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    Clinical Trial Results:
    A Double-blind, Randomized, Active-controlled, Parallel-group Study of Paliperidone Palmitate 6 Month Formulation.

    Summary
    EudraCT number
    2017-001941-28
    Trial protocol
    DE   ES   CZ   PL   IT  
    Global end of trial date
    08 May 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    13 May 2021
    First version publication date
    13 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    R092670PSY3015
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03345342
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Janssen Research & Development, LLC
    Sponsor organisation address
    920 US Highway 202, Raritan, NJ, United States, 08869-1420
    Public contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.com
    Scientific contact
    Clinical Registry Group, Janssen Research & Development, LLC, ClinicalTrialsEU@its.jnj.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
    08 May 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    08 May 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The mail objective of the study was to demonstrate that injection cycles consisting of a single administration of paliperidone palmitate 6-month (PP6M) (700 or 1000 milligrams equivalent [mg eq.]) were not less effective than 2 sequentially administered injections of paliperidone palmitate 3-month (PP3M) (350 or 525 mg eq.) for the prevention of relapse in subjects with schizophrenia previously stabilized on corresponding doses of paliperidone palmitate 1-month (PP1M) (100 or 150 mg eq.) or PP3M (350 or 525 mg eq.).
    Protection of trial subjects
    The study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki and that are consistent with Good Clinical Practices and applicable regulatory requirements. Safety evaluations included the assessment of adverse events (AEs), clinical laboratory tests, electrocardiogram (ECG), vital signs, physical examinations, extrapyramidal symptom assessment scales, injection site evaluations and columbia suicide severity rating Scale (C-SSRS) for assessment of suicidal ideation throughout the study.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    20 Nov 2017
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    Safety
    Long term follow-up duration
    12 Months
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Argentina: 55
    Country: Number of subjects enrolled
    Australia: 4
    Country: Number of subjects enrolled
    Brazil: 90
    Country: Number of subjects enrolled
    Bulgaria: 46
    Country: Number of subjects enrolled
    Czechia: 45
    Country: Number of subjects enrolled
    France: 7
    Country: Number of subjects enrolled
    Hong Kong: 4
    Country: Number of subjects enrolled
    Hungary: 20
    Country: Number of subjects enrolled
    India: 42
    Country: Number of subjects enrolled
    Italy: 8
    Country: Number of subjects enrolled
    Korea, Republic of: 4
    Country: Number of subjects enrolled
    Malaysia: 22
    Country: Number of subjects enrolled
    Mexico: 23
    Country: Number of subjects enrolled
    Poland: 68
    Country: Number of subjects enrolled
    Russian Federation: 139
    Country: Number of subjects enrolled
    Spain: 29
    Country: Number of subjects enrolled
    Taiwan: 31
    Country: Number of subjects enrolled
    Turkey: 26
    Country: Number of subjects enrolled
    Ukraine: 50
    Country: Number of subjects enrolled
    United States: 125
    Worldwide total number of subjects
    838
    EEA total number of subjects
    223
    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)
    822
    From 65 to 84 years
    16
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    -

    Pre-assignment
    Screening details
    A total of 838 subjects were enrolled either in paliperidone palmitate 1-month (PP1M) or PP3M in Open-label (OL) Phase. Out of 838 subjects, 702 entered the Double-blind (DB) Phase. 702 subjects were randomized in DB Phase (PP6M: n=478; PP3M: n=224), out of which 202 and 416 subjects completed the study in PP3M and PP6M, respectively.

    Period 1
    Period 1 title
    Open-Label Phase
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    Open Label (OL) PP1M/PP3M (4 Months)
    Arm description
    Subjects previously treated with oral antipsychotics, or injectable risperidone, or a moderate or higher dose of PP1M with previous initiation but without previous stabilization (where stabilization was defined as at least 3 months of injections with the last 2 doses being the same strength) received 1 to 5 intramuscular (IM) injections of paliperidone palmitate 1-month (PP1M) 50 to 150 milligrams equivalent (mg eq.) to achieve stability during Open-label (OL) transition phase and to initiate the OL maintenance phase. Subjects received single dose of IM injections of PP1M as 100 or 150 mg eq. or paliperidone palmitate 3-month (PP3M) as 350 or 525 mg eq was administered during the OL-maintenance Phase. Open-label phase duration was of 4 Months (OL-transition of 1 month and OL-maintenance of 3 months).
    Arm type
    Experimental

    Investigational medicinal product name
    PP3M (350 or 525 mg eq.)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects were administered single dose of PP3M (350 or 525 mg eq.) injection for 3-month during the OL-maintenance Phase.

