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    Clinical Trial Results:
    A Phase 3, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Pimavanserin as Adjunctive Treatment for the Negative Symptoms of Schizophrenia (ADVANCE 2)

    Summary
    EudraCT number
    		 2019-003343-29
    Trial protocol
    		 CZ   PL   HU   BG   ES   LT   IT   HR  
    Global end of trial date
    19 Feb 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Dec 2024
    First version publication date
    26 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACP-103-064
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT04531982
    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, CA 92130
    Public contact
    Chelsea Gavilanes, ACADIA Pharmaceuticals Inc., 1 8582612934, cgavilanes@ACADIA-Pharm.com
    Scientific contact
    Chelsea Gavilanes, ACADIA Pharmaceuticals Inc., 1 8582612934, cgavilanes@ACADIA-Pharm.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
    19 Feb 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Jan 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Feb 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    • To evaluate the efficacy of pimavanserin compared with placebo in the adjunctive treatment of the negative symptoms of schizophrenia
    Protection of trial subjects
    An independent Data and Safety Monitoring Board (DSMB) reviewed interim safety data, including data on AEs and SAEs. The DSMB was independent of the Sponsor and the Investigators and was empowered to recommend stopping the study due to safety concerns. The DSMB reviewed blinded, unblinded, or partially unblinded data, but the Sponsor and the Investigators remained blinded to the data provided to the DSMB until the official unblinding of the clinical database at the end of the study. The membership, activities, responsibilities, and frequency of meetings were described separately in a DSMB charter.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Aug 2020
    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
    Poland: 8
    Country: Number of subjects enrolled
    Spain: 17
    Country: Number of subjects enrolled
    Croatia: 13
    Country: Number of subjects enrolled
    Bulgaria: 144
    Country: Number of subjects enrolled
    Czechia: 10
    Country: Number of subjects enrolled
    Hungary: 11
    Country: Number of subjects enrolled
    Italy: 5
    Country: Number of subjects enrolled
    Lithuania: 1
    Country: Number of subjects enrolled
    Argentina: 78
    Country: Number of subjects enrolled
    Russian Federation: 77
    Country: Number of subjects enrolled
    Serbia: 45
    Country: Number of subjects enrolled
    Ukraine: 44
    Worldwide total number of subjects
    453
    EEA total number of subjects
    209
    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)
    453
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 640 subjects were screened and 453 were enrolled (=randomized and treated)

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

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    two whole tablets per dose once daily at approximately the same time each day from Baseline to Week 26

    Arm title
    		 Pimavanserin
    Arm description
    		 -
    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
    taken orally as two whole tablets per dose (34 mg: 2x 17 mg) once daily at approximately the same time each day from Baseline until Week 26

    Number of subjects in period 1
    		Placebo Pimavanserin
    Started
    226
    227
    Completed
    188
    195
    Not completed
    38
    32
         Consent withdrawn by subject
    11
    10
         Adverse event, non-fatal
    14
    6
         Non-compliance with study drug
    2
    3
         Use of prohibited medication
    -
    2
         Lost to follow-up
    1
    -
         Geopolitical Conflict (Any Other)
    -
    2
         Lack of efficacy
    1
    -
         Protocol deviation
    9
    6
         Lack of efficacy
    -
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Pimavanserin
    Reporting group description
    		 -

    Reporting group values
    		 Placebo Pimavanserin Total
    Number of subjects
    		 226 227 453
    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)
    		 226 227 453
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 37.5 ( 9.78 ) 36.3 ( 9.61 ) -
    Gender categorical
    Units: Subjects
        Female
    		 90 95 185
        Male
    		 136 132 268
    Race
    Units: Subjects
        White
    		 224 225 449
        American Indian or Alaska Native
    		 1 0 1
        Other
    		 1 2 3
    NSA-16 Total score
    Negative Symptom Assessment-16 (NSA-16) The NSA 16 is a 16 item scale that can be completed in approximately 20 to 30 minutes for most subjects but may take longer (i.e., based on effort and/or response of the subject). The NSA 16 has been validated for the assessment of the negative symptoms of schizophrenia and assesses five domains of negative symptoms: (1) communication, (2) emotion/affect, (3) social involvement, (4) motivation, and (5) retardation.
    Units: score
        arithmetic mean (standard deviation)
    		 60.8 ( 7.86 ) 61.3 ( 8.04 ) -
    CGI-SCH S of negative symptoms score
    Clinical Global Impression of Schizophrenia Scale-Severity (CGI-SCH S) is a clinician rated, 7 point scale that is designed to evaluate positive, negative, depressive, and cognitive symptoms as well as overall severity in schizophrenia. For the purposes of this study, only the negative symptoms were evaluated.
    Units: Score
        arithmetic mean (standard deviation)
    		 4.8 ( 0.57 ) 4.8 ( 0.60 ) -
    Subject analysis sets

