: Number of subjects enrolled
    Germany: 6
    Country: Number of subjects enrolled
    Hungary: 5
    Country: Number of subjects enrolled
    Spain: 9
    Worldwide total number of subjects
    26
    EEA total number of subjects
    23
    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)
    24
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants took part in 12 investigative sites in 5 countries.

    Pre-assignment
    Screening details
    		 Screening period lasted up to 6 weeks. For eligible participants, baseline measurements were performed within 6 days prior to first dose of study treatment. In the Core period participants were randomized (4:1) to receive either branaplam or placebo. The last study visit was performed at Week 69. The open label extension (OLE) period was not opened

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Treatment Arm A: matching placebo oral solution once weekly
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo oral solution administered once weekly.

    Arm title
    		 Branaplam 56 mg
    Arm description
    		 Treatment Arm A: branaplam 56 mg oral solution once weekly
    Arm type
    		 Experimental

    Investigational medicinal product name
    Branaplam
    Investigational medicinal product code
    LMI070
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Branaplam 56 mg oral solution administered once weekly. Branaplam was administered up to maximum 22 weeks.

    Number of subjects in period 1
    		Placebo Branaplam 56 mg
    Started
    5
    21
    Completed
    4
    13
    Not completed
    1
    8
         Physician decision
    -
    1
         Participant decision
    1
    5
         Lost to follow-up
    -
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Treatment Arm A: matching placebo oral solution once weekly

    Reporting group title
    Branaplam 56 mg
    Reporting group description
    		 Treatment Arm A: branaplam 56 mg oral solution once weekly

    Reporting group values
    		 Placebo Branaplam 56 mg Total
    Number of subjects
    		 5 21 26
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 5 19 24
        From 65-84 years
    		 0 2 2
        85 years and over
    		 0 0 0
    Age Continuous
    Units: years
        arithmetic mean (standard deviation)
    		 52.8 ( 15.30 ) 49.6 ( 10.06 ) -
    Sex: Female, Male
    Units: participants
        Female
    		 1 10 11
        Male
    		 4 11 15
    Race/Ethnicity, Customized
    Units: Subjects
        White
    		 5 18 23
        Unknown
    		 0 3 3

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Treatment Arm A: matching placebo oral solution once weekly

    Reporting group title
    Branaplam 56 mg
    Reporting group description
    		 Treatment Arm A: branaplam 56 mg oral solution once weekly

    Primary: Percentage change from baseline to Week 17 in mHTT protein in CSF

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    End point title
    		 Percentage change from baseline to Week 17 in mHTT protein in CSF [1]
    End point description
    Mutant Huntingtin (mHTT) protein was measured in cerebrospinal fluid (CSF) obtained via lumbar puncture. The percentage change from baseline to Week 17 in mHTT protein in CSF was calculated with the following formula: (mHTTweek17 - mHTTbaseline)/ mHTTbaseline * 100. Baseline value for mHTT is the last evaluable measurements prior to the first administration of study drug.
    End point type
    Primary
    End point timeframe
    Baseline, Week 17
    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 were planned for this endpoint.
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    4
    9
    Units: % change in mHTT protein
        arithmetic mean (standard deviation)
    -1.38 ( 20.517 )
    -26.61 ( 22.354 )
    No statistical analyses for this end point

    Primary: Number of participants with adverse events (AEs) and serious adverse events (SAEs)

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    End point title
    		 Number of participants with adverse events (AEs) and serious adverse events (SAEs) [2]
    End point description
    Incidence of AEs (any AEs regardless of seriousness) and SAEs, including changes in vital signs, neurological examination, electrocardiograms (ECGs) and laboratory parameters qualifying and reported as AEs. Participants received study treatment up to maximum Week 20 (placebo) and Week 22 (branaplam).
    End point type
    Primary
    End point timeframe
    From first dose of study treatment up to Week 69
    Notes
    [2] - 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 were planned for this endpoint.
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    5
    21
    Units: participants
        AEs
    2
    18
        Study drug-related AEs
    1
    14
        SAEs
    0
    4
        Study drug-related SAEs
    0
    3
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in total brain volume