    Investigational medicinal product name
    PP1M (50 or 150 mg eq.)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects were administered single dose of PP1M (50 or 150 mg eq.) injection for 1-month during the OL-transition Phase.

    Number of subjects in period 1
    Open Label (OL) PP1M/PP3M (4 Months)
    Started
    838
    Completed
    702
    Not completed
    136
         Protocol deviation
    8
         Other
    15
         Physician decision
    4
         Non-compliance with study drug
    4
         Lack of efficacy
    6
         Adverse event, serious fatal
    1
         Initiated prohibited medication
    2
         Adverse event, non-fatal
    30
         Consent withdrawn by subject
    57
         Lost to follow-up
    9
    Period 2
    Period 2 title
    Double Blind Phase (12 Months)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Subject, Carer

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Double-blind (DB) PP3M
    Arm description
    Subjects received four doses of PP3M (350 or 525 mg eq.) IM injection for up to 12 months (one dose every 3 month) during DB phase.
    Arm type
    Active comparator

    Investigational medicinal product name
    PP3M
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects were administered single dose of PP3M (350 or 525 mg eq.) injection every 3-month for up to 12 months during the DB Phase.

    Arm title
    Double-blind (DB) PP6M
    Arm description
    Subjects received two doses of PP6M (700 or 1000 mg eq.) IM injection for 12 months (one dose every 6 months), during the DB Phase. To maintain blinding, subjects who were assigned to treatment with PP6M in this arm, received IM injections of matching placebo at the 3-month time points between their 6-month doses of PP6M drug.
    Arm type
    Experimental

    Investigational medicinal product name
    PP6M
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects were administered two doses of PP6M (700 or 1000 mg eq.) injection every 6-months for up to 12 Months during the DB Phase.

    Number of subjects in period 2
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Started
    224
    478
    Completed
    202
    416
    Not completed
    22
    62
         Protocol deviation
    -
    1
         Other
    1
    3
         Physician decision
    1
    4
         Adverse event, serious fatal
    2
    1
         Initiated prohibited medication
    -
    2
         Adverse event, non-fatal
    1
    6
         Consent withdrawn by subject
    16
    38
         Lost to follow-up
    1
    7
    Period 3
    Period 3 title
    Follow-up Phase (12 Months)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Subject, Investigator, Monitor, Carer

    Arms
    Are arms mutually exclusive
    No

    Arm title
    Follow-up (FU) Phase PP3M
    Arm description
    Subjects who have received at least 1 dose of PP3M (350 or 525 mg eq.) IM injection during double-blind phase but then have relapsed or have met other relevant conditions for withdrawal or discontinuation can participate in the Follow-up phase PP3M (350 or 525 mg eq.) IM injection for up to 12 months for evaluating efficacy and safety.
    Arm type
    Active comparator

    Investigational medicinal product name
    PP3M
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects who received PP3M (350 or 525 mg eq.) IM injection during DB-phase were followed-up to 12 months during FU phase.

    Arm title
    Follow-up (FU) Phase PP6M
    Arm description
    Subjects who received PP6M (700 or 1000 mg eq.) IM injection for up to 12 months for evaluating efficacy and safety
    Arm type
    Experimental

    Investigational medicinal product name
    PP6M
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects who received two doses of PP6M (700 or 1000 mg eq.) IM injection during DB-phase were followed-up to 12 months during FU phase.

