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    Clinical Trial Results:
    A Phase 1, Open Label, Multiple Ascending Dose Study to Assess the Pharmacokinetics, Safety, and Tolerability of Pimavanserin in Adolescents with Psychiatric Disorders

    Summary
    EudraCT number
    		 2018-001064-30
    Trial protocol
    		 BG  
    Global end of trial date
    26 Sep 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Aug 2022
    First version publication date
    21 Aug 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACP-103-050
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Acadia Pharmaceuticals Inc.
    Sponsor organisation address
    12830 El Camino Real, Suite 400, San DIego, United States, 92130
    Public contact
    Sr. Dir. Medical Information and Medical Communications, Acadia Pharmaceuticals Inc., 1 8582612897, medicalinformation@acadia-pharm.com
    Scientific contact
    Sr. Dir. Medical Information and Medical Communications, Acadia Pharmaceuticals Inc., 1 8582612897, medicalinformation@acadia-pharm.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-001688-PIP03-16
    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?
    Yes
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 May 2020
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Sep 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Sep 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the pharmacokinetics (PK) and safety and tolerability following multiple doses of pimavanserin (10, 20, or 34 mg) in adolescents with psychiatric disorders
    Protection of trial subjects
    Not applicable
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    17 Jul 2018
    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
    Bulgaria: 10
    Country: Number of subjects enrolled
    Russian Federation: 2
    Country: Number of subjects enrolled
    United States: 22
    Worldwide total number of subjects
    34
    EEA total number of subjects
    10
    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)
    34
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was conducted as a multicenter, open-label, multiple ascending dose (10, 20, or 34 mg) study in adolescents with psychiatric disorders. Subjects who prematurely discontinued from the study for any reason could have been replaced to ensure the minimum subject requirements were met for each age subset.

    Pre-assignment
    Screening details
    		 During the Screening period, subjects were assessed for study eligibility. The Screening period was 1 to 28 days in duration.

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Pimavanserin 10 mg
    Arm description
    		 Pimavanserin, 10 mg (1×10 mg tablets), once daily as a single oral dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pimavanserin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pimavanserin, tablet, once daily as a single oral dose

    Arm title
    		 Pimavanserin 20 mg
    Arm description
    		 Pimavanserin, 20 mg (2×10 mg tablets), once daily as a single oral dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pimavanserin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pimavanserin, tablet, once daily as a single oral dose

    Arm title
    		 Pimavanserin 34 mg
    Arm description
    		 Pimavanserin, 34 mg (2×17 mg tablets), once daily as a single oral dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pimavanserin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Pimavanserin, tablet, once daily as a single oral dose

    Number of subjects in period 1
    		Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg
    Started
    12
    10
    12
    Completed
    10
    10
    11
    Not completed
    2
    0
    1
         Physician decision
    1
    -
    -
         Consent withdrawn by subject or parent/guardian
    1
    -
    -
         Protocol deviation
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Pimavanserin 10 mg
    Reporting group description
    		 Pimavanserin, 10 mg (1×10 mg tablets), once daily as a single oral dose

    Reporting group title
    Pimavanserin 20 mg
    Reporting group description
    		 Pimavanserin, 20 mg (2×10 mg tablets), once daily as a single oral dose

    Reporting group title
    Pimavanserin 34 mg
    Reporting group description
    		 Pimavanserin, 34 mg (2×17 mg tablets), once daily as a single oral dose

    Reporting group values
    		 Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg Total
    Number of subjects
    		 12 10 12 34
    Age categorical
    Safety Analysis Set
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 12 10 12 34
        Adults (18-64 years)
    		 0 0 0 0
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 4 5 5 14
        Male
    		 8 5 7 20
    Age, Study-Specific Categories
    Units: Subjects
        13 to <15 years
    		 6 4 4 14
        15 to <18 years
    		 6 6 8 20

    End points

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    End points reporting groups
    Reporting group title
    Pimavanserin 10 mg
    Reporting group description
    		 Pimavanserin, 10 mg (1×10 mg tablets), once daily as a single oral dose

    Reporting group title
    Pimavanserin 20 mg
    Reporting group description
    		 Pimavanserin, 20 mg (2×10 mg tablets), once daily as a single oral dose

    Reporting group title
    Pimavanserin 34 mg
    Reporting group description
    		 Pimavanserin, 34 mg (2×17 mg tablets), once daily as a single oral dose

    Primary: Maximum plasma concentration at steady state (Cmax,ss)