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    End point title
    		 Percentage change from baseline in total brain volume
    End point description
    Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33, Week 53, Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    4
    17
    Units: % change in total brain volume
    arithmetic mean (standard deviation)
        Week 17 (n=4, 17)
    -0.20 ( 0.332 )
    -0.43 ( 2.362 )
        Week 33 (n=3, 17)
    -0.67 ( 0.352 )
    -0.88 ( 0.681 )
        Week 53 (n=1, 12)
    -0.25 ( 999 )
    -1.34 ( 0.848 )
        Week 69 (n=0, 12)
    999 ( 999 )
    -1.63 ( 0.877 )
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in total brain volume excluding patients with subdural hematoma

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    End point title
    		 Percentage change from baseline in total brain volume excluding patients with subdural hematoma
    End point description
    Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33, Week 53, Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    4
    15
    Units: % change in total brain volume
    arithmetic mean (standard deviation)
        Week 17 (n=4, 15)
    -0.20 ( 0.332 )
    -1.09 ( 0.599 )
        Week 33 (n=3, 15)
    -0.67 ( 0.352 )
    -0.80 ( 0.675 )
        Week 53 (n=1, 10)
    -0.25 ( 999 )
    -1.30 ( 0.748 )
        Week 69 (n=0, 10)
    999 ( 999 )
    -1.68 ( 0.751 )
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in lateral ventricles volume

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    End point title
    		 Percentage change from baseline in lateral ventricles volume
    End point description
    Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33, Week 53, Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    3
    17
    Units: % change in lateral ventricles volume
    arithmetic mean (standard deviation)
        Week 17 (n=3, 17)
    1.63 ( 1.392 )
    8.84 ( 11.599 )
        Week 33 (n=3, 17)
    5.51 ( 1.772 )
    11.73 ( 9.799 )
        Week 53 (n=1, 12)
    3.43 ( 999 )
    15.77 ( 10.842 )
        Week 69 (n=0, 12)
    999 ( 999 )
    17.40 ( 10.182 )
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in lateral ventricles volume excluding patients with subdural hematoma

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    End point title
    		 Percentage change from baseline in lateral ventricles volume excluding patients with subdural hematoma
    End point description
    Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33, Week 53, Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    3
    15
    Units: % change in lateral ventricles volume
    arithmetic mean (standard deviation)
        Week 17 (n=3, 15)
    1.63 ( 1.392 )
    9.47 ( 6.061 )
        Week 33 (n=3, 15)
    5.51 ( 1.772 )
    9.43 ( 5.673 )
        Week 53 (n=1, 10)
    3.43 ( 999 )
    12.38 ( 6.193 )
        Week 69 (n=0, 10)
    999 ( 999 )
    14.45 ( 6.040 )
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in left caudate volume

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    End point title
    		 Percentage change from baseline in left caudate volume
    End point description
    Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33, Week 53, Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    4
    17
    Units: % change in left caudate volume
    arithmetic mean (standard deviation)
        Week 17 (n=4, 16)
    -0.93 ( 3.782 )
    -4.44 ( 3.005 )
        Week 33 (n=3, 17)
    -3.95 ( 2.147 )
    -4.30 ( 3.331 )
        Week 53 (n=1, 11)
    -2.69 ( 999 )
    -6.33 ( 4.417 )
        Week 69 (n=0, 12)
    999 ( 999 )
    -5.44 ( 7.864 )
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in left caudate volume excluding patients with subdural hematoma

