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    Clinical Trial Results:
    A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled Study of the Efficacy and Safety of ALKS 9072 in Subjects with Acute Exacerbation of Schizophrenia

    Summary
    EudraCT number
    2012-003445-15
    Trial protocol
    BG  
    Global end of trial date
    11 Mar 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    14 Aug 2016
    First version publication date
    14 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    ALK9072-003
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT01469039
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Alkermes
    Sponsor organisation address
    852 Winter Street, Waltham, United States, 02451
    Public contact
    ARISTADA Medical Information, Alkermes, Inc., 01 866-274-7823, usmedinfo@alkermes.com
    Scientific contact
    ARISTADA Medical Information, Alkermes, Inc., 01 866-274-7823, usmedinfo@alkermes.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
    03 Jul 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    11 Jan 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    11 Mar 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study will determine the efficacy of ALKS 9072 (also known as aripiprazole lauroxil or ALKS 9070) for the treatment of schizophrenia in subjects experiencing an acute exacerbation.
    Protection of trial subjects
    Subjects were monitored in an inpatient setting for at least 2 weeks after administration of the 1st dose of intramuscular (IM) study drug. Subjects were discharged from the inpatient facility when assessed as clinically stable and appropriate for discharge as determined by the study investigator. For subjects who had never taken aripiprazole, a test dose of oral aripiprazole 5 mg was administered by mouth daily for 2 days prior to randomization, in order to assess individual tolerability prior to proceeding to injectable study drug.
    Background therapy
    Currently prescribed antipsychotics were required to be discontinued during screening and prior to administration of study drug.
    Evidence for comparator
    -
    Actual start date of recruitment
    15 Dec 2011
    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
    Ukraine: 90
    Country: Number of subjects enrolled
    United States: 307
    Country: Number of subjects enrolled
    Bulgaria: 59
    Country: Number of subjects enrolled
    Malaysia: 24
    Country: Number of subjects enrolled
    Philippines: 53
    Country: Number of subjects enrolled
    Romania: 17
    Country: Number of subjects enrolled
    Russian Federation: 73
    Worldwide total number of subjects
    623
    EEA total number of subjects
    76
    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)
    621
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Included subjects with schizophrenia experiencing an acute exacerbation episode.

    Pre-assignment
    Screening details
    Subjects were admitted to an inpatient study unit. Currently prescribed antipsychotics were discontinued prior to administration of study drug. One randomized subject was discontinued for a protocol violation prior to receiving investigational treatment.

    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
    Carer, Assessor, Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    All IM injections were administered under double-blind conditions. An unblinded pharmacist prepared investigational product for IM administration. The unblinded pharmacist provided the IM study drug (in a syringe) to an identified blinded qualified staff member (injector) for administration.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    aripiprazole lauroxil 441 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    aripiprazole lauroxil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    441 mg IM injection, given monthly

    Arm title
    aripiprazole lauroxil 882 mg
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    aripiprazole lauroxil
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    881 mg IM injection, given monthly

    Arm title
    AL Placebo
    Arm description
    aripiprazole lauroxil-matched placebo
    Arm type
    Placebo

    Investigational medicinal product name
    Matched Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Emulsion for injection/infusion
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Volume-matched to aripiprazole lauroxil doses, given monthly

    Number of subjects in period 1
    aripiprazole lauroxil 441 mg aripiprazole lauroxil 882 mg AL Placebo
    Started
    207
    208
    208
    Completed
    130
    135
    95
    Not completed
    77
    73
    113
         Protocol deviation
    6
    3
    4
         Physician decision
    3
    -
    -
         Non-compliance with study drug
    -
    -
    1
         Incarceration
    -
    3
    -
         Lack of efficacy
    9
    17
    38
         Adverse event, serious fatal
    -
    -
    1
         LTFU, then returned for follow-up
    -
    -
    1
         Adverse event, non-fatal
    14
    6
    36
         Consent withdrawn by subject
    35
    29
    22
         Lost to follow-up
    10
    15
    10

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    aripiprazole lauroxil 441 mg
    Reporting group description
    -

    Reporting group title
    aripiprazole lauroxil 882 mg
    Reporting group description
    -

    Reporting group title
    AL Placebo
    Reporting group description
    aripiprazole lauroxil-matched placebo

