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    Clinical Trial Results:
    A Double-Blind, Placebo-Controlled Study to Examine the Safety and Efficacy of Pimavanserin for the Treatment of Agitation and Aggression in Alzheimer’s Disease

    Summary
    EudraCT number
    		 2016-001127-32
    Trial protocol
    		 ES   GB  
    Global end of trial date
    16 Feb 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Mar 2019
    First version publication date
    03 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ACP-103-032
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02992132
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    ACADIA Pharmaceuticals Inc.
    Sponsor organisation address
    3611 Valley Centre Drive, Ste. 300 , San Diego, CA, United States, 92130
    Public contact
    Sr. Dir. Medical Information and Medical Communications, ACADIA Pharmaceuticals Inc., +1 858-261-2897, medicalinformation@acadia-pharm.com
    Scientific contact
    Sr. Dir. Medical Information and Medical Communications, ACADIA Pharmaceuticals Inc., +1 858-261-2897, medicalinformation@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
    16 Feb 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Feb 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Feb 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of pimavanserin treatment compared with placebo in reducing the severity of agitation and Aggression in Alzheimer's disease after 12 weeks of treatment.
    Protection of trial subjects
    Not applicable
    Background therapy
    		 Patients were allowed to continue protocol-permitted medications (e.g. antidepressants, etc.) as long as they had been stable on the same dose for at least 4 weeks prior to baseline (Day 1) and expected to remain on this dose for the duration of the study. Cholinesterase inhibitors or memantine had to be stable for at least 12 weeks before baseline and expected to remain unchanged until the patient’s final visit.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    07 Nov 2016
    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
    Chile: 34
    Country: Number of subjects enrolled
    United States: 57
    Country: Number of subjects enrolled
    Spain: 7
    Country: Number of subjects enrolled
    United Kingdom: 5
    Country: Number of subjects enrolled
    France: 8
    Worldwide total number of subjects
    111
    EEA total number of subjects
    20
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    9
    From 65 to 84 years
    80
    85 years and over
    22

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study was planned to be conducted in approximately 432 patients. For business reasons, and not related to safety, recruitment of patients was stopped after 111 patients were randomised. The last patient was randomised on 2 Nov 2017. See Limitations and Caveats.

    Pre-assignment
    Screening details
    		 The screening visit was followed by a 2- to 4-week screening period, including wash-out of antipsychotic agents prohibited during the Treatment period (exception: protocol specified agents). Patients had to be on stable doses of permitted medications for >=4 weeks before Baseline (>=12 weeks for cholinesterase Inhibitors and memantine).

    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, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Placebo, taken as two tablets, once daily by mouth
    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
    Placebo, taken as two tablets, once daily by mouth

    Arm title
    		 Pimavanserin 20 mg
    Arm description
    		 Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth
    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 20 mg, tablet, taken as two 10 mg tablets, once daily by mouth

    Arm title
    		 Pimavanserin 34 mg
    Arm description
    		 Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth
    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 34 mg, tablet, taken as two 17 mg tablets, once daily by mouth

    Number of subjects in period 1
    		Placebo Pimavanserin 20 mg Pimavanserin 34 mg
    Started
    40
    35
    36
    Completed
    27
    27
    29
    Not completed
    13
    8
    7
         Consent withdrawn by subject
    -
    2
    1
         Physician decision
    -
    -
    1
         Adverse event, non-fatal
    4
    1
    3
         Non-compliance with study drug
    2
    -
    -
         Caregiver withdrew consent
    2
    3
    2
         Progressive disease
    1
    -
    -
         Lack of efficacy
    2
    -
    -
         Protocol deviation
    2
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, taken as two tablets, once daily by mouth

    Reporting group title
    Pimavanserin 20 mg
    Reporting group description
    		 Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth

    Reporting group title
    Pimavanserin 34 mg
    Reporting group description
    		 Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth

    Reporting group values
    		 Placebo Pimavanserin 20 mg Pimavanserin 34 mg Total
    Number of subjects
    		 40 35 36 111
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 2 4 3 9
        From 65-84 years
    		 29 23 28 80
        85 years and over
    		 9 8 5 22
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 78.9 ( 7.58 ) 76.5 ( 8.74 ) 75.0 ( 7.90 ) -
    Gender categorical
    Units: Subjects
        Female
    		 25 15 18 58
        Male
    		 15 20 18 53

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, taken as two tablets, once daily by mouth