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    End point title
    		 Percentage change from baseline in left caudate volume excluding patients with subdural hematoma
    End point description
    Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33, Week 53, Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    4
    15
    Units: % change in left caudate volume
    arithmetic mean (standard deviation)
        Week 17 (n=4, 14)
    -0.93 ( 3.782 )
    -4.14 ( 2.300 )
        Week 33 (n=3, 15)
    -3.95 ( 2.147 )
    -3.58 ( 2.692 )
        Week 53 (n=1, 9)
    -2.69 ( 999 )
    -6.24 ( 4.788 )
        Week 69 (n=0, 10)
    999 ( 999 )
    -4.81 ( 8.351 )
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in right caudate volume

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    End point title
    		 Percentage change from baseline in right caudate volume
    End point description
    Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33, Week 53, Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    3
    17
    Units: % change in right caudate volume
    arithmetic mean (standard deviation)
        Week 17 (n=3, 17)
    -3.28 ( 3.496 )
    -2.79 ( 4.604 )
        Week 33 (n=3, 17)
    -6.91 ( 1.895 )
    -4.11 ( 4.146 )
        Week 53 (n=1, 11)
    -5.34 ( 999 )
    -6.81 ( 4.251 )
        Week 69 (n=0, 12)
    999 ( 999 )
    -6.34 ( 6.934 )
    No statistical analyses for this end point

    Secondary: Percentage change from baseline in right caudate volume excluding patients with subdural hematoma

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    End point title
    		 Percentage change from baseline in right caudate volume excluding patients with subdural hematoma
    End point description
    Three-dimensional magnetic resonance imaging (MRI) data was acquired and used to measure brain volume at each time point and changes in brain volume longitudinally. Brain MRI scans were performed at each time point without gadolinium contrast. Changes in volumetric MRI were measured in regions of interests: ventricular, caudate (left and right) and total brain volume. The baseline MRI scan was obtained within 6 days prior to the first dose of study treatment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33, Week 53, Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    3
    15
    Units: % change in right caudate volume
    arithmetic mean (standard deviation)
        Week 17 (n=3, 15)
    -3.28 ( 3.496 )
    -2.67 ( 4.850 )
        Week 33 (n=3, 15)
    -6.91 ( 1.895 )
    -3.23 ( 3.437 )
        Week 53 (n=1, 9)
    -5.34 ( 999 )
    -6.57 ( 4.418 )
        Week 69 (n=0, 10)
    999 ( 999 )
    -5.60 ( 7.249 )
    No statistical analyses for this end point

    Secondary: Change from baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)

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    End point title
    		 Change from baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Functional Capacity (TFC)
    End point description
    The TFC focuses on the investigator's assessment of the participant's capacity to perform a range of activities of daily living. The responses are derived from interview with the participant and/or companion, if applicable. TFC score range from 0 to 13, with higher scores representing better functioning. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33 and Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    5
    19
    Units: score on scale
    arithmetic mean (standard deviation)
        Week 17 (n=5, 19)
    -1.0 ( 2.35 )
    -0.8 ( 2.39 )
        Week 33 (n=4, 17)
    -0.5 ( 2.52 )
    -1.3 ( 2.31 )
        Week 69 (n=0, 13)
    999 ( 999 )
    -1.2 ( 2.94 )
    No statistical analyses for this end point

    Secondary: Change from baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)

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    End point title
    		 Change from baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Total Motor Scale (TMS)
    End point description
    The TMS is the cumulative sum of the individual motor ratings obtained during the administration of the motor assessment portion of the UHDRS. TMS score range from 0 to 124 with higher scores representing more significant impairment. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33 and Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    5
    19
    Units: score on scale
    arithmetic mean (standard deviation)
        Week 17 (n=5, 19)
    6.0 ( 11.29 )
    5.1 ( 9.14 )
        Week 33 (n=4, 17)
    2.5 ( 10.34 )
    2.6 ( 8.83 )
        Week 69 (n=0, 13)
    999 ( 999 )
    3.6 ( 8.99 )
    No statistical analyses for this end point

    Secondary: Change from baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)