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    End point title
    		 Maximum plasma concentration at steady state (Cmax,ss) [1]
    End point description
    Maximum observed plasma concentration of pimavanserin at steady state
    End point type
    Primary
    End point timeframe
    Steady state profile blood samples were collected on Day 20 predose (within 30 min prior to dosing) and 1, 2, 4, 6, 9, 12, 16, and 24 h after last dose of pimavanserin administration.
    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 inferential statistical analyses were planned or performed for this Phase I, multiple-ascending dose study.
    End point values
    		 Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg
    Number of subjects analysed
    10
    10
    7
    Units: ng/mL
    arithmetic mean (standard deviation)
        Overall
    17.8 ( 4.14 )
    43.2 ( 15.0 )
    80.5 ( 24.2 )
    No statistical analyses for this end point

    Primary: Time to maximum plasma concentration at steady state (Tmax,ss)

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    End point title
    		 Time to maximum plasma concentration at steady state (Tmax,ss) [2]
    End point description
    Time to maximum plasma concentration of pimavanserin at steady state
    End point type
    Primary
    End point timeframe
    Steady state profile blood samples were collected on Day 20 predose (within 30 min prior to dosing) and 1, 2, 4, 6, 9, 12, 16, and 24 h after last dose of pimavanserin administration.
    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 inferential statistical analyses were planned or performed for this Phase I, multiple-ascending dose study.
    End point values
    		 Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg
    Number of subjects analysed
    10
    10
    7
    Units: hr
    median (full range (min-max))
        Overall
    6.00 (4.00 to 12.0)
    5.98 (4.00 to 12.0)
    9.00 (2.00 to 12.0)
    No statistical analyses for this end point

    Primary: Area under the concentration-time curve during any dosing interval at steady state (AUCτ)

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    End point title
    		 Area under the concentration-time curve during any dosing interval at steady state (AUCτ) [3]
    End point description
    Area under the concentration-time curve of pimavanserin during any dosing interval at steady state
    End point type
    Primary
    End point timeframe
    Steady state profile blood samples were collected on Day 20 predose (within 30 min prior to dosing) and 1, 2, 4, 6, 9, 12, 16, and 24 h after last dose of pimavanserin administration.
    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 inferential statistical analyses were planned or performed for this Phase I, multiple-ascending dose study.
    End point values
    		 Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg
    Number of subjects analysed
    10
    10
    7
    Units: ng×hr/mL
    arithmetic mean (standard deviation)
        Overall
    348 ( 92.3 )
    812 ( 297 )
    1683 ( 538 )
    No statistical analyses for this end point

    Secondary: Accumulation ratio based on Cmax (Rac)

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    End point title
    		 Accumulation ratio based on Cmax (Rac)
    End point description
    The accumulation of pimavanserin was evaluated based on the Cmax,ss of Day 20 (multiple dose) vs the Cmax of Day 1 (single dose), for each pimavanserin dose, using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    The 24-hour PK sampling was done on Day 1 through 2 and Day 20 through 21. Steady state profile blood samples were collected on Day 20 predose (within 30 min before dosing) and 1, 2, 4, 6, 9, 12, 16, and 24 h after last dose of pimavanserin administrated.
    End point values
    		 Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg
    Number of subjects analysed
    10
    10
    7
    Units: Cmax
    arithmetic mean (standard deviation)
        Overall
    3.13 ( 0.852 )
    3.73 ( 0.695 )
    4.15 ( 1.29 )
    No statistical analyses for this end point

    Secondary: Accumulation ratio based on AUC (Rac)

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    End point title
    		 Accumulation ratio based on AUC (Rac)
    End point description
    The accumulation of pimavanserin was evaluated based on the AUCτ on Day 20 (multiple dose) vs the AUC0-24 ofnDay 1 (single dose), for each pimavanserin dose, using descriptive statistics.
    End point type
    Secondary
    End point timeframe
    The 24-hour PK sampling was done on Day 1 through 2 and Day 20 through 21. Steady state profile blood samples were collected on Day 20 predose (within 30 min before dosing) and 1, 2, 4, 6, 9, 12, 16, and 24 h after last dose of pimavanserin administrated.
    End point values
    		 Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg
    Number of subjects analysed
    10
    10
    7
    Units: AUCτ
    arithmetic mean (standard deviation)
        Overall
    3.59 ( 1.07 )
    4.15 ( 0.726 )
    4.88 ( 1.66 )
    No statistical analyses for this end point