    Reporting group title
    Pimavanserin 20 mg
    Reporting group description
    		 Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth

    Reporting group title
    Pimavanserin 34 mg
    Reporting group description
    		 Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth

    Primary: Cohen-Mansfield Agitation Inventory (CMAI)

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    End point title
    		 Cohen-Mansfield Agitation Inventory (CMAI)
    End point description
    Change from Baseline to Week 12 in the Cohen-Mansfield Agitation Inventory (CMAI) total score. The CMAI is a 29-item scale designed to systematically assess agitation, rated on a 7-point (1-7) scale of frequency. Higher scores indicate worse outcome.
    End point type
    Primary
    End point timeframe
    Approximately 12 weeks
    End point values
    		 Placebo Pimavanserin 20 mg Pimavanserin 34 mg
    Number of subjects analysed
    37 [1]
    34 [2]
    35 [3]
    Units: Score points
    arithmetic mean (standard error)
        Baseline
    70.3 ( 4.5 )
    56.9 ( 2.2 )
    68.0 ( 3.3 )
        Week 12
    54.3 ( 4.3 )
    52.5 ( 4.3 )
    53.7 ( 3.0 )
        Week 12 change from baseline
    -16.8 ( 5.0 )
    -3.7 ( 3.7 )
    -12.3 ( 2.7 )
    Notes
    [1] - Patients randomised and treated and with both a baseline and at least 1 post-baseline CMAI score
    [2] - Patients randomised and treated and with both a baseline and at least 1 post-baseline CMAI score
    [3] - Patients randomised and treated and with both a baseline and at least 1 post-baseline CMAI score
    Statistical analysis title
    		 Primary endpoint, pimavanserin 20 mg vs placebo
    Statistical analysis description
    Mixed-effect model repeated measures (MMRM), with the dependent variable being the change from Baseline in CMAI total score.
    Comparison groups
    Placebo v Pimavanserin 20 mg
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LSM
    Point estimate
    5.1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.8
         upper limit
    		 15
    Variability estimate
    Standard error of the mean
    Dispersion value
    5
    Statistical analysis title
    		 Primary endpoint, pimavanserin 34 mg vs placebo
    Statistical analysis description
    Mixed-effect model repeated measures (MMRM), with the dependent variable being the change from Baseline in CMAI total score.
    Comparison groups
    Placebo v Pimavanserin 34 mg
    Number of subjects included in analysis
    72
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Difference in LSM
    Point estimate
    1
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.5
         upper limit
    		 10.5
    Variability estimate
    Standard error of the mean
    Dispersion value
    4.8

    Secondary: Zarit Burden Interview

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    End point title
    		 Zarit Burden Interview
    End point description
    The ZBI was designed to assess the stresses experienced by caregivers of patients with dementia. It comprises a series of 22 questions about the impact of the patient’s disabilities on their life. For each item, caregivers are to indicate how often they felt that way (never, rarely, sometimes, quite frequently, or nearly always). Higher scores indicate worse outcome.
    End point type
    Secondary
    End point timeframe
    Approximately 12 weeks
    End point values
    		 Placebo Pimavanserin 20 mg Pimavanserin 34 mg
    Number of subjects analysed
    34 [4]
    33 [5]
    32 [6]
    Units: Score points
    arithmetic mean (standard error)
        Baseline
    41.5 ( 2.6 )
    40.8 ( 2.4 )
    41.7 ( 2.5 )
        Week 12
    37.0 ( 3.2 )
    36.8 ( 3.7 )
    35.7 ( 3.5 )
        Week 12 change from baseline
    -6.5 ( 2.3 )
    -4.9 ( 2.3 )
    -5.5 ( 2.5 )
    Notes
    [4] - Patients randomised and treated and with both a baseline and at least 1 post-baseline CMAI score
    [5] - Patients randomised and treated and with both a baseline and at least 1 post-baseline CMAI score
    [6] - Patients randomised and treated and with both a baseline and at least 1 post-baseline CMAI score
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the time of informed consent through the completion of procedures at the Week 12 visit (for subjects continuing into an Open-Label Extension study) or through to 30 days after the last dose of study drug (for all other subjects)
    Adverse event reporting additional description
    Not applicable
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, taken as two tablets, once daily by mouth

    Reporting group title
    Pimavanserin 20 mg
    Reporting group description
    		 Drug- pimavanserin tartrate, 20 mg, taken as two 10 mg tablets, once daily by mouth