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Randomized and treated with at least one dose of study drug

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Randomized and treated with at least one dose of study drug, and have both a Baseline and at least one postbaseline NSA-16 total score

    Subject analysis sets values
    		 Safety Analysis Set Full Analysis Set
    Number of subjects
    453
    446
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    453
    446
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    36.9 ( 9.71 )
    36.9 ( 9.76 )
    Gender categorical
    Units: Subjects
        Female
    185
    181
        Male
    268
    265
    Race
    Units: Subjects
        White
    449
    442
        American Indian or Alaska Native
    1
    1
        Other
    3
    3
    NSA-16 Total score
    Negative Symptom Assessment-16 (NSA-16) The NSA 16 is a 16 item scale that can be completed in approximately 20 to 30 minutes for most subjects but may take longer (i.e., based on effort and/or response of the subject). The NSA 16 has been validated for the assessment of the negative symptoms of schizophrenia and assesses five domains of negative symptoms: (1) communication, (2) emotion/affect, (3) social involvement, (4) motivation, and (5) retardation.
    Units: score
        arithmetic mean (standard deviation)
    61.1 ( 7.95 )
    61.1 ( 7.98 )
    CGI-SCH S of negative symptoms score
    Clinical Global Impression of Schizophrenia Scale-Severity (CGI-SCH S) is a clinician rated, 7 point scale that is designed to evaluate positive, negative, depressive, and cognitive symptoms as well as overall severity in schizophrenia. For the purposes of this study, only the negative symptoms were evaluated.
    Units: Score
        arithmetic mean (standard deviation)
    4.8 ( 0.58 )
    4.8 ( 0.59 )

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    Pimavanserin
    Reporting group description
    		 -

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Randomized and treated with at least one dose of study drug

    Subject analysis set title
    Full Analysis Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Randomized and treated with at least one dose of study drug, and have both a Baseline and at least one postbaseline NSA-16 total score

    Primary: Change From Baseline to Week 26 in NSA-16 Total Score

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    End point title
    		 Change From Baseline to Week 26 in NSA-16 Total Score
    End point description
    End point type
    Primary
    End point timeframe
    Baseline to Week 26 of treatment
    End point values
    		 Placebo Pimavanserin
    Number of subjects analysed
    222
    224
    Units: score
        arithmetic mean (standard deviation)
    -11.09 ( 9.18 )
    -12.14 ( 10.29 )
    Statistical analysis title
    		 Difference between treatments
    Statistical analysis description
    Difference between LSM changes for adjunctive pimavanserin and adjunctive placebo (pimavanserin – placebo) at the specified visit from MMRM analysis.
    Comparison groups
    Placebo v Pimavanserin
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4825 [1]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [1] - Two-sided p-value for treatment difference at Week 26 from MMRM analysis

    Secondary: Change From Baseline to Week 26 in the CGI-SCH-S Score

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    End point title
    		 Change From Baseline to Week 26 in the CGI-SCH-S Score
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline to Week 26
    End point values
    		 Placebo Pimavanserin
    Number of subjects analysed
    222
    224
    Units: score
        arithmetic mean (standard deviation)
    -087 ( 0.92 )
    -0.88 ( 0.91 )
    Statistical analysis title
    		 Difference between treatments
    Comparison groups
    Placebo v Pimavanserin
    Number of subjects included in analysis
    446
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.8872 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [2] - Two-sided p-value for treatment difference at Week 26 from MMRM analysis

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    05 August 2020 - 19 February 2024
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo group

    Reporting group title
    Pimavanserin
    Reporting group description
    		 Pimavanserin 34 mg daily

    Serious adverse events
    		 Placebo Pimavanserin
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 226 (3.10%)
    2 / 227 (0.88%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Acute respiratory failure
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Schizophrenia
         subjects affected / exposed
    4 / 226 (1.77%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    1 / 4
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anxiety
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Irritability
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess limb
         subjects affected / exposed
    0 / 226 (0.00%)
    1 / 227 (0.44%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    COVID-19
         subjects affected / exposed
    1 / 226 (0.44%)
    0 / 227 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo Pimavanserin
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    16 / 226 (7.08%)
    9 / 227 (3.96%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 226 (7.08%)
    9 / 227 (3.96%)
         occurrences all number
    18
    12

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    14 Jan 2020
    change the dosing regimen to a fixed 34 mg dose and adjust the efficacy endpoints in comparison to the original protocol
    07 Aug 2020
    increase the sample size, number of sites, and country number
    05 Oct 2022
    adjust the Screening Period from 4 to 6 weeks to up to 6 weeks. The minimum period of 28 days was not required, as inclusion criteria #17 ensured that subjects were stable prior to Screening and inclusion in the study

    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
    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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