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    Clinical Trial Results:
    A Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of NBI-827104 in Subjects with Essential Tremor

    Summary
    EudraCT number
    		 2020-006012-24
    Trial protocol
    		 NL  
    Global end of trial date
    13 Jun 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Jun 2023
    First version publication date
    24 Jun 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NBI-827104-ET2016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04880616
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Toetsingonline number: NL76780.056.21, Sponsor internal number: NBI-827104-ET2016
    Sponsors
    Sponsor organisation name
    Neurocrine Biosciences
    Sponsor organisation address
    12780 El Camino Real, San Diego, United States, 92130
    Public contact
    Neurocrine Medical Information, Neurocrine Biosciences, +1 877-641-3461, medinfo@neurocrine.com
    Scientific contact
    Neurocrine Medical Information, Neurocrine Biosciences, +1 877-641-3461, medinfo@neurocrine.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
    13 Jun 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    13 Jun 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Jun 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of the trial were to evaluate the efficacy, safety, and tolerability of NBI-827104 in participants with essential tremor (ET).
    Protection of trial subjects
    The study was conducted in full compliance with International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Good Clinical Practice (GCP) guidelines and with the laws and regulations of the country in which the study was conducted.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    20 Apr 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 31
    Worldwide total number of subjects
    31
    EEA total number of subjects
    31
    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)
    16
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Participants were randomized (1:1) to 1 of 2 treatment sequences - Treatment Sequence 1: NBI-827104-Placebo or Treatment Sequence 2: Placebo-NBI-827104.

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Treatment Sequence 1: NBI-827104-Placebo
    Arm description
    		 Participants received NBI-827104 for 28 days in treatment period 1 and placebo for 28 days in treatment period 2. There was a 14-day washout period between treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NBI-827104
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    NBI-827104 was administered per schedule specified in the arm description.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to NBI-827104 was administered per schedule specified in the arm description.

    Arm title
    		 Treatment Sequence 2: Placebo-NBI-827104
    Arm description
    		 Participants received placebo for 28 days in treatment period 1 and NBI-827104 for 28 days in treatment period 2. There was a 14-day washout period between treatments.
    Arm type
    		 Experimental

    Investigational medicinal product name
    NBI-827104
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    NBI-827104 was administered per schedule specified in the arm description.

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo matched to NBI-827104 was administered per schedule specified in the arm description.

    Number of subjects in period 1
    		Treatment Sequence 1: NBI-827104-Placebo Treatment Sequence 2: Placebo-NBI-827104
    Started
    16
    15
    Received at least 1 dose of study drug
    16
    15
    Completed
    14
    14
    Not completed
    2
    1
         Adverse event
    1
    1
         Withdrawal by Subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment Sequence 1: NBI-827104-Placebo
    Reporting group description
    		 Participants received NBI-827104 for 28 days in treatment period 1 and placebo for 28 days in treatment period 2. There was a 14-day washout period between treatments.

    Reporting group title
    Treatment Sequence 2: Placebo-NBI-827104
    Reporting group description
    		 Participants received placebo for 28 days in treatment period 1 and NBI-827104 for 28 days in treatment period 2. There was a 14-day washout period between treatments.

    Reporting group values
    		 Treatment Sequence 1: NBI-827104-Placebo Treatment Sequence 2: Placebo-NBI-827104 Total
    Number of subjects
    		 16 15 31
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 8 8 16
        From 65-84 years
    		 8 7 15
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 56.4 ( 18.2 ) 60.0 ( 11.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 2 6 8
        Male
    		 14 9 23

    End points

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    End points reporting groups
    Reporting group title
    Treatment Sequence 1: NBI-827104-Placebo
    Reporting group description
    		 Participants received NBI-827104 for 28 days in treatment period 1 and placebo for 28 days in treatment period 2. There was a 14-day washout period between treatments.

    Reporting group title
    Treatment Sequence 2: Placebo-NBI-827104
    Reporting group description
    		 Participants received placebo for 28 days in treatment period 1 and NBI-827104 for 28 days in treatment period 2. There was a 14-day washout period between treatments.

    Subject analysis set title
    Placebo
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received placebo for 28 days in either treatment period 1 or 2.