    Reporting group values
    aripiprazole lauroxil 441 mg aripiprazole lauroxil 882 mg AL Placebo Total
    Number of subjects
    207 208 208 623
    Age Categorical
    Units: participants
        <=18 years
    0 0 0 0
        Between 18 and 65 years
    207 207 207 621
        >=65 years
    0 1 1 2
    Age Continuous
    Units: Years
        arithmetic mean (standard deviation)
    39.9 ± 10.13 39.7 ± 11.06 39.5 ± 11.85 -
    Gender, Male/Female
    Units: participants
        Female
    66 65 69 200
        Male
    141 143 139 423
    Race (NIH/OMB)
    Units: Subjects
        American Indian or Alaska Native
    0 1 1 2
        Asian
    24 28 29 81
        Native Hawaiian or Other Pacific Islander
    1 0 0 1
        Black or African American
    83 81 84 248
        White
    99 98 94 291
        More than one race
    0 0 0 0
        Unknown or Not Reported
    0 0 0 0
    Region of Enrollment
    Units: Subjects
        United States
    103 102 102 307
        Philippines
    16 21 16 53
        Malaysia
    7 7 10 24
        Ukraine
    29 29 32 90
        Romania
    5 6 6 17
        Bulgaria
    23 19 17 59
        Russian Federation
    24 24 25 73

    End points

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    End points reporting groups
    Reporting group title
    aripiprazole lauroxil 441 mg
    Reporting group description
    -

    Reporting group title
    aripiprazole lauroxil 882 mg
    Reporting group description
    -

    Reporting group title
    AL Placebo
    Reporting group description
    aripiprazole lauroxil-matched placebo

    Primary: The change from Baseline at Day 85 in Positive and Negative Syndrome Scale (PANSS) total score

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    End point title
    The change from Baseline at Day 85 in Positive and Negative Syndrome Scale (PANSS) total score
    End point description
    The PANSS scale contains 30 questions, each containing an answer range of 1-7. A total PANSS score can range from between 30 to 210; a higher score indicates a worse disease condition.
    End point type
    Primary
    End point timeframe
    Data collected from baseline to day 85
    End point values
    aripiprazole lauroxil 441 mg aripiprazole lauroxil 882 mg AL Placebo
    Number of subjects analysed
    196
    204
    196
    Units: units on a scale
        least squares mean (standard error)
    -20.9 ± 1.39
    -21.8 ± 1.35
    -9.8 ± 1.39
    Statistical analysis title
    p-value
    Statistical analysis description
    Significant p-value, active (441 mg) vs placebo
    Comparison groups
    aripiprazole lauroxil 441 mg v AL Placebo
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Confidence interval
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Statistical analysis title
    p-value
    Statistical analysis description
    Significant p-value, active (882 mg) vs placebo
    Comparison groups
    aripiprazole lauroxil 882 mg v AL Placebo
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    ANCOVA
    Confidence interval
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Secondary: Clinical Global Impression - Improvement (CGI-I) Scores at Day 85

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    End point title
    Clinical Global Impression - Improvement (CGI-I) Scores at Day 85
    End point description
    The CGI-I is a 7-point scale that requires the clinician to assess how much the participant's illness has improved or worsened relative to a baseline state at the beginning of the study. Participants were categorized as: "1: very much improved"; "2: much improved"; "3: minimally improved"; "4: no change"; "5: minimally worse"; "6: much worse"; or "7: very much worse".
    End point type
    Secondary
    End point timeframe
    85 Days
    End point values
    aripiprazole lauroxil 441 mg aripiprazole lauroxil 882 mg AL Placebo
    Number of subjects analysed
    196
    204
    196
    Units: participants in category
    number (not applicable)
        CGI Score: Very much improved
    27
    25
    15
        CGI Score: Much improved
    68
    81
    33
        GCI Score: Minimally improved
    45
    52
    43
        CGI Score: No change
    32
    24
    42
        CGI Score: Minimally worse
    11
    16
    37
        CGI Score: Much worse
    12
    5
    23
        CGI Score: Very much worse
    1
    1
    3
    Statistical analysis title
    p-value active (441 mg) v placebo
    Comparison groups
    aripiprazole lauroxil 441 mg v AL Placebo
    Number of subjects included in analysis
    392
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [1]
    Method
    Wilcoxon rank sum test based on LOCF
    Confidence interval
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Notes
    [1] - significant p-value, active vs placebo
    Statistical analysis title
    p-value active (881 mg) v placebo
    Comparison groups
    aripiprazole lauroxil 882 mg v AL Placebo
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001 [2]
    Method
    Wilcoxon rank sum test based on LOCF
    Confidence interval
         sides
    2-sided
         lower limit
    -
         upper limit
    -
    Notes
    [2] - significant p-value, active vs placebo