    Secondary: Apparent systemic clearance following oral administration (CL/F)

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    End point title
    		 Apparent systemic clearance following oral administration (CL/F)
    End point description
    Apparent systemic clearance following oral administration of pimavanserin determined on Day 20 (steady state)
    End point type
    Secondary
    End point timeframe
    Steady state profile blood samples were collected on Day 20 predose (within 30 min before dosing) and 1, 2, 4, 6, 9, 12, 16, and 24 h after last dose of pimavanserin administrated.
    End point values
    		 Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg
    Number of subjects analysed
    10
    10
    7
    Units: L/hr
    arithmetic mean (standard deviation)
        Overall
    30.8 ( 8.93 )
    27.6 ( 9.45 )
    22.4 ( 8.63 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from the time informed assent/consent was obtained through the Day 50 follow-up visit.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Pimavanserin 10 mg
    Reporting group description
    		 Pimavanserin, 10 mg (1×10 mg tablets), once daily as a single oral dose

    Reporting group title
    Pimavanserin 20 mg
    Reporting group description
    		 Pimavanserin, 20 mg (2×10 mg tablets), once daily as a single oral dose

    Reporting group title
    Pimavanserin 34 mg
    Reporting group description
    		 Pimavanserin, 34 mg (2×17 mg tablets), once daily as a single oral dose

    Serious adverse events
    		 Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Pimavanserin 10 mg Pimavanserin 20 mg Pimavanserin 34 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    9 / 12 (75.00%)
    7 / 10 (70.00%)
    4 / 12 (33.33%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Blood prolactin increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Weight increased
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Sinus bradycardia
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 12 (33.33%)
    2 / 10 (20.00%)
    0 / 12 (0.00%)
         occurrences all number
    4
    2
    0
    Sedation
         subjects affected / exposed
    2 / 12 (16.67%)
    3 / 10 (30.00%)
    0 / 12 (0.00%)
         occurrences all number
    2
    3
    0
    Somnolence
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    2 / 12 (16.67%)
         occurrences all number
    0
    1
    6
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Salivary hypersecretion
         subjects affected / exposed
    1 / 12 (8.33%)
    0 / 10 (0.00%)
    0 / 12 (0.00%)
         occurrences all number
    1
    0
    0
    Vomiting
         subjects affected / exposed
    0 / 12 (0.00%)
    0 / 10 (0.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Oropharyngeal pain
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Psychiatric disorders
    Depressed mood
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    2
    0
    Renal and urinary disorders
    Pollakiuria
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Endocrine disorders
    Hyperprolactinaemia
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    1 / 12 (8.33%)
         occurrences all number
    0
    1
    1
    Nasopharyngitis
         subjects affected / exposed
    0 / 12 (0.00%)
    1 / 10 (10.00%)
    0 / 12 (0.00%)
         occurrences all number
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Jul 2018
    - Clarified the descriptions of inpatient and outpatient study procedures - Clarified description of prohibited and restricted medications - Clarified repeat ECG procedure - Revised exclusion criteria to also exclude new onset diabetes - Clarified procedure for screening thyroid function test - Clarified definition of TEAE (to include AEs up to 30 days after the last dose of study drug) - Updated analysis of dose proportionality and analysis of C-SSRS - Added UKU-SERS assessment on Day 28 - Corrected postdose fasting period from 4 to 2 h and clarified that fluids were not allowed during fasting - Corrected time window for predose and postdose PK sampling, vital signs, and ECG
    15 Oct 2018
    - Updated final follow-up visit from 28 to 30 days after last dose - Clarified fasting requirement on Day 1 and Day 20 of PK sampling - Updated semisupine to resting position (sitting or supine) - Corrected lower range of pulse rate from <60 to <50 bpm and that pulse rate was to be measured by ECG - Corrected lower range of hemoglobin value and provided values by sex (<11.3 g/dL for females and <11.0 g/dL for males) - Updated HbA1c value (HbA1c >6.5%) to match for Type 2 diabetes - Allowed for a repeat set of triplicate ECGs - Revised age from a fixed effect to a covariate for PK analysis - Clarified visits and requirements for complete UDS - Clarified that UKU-SERS assessment was to be performed after dosing
    05 Nov 2018
    Clarified exclusion criteria related to heart rate and ECGs
    05 Mar 2019
    - Correctied information on amount of blood drawn for safety sampling and total blood volume - Clarified statistical planning for PK analyses - Updated sponsor address

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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