    Subject analysis set title
    NBI-827104
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Participants received NBI-827104 for 28 days in either treatment period 1 or 2.

    Primary: Change from Baseline to Day 28 of Each Treatment Period in Amplitude at Peak Frequency of Postural Tremor in the More Severely Affected Hand (Log Base 10 Scale), Measured Using Laboratory Tremography

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    End point title
    		 Change from Baseline to Day 28 of Each Treatment Period in Amplitude at Peak Frequency of Postural Tremor in the More Severely Affected Hand (Log Base 10 Scale), Measured Using Laboratory Tremography
    End point description
    Tremor amplitude at peak frequency of postural tremor (extended hand position) in the more severely affected hand was measured using laboratory tremography. Tremography was performed using an accelerometer attached to the participant’s hand. Least square (LS) mean and standard error (SE) was calculated using the mixed-effects model for repeated measures. Full analysis set included all randomized participants who had at least 1 dose of study treatment and at least 1 postbaseline assessment for the primary efficacy variable. Overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    Baseline, Day 28 of each treatment period
    End point values
    		 Placebo NBI-827104
    Number of subjects analysed
    30
    30
    Units: milligrams square (mg^2)/hertz (Hz)
        least squares mean (standard error)
    -0.29 ( 0.12 )
    -0.32 ( 0.12 )
    Statistical analysis title
    		 Statistical Analysis 1
    Statistical analysis description
    Actual number of participants analyzed = 30
    Comparison groups
    Placebo v NBI-827104
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.7805
    Method
    		 Mixed models analysis
    Confidence interval

    Secondary: Change from Baseline in Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale (PS) Total Score (Independent Blinded Video Rating) at Day 28 of Each Treatment Period

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    End point title
    		 Change from Baseline in Essential Tremor Rating Assessment Scale (TETRAS) Performance Subscale (PS) Total Score (Independent Blinded Video Rating) at Day 28 of Each Treatment Period
    End point description
    TETRAS -PS was used to assess essential tremor as scored by the independent video raters. TETRAS-PS quantified tremor in the head, face, voice, limbs, and trunk. The overall subscale total score ranges from a minimum of 0 to a maximum of 64. A lower score indicated improvement and a better outcome. LS mean and SE calculated using mixed-effects model for repeated measures. Full analysis set: all randomized participants who had at least 1 dose of study treatment and at least 1 postbaseline assessment for primary efficacy variable. Overall number of participants analyzed=participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28 of each treatment period
    End point values
    		 Placebo NBI-827104
    Number of subjects analysed
    28
    29
    Units: units on a scale
        least squares mean (standard error)
    -0.87 ( 0.77 )
    -1.94 ( 0.75 )
    No statistical analyses for this end point

    Secondary: Change from Baseline in TETRAS Activities of Daily Living (ADL) Total Score at Day 28 of Each Treatment Period

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    End point title
    		 Change from Baseline in TETRAS Activities of Daily Living (ADL) Total Score at Day 28 of Each Treatment Period
    End point description
    TETRAS ADL subscale has 12 items that assess speech, occupational impairment, social impact, and activities affected primarily by upper limb tremor. Each item was rated on a scale of 0 (no impact of tremor) to 4 (severe impact). The sum of the individual scores provided an overall total score, which ranges from a minimum of 0 to a maximum of 48. A lower score indicated improvement and a better outcome. LS mean and SE was calculated using the mixed-effects model for repeated measures. Full analysis set included all randomized participants who had at least 1 dose of study treatment and at least 1 postbaseline assessment for primary efficacy variable. Overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline, Day 28 of each treatment period
    End point values
    		 Placebo NBI-827104
    Number of subjects analysed
    27
    30
    Units: units on a scale
        least squares mean (standard error)
    -1.10 ( 0.87 )
    -2.97 ( 0.82 )
    No statistical analyses for this end point