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    End point title
    		 Change from baseline in the Unified Huntington's Disease Rating Scales (UHDRS) Independence Scale (IS)
    End point description
    The IS represents the investigator's assessment of the participant's level of independence, including topics of employment, finances, self-care and feeding. The scale has 19 discrete scores, from 10 (tube fed, total bed care) to 100 (no special care needed) with 5-point increments in between. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17, Week 33 and Week 69
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    5
    19
    Units: score on scale
    arithmetic mean (standard deviation)
        Week 17 (n=5, 19)
    -1.0 ( 11.40 )
    -1.8 ( 9.16 )
        Week 33 (n=4, 17)
    1.3 ( 16.52 )
    -4.7 ( 8.19 )
        Week 69 (n=0, 13)
    999 ( 999 )
    -6.5 ( 13.29 )
    No statistical analyses for this end point

    Secondary: Concentrations of mHTT protein and total HTT in CSF

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    End point title
    		 Concentrations of mHTT protein and total HTT in CSF
    End point description
    Mutant Huntingtin (mHTT) protein and total HTT measured in cerebrospinal fluid (CSF) obtained via lumbar puncture. Baseline value is the last evaluable measurement prior to the first administration of study drug. Assay issues did not allow a reliable quantification of total HTT in CSF. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not available’). Therefore, not available values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 9, Week 17
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    5
    21
    Units: fmol
    arithmetic mean (standard deviation)
        mHTT - Baseline (n=5, 21)
    86.14 ( 35.590 )
    102.03 ( 48.533 )
        mHTT – Week 9 (n=5, 17)
    86.31 ( 43.265 )
    74.68 ( 37.111 )
        mHTT – Week 17 (n=4, 9)
    77.68 ( 33.077 )
    65.58 ( 41.152 )
        Total HTT – Baseline (n=0, 0)
    999 ( 999 )
    999 ( 999 )
        Total HTT – Week 9 (n=0, 0)
    999 ( 999 )
    999 ( 999 )
        Total HTT – Week 17 (n=0, 0)
    999 ( 999 )
    999 ( 999 )
    No statistical analyses for this end point

    Secondary: Concentrations of mHTT protein and total HTT in plasma

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    End point title
    		 Concentrations of mHTT protein and total HTT in plasma
    End point description
    Mutant Huntingtin (mHTT) protein and total HTT measured in plasma. Baseline value is the last evaluable measurement prior to the first administration of study drug.
    End point type
    Secondary
    End point timeframe
    Baseline, Week 17
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    0 [3]
    0 [4]
    Units: fmol
    arithmetic mean (standard deviation)
        mHTT - Baseline
    ( )
    ( )
        mHTT - Week 17
    ( )
    ( )
        Total HTT – Baseline
    ( )
    ( )
        Total HTT – Week 17
    ( )
    ( )
    Notes
    [3] - Assay issues did not allow a reliable quantification of mHTT protein and total HTT in plasma.
    [4] - Assay issues did not allow a reliable quantification of mHTT protein and total HTT in plasma.
    No statistical analyses for this end point

    Secondary: Maximum observed plasma concentration (Cmax) of branaplam and its metabolite UFB112

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    End point title
    		 Maximum observed plasma concentration (Cmax) of branaplam and its metabolite UFB112 [5]
    End point description
    Pharmacokinetic (PK) parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. Cmax is defined as the maximum (peak) observed concentration following a dose.
    End point type
    Secondary
    End point timeframe
    pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17
    Notes
    [5] - 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 is applicable to branaplam arm only.
    End point values
    		 Branaplam 56 mg
    Number of subjects analysed
    21
    Units: ng/mL
    arithmetic mean (standard deviation)
        Branaplam - Week 1 (n=21)
    26.1 ( 7.99 )
        Branaplam - Week 17 (n=4)
    45.3 ( 7.96 )
        UFB112 - Week 1 (n=21)
    31.9 ( 12.6 )
        UFB112 - Week 17 (n=4)
    53.3 ( 20.4 )
    No statistical analyses for this end point