    Reporting group title
    Pimavanserin 34 mg
    Reporting group description
    		 Drug- pimavanserin tartrate, 34 mg, taken as two 17 mg tablets, once daily by mouth

    Serious adverse events
    		 Placebo Pimavanserin 20 mg Pimavanserin 34 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 40 (7.50%)
    4 / 35 (11.43%)
    3 / 36 (8.33%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Investigations
    Weight decreased
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femoral neck fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Pelvic fracture
         subjects affected / exposed
    0 / 40 (0.00%)
    0 / 35 (0.00%)
    1 / 36 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Encephalopathy
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Diverticulum
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Lower gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Upper gastrointestinal haemorrhage
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Pulmonary embolism
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 35 (0.00%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    1 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Sepsis
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hyponatraemia
         subjects affected / exposed
    0 / 40 (0.00%)
    1 / 35 (2.86%)
    0 / 36 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         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 Pimavanserin 20 mg Pimavanserin 34 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    11 / 40 (27.50%)
    15 / 35 (42.86%)
    15 / 36 (41.67%)
    Injury, poisoning and procedural complications
    Contusion
         subjects affected / exposed
    1 / 40 (2.50%)
    1 / 35 (2.86%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    2
    Fall
         subjects affected / exposed
    1 / 40 (2.50%)
    3 / 35 (8.57%)
    3 / 36 (8.33%)
         occurrences all number
    1
    3
    3
    Blood and lymphatic system disorders
    Anaemia
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    1
    2
    0
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    1 / 40 (2.50%)
    2 / 35 (5.71%)
    2 / 36 (5.56%)
         occurrences all number
    1
    2
    2
    Diarrhoea
         subjects affected / exposed
    3 / 40 (7.50%)
    2 / 35 (5.71%)
    2 / 36 (5.56%)
         occurrences all number
    3
    2
    2
    Gastrointestinal haemorrhage
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 35 (5.71%)
    0 / 36 (0.00%)
         occurrences all number
    0
    2
    0
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    5 / 40 (12.50%)
    5 / 35 (14.29%)
    1 / 36 (2.78%)
         occurrences all number
    5
    5
    1
    Insomnia
         subjects affected / exposed
    0 / 40 (0.00%)
    4 / 35 (11.43%)
    3 / 36 (8.33%)
         occurrences all number
    0
    5
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 40 (2.50%)
    0 / 35 (0.00%)
    2 / 36 (5.56%)
         occurrences all number
    1
    0
    2
    Urinary tract infection
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 35 (5.71%)
    1 / 36 (2.78%)
         occurrences all number
    0
    2
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 40 (0.00%)
    2 / 35 (5.71%)
    2 / 36 (5.56%)
         occurrences all number
    0
    2
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Aug 2016
    - Primary efficacy endpoint changed from NPI-C to CMAI total score - Key secondary efficacy endpoint changed from NPI total caregiver distress score to ZBI total score - Changed secondary objective for efficacy evaluation of pimavanserin vs placebo for cognition to exploratory objective - Revised secondary efficacy endpoints assessment scale from NPI to NPI-C; specified timeframes for evaluation
    18 Jul 2017
    - Changed IN 1 (clarify requirement for informed consent (IC) if subject not competent to provide IC) - Changed IN 8 (clarify eligibility of subjects capable to visit clinic as outpatient) - Added suicidal ideation and behavior as safety assessment
    20 Nov 2017
    The original planned sample size was approximately 432. For business reasons, and not related to safety, enrollment (randomisation) of new subjects into the study was stopped after 111 subjects were randomised. The Amendment: - Revised study objectives, number of planned subjects, description of endpoints, exploratory objectives and endpoints, statistical methods - Specified that this study was not powered to detect differences between the Treatment groups due to early termination by the Sponsor and consequent reduced sample size - Revised PK endpoints and specified that only the plasma concentration data would be provided; this change was made to align with the study termination and resultant limited number of subjects that would not support additional analyses - For all efficacy endpoints, removed hypothesis testing and sensitivity analyses and specified that only descriptive summaries would be provided for evaluation of efficacy; this change was made to align with the study termination

    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.
    The original study (n=432) was powered to detect a treatment effect on CMAI however recruitment was discontinued early for business reasons and amended accordingly The final study (n=111) was no longer adequately powered to detect a treatment effect
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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
    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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