    Secondary: Clinical Global Impression of Change (CGI-C) Score

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    End point title
    		 Clinical Global Impression of Change (CGI-C) Score
    End point description
    The CGI-C is a 7-point scale that rated the overall global improvement since the initiation of study drug dosing, ranging from 1 (very much improved) to 7 (very much worse), as assessed by the clinician. Lower scores indicated better quality of life. LS mean and SE was calculated using the mixed-effects model for repeated measures. Full analysis set included all randomized participants who had at least 1 dose of study treatment and at least 1 postbaseline assessment for primary efficacy variable. Overall number of participants analyzed = participants evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Day 28 of each treatment period
    End point values
    		 Placebo NBI-827104
    Number of subjects analysed
    28
    29
    Units: units on a scale
        least squares mean (standard error)
    3.61 ( 0.16 )
    3.43 ( 0.16 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Day 1 (after dosing) up to Day 84
    Adverse event reporting additional description
    Safety analysis set included all randomized participants who had at least 1 dose of study treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    24.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Participants received placebo for 28 days in either treatment period 1 or 2.

    Reporting group title
    NBI-827104
    Reporting group description
    		 Participants received NBI-827104 for 28 days in either treatment period 1 or 2.

    Serious adverse events
    		 Placebo NBI-827104
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo NBI-827104
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 30 (70.00%)
    24 / 30 (80.00%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    14
    Vascular disorders
    Haematoma
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    19
    Orthostatic hypotension
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    13
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    5
    16
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    11
    45
    Dizziness
         subjects affected / exposed
    4 / 30 (13.33%)
    11 / 30 (36.67%)
         occurrences all number
    37
    154
    Dizziness postural
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    5
    Essential tremor
         subjects affected / exposed
    3 / 30 (10.00%)
    6 / 30 (20.00%)
         occurrences all number
    26
    40
    Headache
         subjects affected / exposed
    13 / 30 (43.33%)
    9 / 30 (30.00%)
         occurrences all number
    76
    40
    Paraesthesia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    46
    Presyncope
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    47
    26
    Somnolence
         subjects affected / exposed
    1 / 30 (3.33%)
    6 / 30 (20.00%)
         occurrences all number
    1
    69
    General disorders and administration site conditions
    Asthenia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    12
    Fatigue
         subjects affected / exposed
    5 / 30 (16.67%)
    5 / 30 (16.67%)
         occurrences all number
    39
    87
    Injection site haematoma
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    5
    9
    Eye disorders
    Dry eye
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    30
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    2 / 30 (6.67%)
    1 / 30 (3.33%)
         occurrences all number
    8
    5
    Dry mouth
         subjects affected / exposed
    1 / 30 (3.33%)
    4 / 30 (13.33%)
         occurrences all number
    6
    23
    Nausea
         subjects affected / exposed
    4 / 30 (13.33%)
    1 / 30 (3.33%)
         occurrences all number
    22
    10
    Psychiatric disorders
    Euphoric mood
         subjects affected / exposed
    1 / 30 (3.33%)
    2 / 30 (6.67%)
         occurrences all number
    2
    27
    Insomnia
         subjects affected / exposed
    3 / 30 (10.00%)
    1 / 30 (3.33%)
         occurrences all number
    25
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    2 / 30 (6.67%)
    0 / 30 (0.00%)
         occurrences all number
    28
    0
    Myalgia
         subjects affected / exposed
    0 / 30 (0.00%)
    2 / 30 (6.67%)
         occurrences all number
    0
    13
    Infections and infestations
    COVID-19
         subjects affected / exposed
    2 / 30 (6.67%)
    4 / 30 (13.33%)
         occurrences all number
    13
    24
    Nasopharyngitis
         subjects affected / exposed
    2 / 30 (6.67%)
    3 / 30 (10.00%)
         occurrences all number
    8
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    23 Mar 2021
    • Changed the observation period post in-clinic dosing. • Added an extra overnight stay to collect a pharmacokinetic (PK) sample. • Updated instructions for digital spiral analysis per the study center’s standard operating procedure. • Added duplicate baseline measurements for resting-state electroencephalogram and digital spiral analysis. • Added duplicate tremography measurements at baseline and each postbaseline timepoint.
    13 Aug 2021
    • Clarified that stable use of medication that might produce tremor or interfere with the evaluation of tremor could be continued if the Principal Investigator agreed that stable use of the medication was not the cause of the tremor or influenced the tremor intensity. • Removed restrictions regarding the timing of in-clinic meals other than breakfast. • Removed restriction around timing of the ophthalmic exam during the screening period.

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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