    Secondary: Time to reach maximum plasma concentration (Tmax) of branaplam and its metabolite UFB112

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    End point title
    		 Time to reach maximum plasma concentration (Tmax) of branaplam and its metabolite UFB112 [6]
    End point description
    PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. Tmax is defined as the time to reach maximum (peak) concentration following a dose. Actual recorded sampling times were considered for the calculations.
    End point type
    Secondary
    End point timeframe
    pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17
    Notes
    [6] - 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 is applicable to branaplam arm only.
    End point values
    		 Branaplam 56 mg
    Number of subjects analysed
    21
    Units: hours
    median (full range (min-max))
        Branaplam - Week 1 (n=21)
    7.00 (3.77 to 23.0)
        Branaplam - Week 17 (n=4)
    4.18 (4.00 to 7.00)
        UFB112 - Week 1 (n=21)
    7.00 (4.00 to 72.00)
        UFB112 - Week 17 (n=4)
    14.5 (4.28 to 22.00)
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve from time zero to 168 hours (AUC0-168h) of branaplam and its metabolite UFB112

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    End point title
    		 Area under the plasma concentration-time curve from time zero to 168 hours (AUC0-168h) of branaplam and its metabolite UFB112 [7]
    End point description
    PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. The linear trapezoidal method was used for AUC0-168h calculation.
    End point type
    Secondary
    End point timeframe
    pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1 and Week 17
    Notes
    [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 is applicable to branaplam arm only.
    End point values
    		 Branaplam 56 mg
    Number of subjects analysed
    21
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Branaplam - Week 1 (n=20)
    1880 ( 368 )
        Branaplam - Week 17 (n=4)
    3190 ( 455 )
        UFB112 - Week 1 (n=21)
    3670 ( 1560 )
        UFB112 - Week 17 (n=4)
    5640 ( 2750 )
    No statistical analyses for this end point

    Secondary: Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of branaplam and its metabolite UFB112

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    End point title
    		 Area under the plasma concentration-time curve from time zero to infinity (AUCinf) of branaplam and its metabolite UFB112 [8]
    End point description
    PK parameters were calculated based on branaplam and its metabolite UFB112 plasma concentrations by using non-compartmental methods. The linear trapezoidal method and the regression analysis of the terminal elimination phase were used for AUCinf calculation. Due to EudraCT system limitations, data fields in the table cannot contain letters (eg. NA indicating ‘not applicable’). Therefore, not applicable values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    pre-dose and 4, 7, 12, 22, 72 and 168 hours after branaplam dose at Week 1
    Notes
    [8] - 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 is applicable to branaplam arm only.
    End point values
    		 Branaplam 56 mg
    Number of subjects analysed
    21
    Units: hr*ng/mL
    arithmetic mean (standard deviation)
        Branaplam - Week 1 (n=13)
    2270 ( 467 )
        UFB112 - Week 1 (n=1)
    3530 ( 999 )
    No statistical analyses for this end point

    Secondary: Trough concentration (Ctrough) of branaplam and its metabolite UFB112 in plasma

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    End point title
    		 Trough concentration (Ctrough) of branaplam and its metabolite UFB112 in plasma [9]
    End point description
    Branaplam and its metabolite UFB112 concentrations were determined in plasma. Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
    End point type
    Secondary
    End point timeframe
    pre-dose at Weeks 2, 3, 5, 9, 13 and 17
    Notes
    [9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to branaplam arm only.
    End point values
    		 Branaplam 56 mg
    Number of subjects analysed
    20
    Units: ng/mL
    arithmetic mean (standard deviation)
        Branaplam - Week 2 (n=20)
    4.10 ( 1.29 )
        Branaplam - Week 3 (n=20)
    6.54 ( 1.78 )
        Branaplam - Week 5 (n=20)
    8.50 ( 3.20 )
        Branaplam - Week 9 (n=15)
    7.85 ( 2.12 )
        Branaplam - Week 13 (n=9)
    8.54 ( 2.27 )
        Branaplam - Week 17 (n=6)
    7.88 ( 2.11 )
        UFB112 - Week 2 (n=20)
    12.1 ( 6.22 )
        UFB112 - Week 3 (n=20)
    18.0 ( 8.25 )
        UFB112 - Week 5 (n=20)
    21.9 ( 11.5 )
        UFB112 - Week 9 (n=15)
    21.2 ( 11.5 )
        UFB112 - Week 13 (n=9)
    18.5 ( 8.71 )
        UFB112 - Week 17 (n=6)
    16.1 ( 5.33 )
    No statistical analyses for this end point