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were collected during the 85-day treatment period.
    Adverse event reporting additional description
    One randomized subject was discontinued for a protocol violation prior to receiving IM study drug (placebo), and this subject was not included in the safety population. This changes the overall number of subjects in the placebo group to include 207.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    aripiprazole lauroxil 441 mg
    Reporting group description
    Intramuscular injection, given monthly

    Reporting group title
    placebo
    Reporting group description
    Intramuscular injection, given monthly

    Reporting group title
    aripiprazole lauroxil 882 mg
    Reporting group description
    Intramuscular injection, given monthly

    Serious adverse events
    aripiprazole lauroxil 441 mg placebo aripiprazole lauroxil 882 mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 207 (1.45%)
    4 / 207 (1.93%)
    4 / 208 (1.92%)
         number of deaths (all causes)
    0
    1
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Cardiac disorders
    Angina unstable
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 207 (0.00%)
    0 / 208 (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
    Social circumstances
    Victim of homicide
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 207 (0.48%)
    0 / 208 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Drug Abuse
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Psychotic disorder
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 207 (0.48%)
    0 / 208 (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
    Suicide attempt
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 207 (0.48%)
    0 / 208 (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
    Peritoneal adhesions
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 207 (0.00%)
    0 / 208 (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
    Reproductive system and breast disorders
    Cervical dysplasia
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 207 (0.00%)
    0 / 207 (0.00%)
    1 / 208 (0.48%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 207 (0.48%)
    0 / 207 (0.00%)
    0 / 208 (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
    Pneumonia
         subjects affected / exposed
    0 / 207 (0.00%)
    1 / 207 (0.48%)
    0 / 208 (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
    aripiprazole lauroxil 441 mg placebo aripiprazole lauroxil 882 mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    66 / 207 (31.88%)
    76 / 207 (36.71%)
    68 / 208 (32.69%)
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    24 / 207 (11.59%)
    9 / 207 (4.35%)
    23 / 208 (11.06%)
         occurrences all number
    26
    9
    30
    Headache
         subjects affected / exposed
    17 / 207 (8.21%)
    17 / 207 (8.21%)
    18 / 208 (8.65%)
         occurrences all number
    20
    20
    22
    Psychiatric disorders
    Agitation
         subjects affected / exposed
    3 / 207 (1.45%)
    11 / 207 (5.31%)
    3 / 208 (1.44%)
         occurrences all number
    4
    11
    3
    Anxiety
         subjects affected / exposed
    6 / 207 (2.90%)
    14 / 207 (6.76%)
    11 / 208 (5.29%)
         occurrences all number
    11
    16
    14
    Insomnia
         subjects affected / exposed
    20 / 207 (9.66%)
    24 / 207 (11.59%)
    25 / 208 (12.02%)
         occurrences all number
    26
    29
    27
    Schizophrenia
         subjects affected / exposed
    12 / 207 (5.80%)
    22 / 207 (10.63%)
    5 / 208 (2.40%)
         occurrences all number
    13
    22
    5

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Dec 2011
    Reclassified previous secondary efficacy evaluations; clarified washout period for discontinuing current antipsychotics; changed the allowable time window for predose ECG measurement; adjusted order of clinical assessments during visits; changed exclusion criterion of baseline ECG; added a requirement that the site would develop a compliance plan to ensure that subjects adhered to oral dosing in the outpatient setting and returned to clinic for subsequent visits; allowed the injector to be unblinded, as long as the injector did not participate in the assessments, ratings, observations, or any other clinical assessments of the subject.
    11 Oct 2012
    Further clarify the purpose of the unblinded interim analysis; allow additional visits, hospitalization for psychosocial issues or respite care to improve subject retention; change allowable time windows for orthostatic vital sign measurements and postdose ECT measurements; adjust order of clinical assessments during visits; add exceptions to the definition of SAE, if the AE required inpatient hospitalization or prolongation of existing hospitalization.

    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.
    One randomized subject (placebo group) was discontinued for a protocol violation prior to receiving IM study drug.
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