    Secondary: Trough concentration (Ctrough) of branaplam and its metabolite UFB112 in CSF

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    End point title
    		 Trough concentration (Ctrough) of branaplam and its metabolite UFB112 in CSF [10]
    End point description
    Branaplam and its metabolite UFB112 concentrations were determined in cerebrospinal fluid (CSF) obtained via lumbar puncture. Ctrough is defined as the concentration reached immediately before the next dose is administered. All drug concentrations below the lower limit of quantification were treated as zero for the calculation of PK parameters.
    End point type
    Secondary
    End point timeframe
    pre-dose at Weeks 9 and 17
    Notes
    [10] - 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 is applicable to branaplam arm only.
    End point values
    		 Branaplam 56 mg
    Number of subjects analysed
    12
    Units: ng/mL
    arithmetic mean (standard deviation)
        Branaplam - Week 9 (n=12)
    0.870 ( 0.311 )
        Branaplam - Week 17 (n=5)
    0.602 ( 0.355 )
        UFB112 - Week 9 (n=12)
    0.269 ( 0.184 )
        UFB112 - Week 17 (n=5)
    0.230 ( 0.154 )
    No statistical analyses for this end point

    Secondary: Concentration ratio CSF/plasma of branaplam and its metabolite UFB112

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    End point title
    		 Concentration ratio CSF/plasma of branaplam and its metabolite UFB112 [11]
    End point description
    Branaplam and its metabolite UFB112 concentrations were determined plasma and in cerebrospinal fluid (CSF) obtained via lumbar puncture. Concentration ratios CSF/plasma were calculated for subjects for whom CSF and plasma concentrations were available at the respective time point. Standard deviation was not planned to be calculated for the concentration ratio CSF/plasma. Since data fields in the table cannot contain letters (eg. NA indicating ‘not available’) due to EudraCT system limitations, NA values are indicated as ‘999’.
    End point type
    Secondary
    End point timeframe
    pre-dose at Weeks 9 and 17
    Notes
    [11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: This endpoint is applicable to branaplam arm only.
    End point values
    		 Branaplam 56 mg
    Number of subjects analysed
    11
    Units: concentration ratio
    arithmetic mean (standard deviation)
        Branaplam - Week 9
    0.115 ( 999 )
        Branaplam - Week 17
    0.0864 ( 999 )
        UFB112 - Week 9
    0.0141 ( 999 )
        UFB112 - Week 17
    0.0161 ( 999 )
    No statistical analyses for this end point

    Other pre-specified: Number of participants with NfL increase and recovery

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    End point title
    		 Number of participants with NfL increase and recovery
    End point description
    Neurofilament light chain (NfL) is a neuronal cytoplasmic protein highly expressed in large calibre myelinated axons. Its levels increase in cerebrospinal fluid (CSF) and serum in case of axonal damage in a variety of neurological disorders. The levels of NfL were determined in serum and CSF and the following 3 categories were defined: • Serum NfL (sNfL) increase: > 100 pg/mL or > 2 x baseline (BL) sNfL • sNfL recovery: Worsening criteria are no longer met (sNfL <= 100 pg/mL or sNfL <= 2 x BL sNfL) for visits after last visit with increase • CSF NfL increase: > 10000 pg/mL or > 2 x BL CSF NfL or > 2 x CSF NfL of the previous assessment
    End point type
    Other pre-specified
    End point timeframe
    From baseline (before first dose of study treatment) up to Week 17 (CSF) and Week 69 (serum)
    End point values
    		 Placebo Branaplam 56 mg
    Number of subjects analysed
    5
    21
    Units: participants
        sNfL increase (n=5, 21)
    0
    16
        sNfL recovery(n=0, 16)
    0
    14
        CSF NfL increase (n=5, 21)
    0
    13
    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 Week 69
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Treatment Arm A: matching placebo oral solution once weekly

    Reporting group title
    Overall
    Reporting group description
    		 All participants

    Reporting group title
    Branaplam 56 mg
    Reporting group description
    		 Treatment Arm A: branaplam 56 mg oral solution once weekly

    Serious adverse events
    		 Placebo Overall Branaplam 56 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
    4 / 26 (15.38%)
    4 / 21 (19.05%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Injury, poisoning and procedural complications
    Subdural haematoma
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 26 (7.69%)
    2 / 21 (9.52%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 26 (3.85%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Vestibular neuronitis
         subjects affected / exposed
    0 / 5 (0.00%)
    1 / 26 (3.85%)
    1 / 21 (4.76%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Overall Branaplam 56 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    17 / 26 (65.38%)
    15 / 21 (71.43%)
    Injury, poisoning and procedural complications
    Head injury
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 26 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 26 (11.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    2
    Balance disorder
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 26 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Polyneuropathy
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 26 (11.54%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    3
    Paraesthesia
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 26 (11.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    4
    3
    Neuropathy peripheral
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 26 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 5 (20.00%)
    5 / 26 (19.23%)
    4 / 21 (19.05%)
         occurrences all number
    1
    7
    6
    Thrombocytosis
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 26 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    General disorders and administration site conditions
    Puncture site pain
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 26 (11.54%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    3
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 26 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    3
    Reproductive system and breast disorders
    Benign prostatic hyperplasia
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 26 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 26 (3.85%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Psychiatric disorders
    Delusional disorder, persecutory type
         subjects affected / exposed
    1 / 5 (20.00%)
    1 / 26 (3.85%)
    0 / 21 (0.00%)
         occurrences all number
    1
    1
    0
    Musculoskeletal and connective tissue disorders
    Muscular weakness
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 26 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    0
    2
    2
    Back pain
         subjects affected / exposed
    0 / 5 (0.00%)
    2 / 26 (7.69%)
    2 / 21 (9.52%)
         occurrences all number
    0
    3
    3
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 5 (20.00%)
    3 / 26 (11.54%)
    2 / 21 (9.52%)
         occurrences all number
    1
    3
    2
    Cystitis
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 26 (11.54%)
    3 / 21 (14.29%)
         occurrences all number
    0
    4
    4
    Urinary tract infection
         subjects affected / exposed
    0 / 5 (0.00%)
    3 / 26 (11.54%)
    3 / 21 (14.29%)
         occurrences all number
    0
    3
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 May 2022
    • Revisions to the exploratory objectives; • Clarification of language in several protocol sections
    30 Jan 2023
    This amendment documented the changes regarding follow-up of participants after the Urgent Safety Measure (USM) Investigator Notifications (IN) distributed on 05-Aug-2022 and 06-Dec-2022, addressing temporary and then permanent study treatment discontinuation, respectively.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    05 Aug 2022
    The Urgent Safety Measure (USM) Investigator Notification (IN) (05-Aug-2022) was issued by Novartis to immediately and temporarily suspend study treatment for all participants in the study. With the USM Follow-up IN (06-Dec-2022), study drug was permanently discontinued in the VIBRANT-HD study and no further cohorts were initiated. Participants randomized to placebo did not require additional safety assessments and could be discontinued from the study at their upcoming Week 33 visit or immediately if this visit had already been completed. Participants randomized to branaplam were requested to continue assessments for approximately one year from last dose.
    -

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

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