    Number of subjects in period 3
    Follow-up (FU) Phase PP3M Follow-up (FU) Phase PP6M
    Started
    42
    109
    Completed
    34
    78
    Not completed
    8
    31
         Physician decision
    -
    5
         Other
    3
    1
         Adverse event, non-fatal
    -
    4
         Consent withdrawn by subject
    5
    15
         Lost to follow-up
    -
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Open Label (OL) PP1M/PP3M (4 Months)
    Reporting group description
    Subjects previously treated with oral antipsychotics, or injectable risperidone, or a moderate or higher dose of PP1M with previous initiation but without previous stabilization (where stabilization was defined as at least 3 months of injections with the last 2 doses being the same strength) received 1 to 5 intramuscular (IM) injections of paliperidone palmitate 1-month (PP1M) 50 to 150 milligrams equivalent (mg eq.) to achieve stability during Open-label (OL) transition phase and to initiate the OL maintenance phase. Subjects received single dose of IM injections of PP1M as 100 or 150 mg eq. or paliperidone palmitate 3-month (PP3M) as 350 or 525 mg eq was administered during the OL-maintenance Phase. Open-label phase duration was of 4 Months (OL-transition of 1 month and OL-maintenance of 3 months).

    Reporting group values
    Open Label (OL) PP1M/PP3M (4 Months) Total
    Number of subjects
    838 838
    Title for AgeCategorical
    Units: subjects
        Children (2-11 years)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    822 822
        From 65 to 84 years
    16 16
        85 years and over
    0 0
    Title for AgeContinuous
    Units: years
        arithmetic mean (standard deviation)
    40.8 ± 11.68 -
    Title for Gender
    Units: subjects
        Female
    285 285
        Male
    553 553

    End points

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    End points reporting groups
    Reporting group title
    Open Label (OL) PP1M/PP3M (4 Months)
    Reporting group description
    Subjects previously treated with oral antipsychotics, or injectable risperidone, or a moderate or higher dose of PP1M with previous initiation but without previous stabilization (where stabilization was defined as at least 3 months of injections with the last 2 doses being the same strength) received 1 to 5 intramuscular (IM) injections of paliperidone palmitate 1-month (PP1M) 50 to 150 milligrams equivalent (mg eq.) to achieve stability during Open-label (OL) transition phase and to initiate the OL maintenance phase. Subjects received single dose of IM injections of PP1M as 100 or 150 mg eq. or paliperidone palmitate 3-month (PP3M) as 350 or 525 mg eq was administered during the OL-maintenance Phase. Open-label phase duration was of 4 Months (OL-transition of 1 month and OL-maintenance of 3 months).
    Reporting group title
    Double-blind (DB) PP3M
    Reporting group description
    Subjects received four doses of PP3M (350 or 525 mg eq.) IM injection for up to 12 months (one dose every 3 month) during DB phase.

    Reporting group title
    Double-blind (DB) PP6M
    Reporting group description
    Subjects received two doses of PP6M (700 or 1000 mg eq.) IM injection for 12 months (one dose every 6 months), during the DB Phase. To maintain blinding, subjects who were assigned to treatment with PP6M in this arm, received IM injections of matching placebo at the 3-month time points between their 6-month doses of PP6M drug.
    Reporting group title
    Follow-up (FU) Phase PP3M
    Reporting group description
    Subjects who have received at least 1 dose of PP3M (350 or 525 mg eq.) IM injection during double-blind phase but then have relapsed or have met other relevant conditions for withdrawal or discontinuation can participate in the Follow-up phase PP3M (350 or 525 mg eq.) IM injection for up to 12 months for evaluating efficacy and safety.

    Reporting group title
    Follow-up (FU) Phase PP6M
    Reporting group description
    Subjects who received PP6M (700 or 1000 mg eq.) IM injection for up to 12 months for evaluating efficacy and safety

    Primary: Time to Relapse During the Double-Blind (DB) Phase

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    End point title
    Time to Relapse During the Double-Blind (DB) Phase
    End point description
    Relapse: a) Psychiatric hospitalization; b) Positive and Negative Syndrome Scale (PANSS) total score: Increase of 25%,10point increase in PANSS for 2 analysis separated by 3-7 days if score was greater than (>) 40, less than equal to (=<)40 ; c) Subject inflicted knowing self-injury/shown violent behavior leading to suicide, clinically significant injury to him/herself or other person/property; d)Subject had suicidal/homicidal ideation/violent behavior that was clinically significant as per investigator; e) PANSS items P1- delusions,P2- conceptual disorganization, P3-hallucinatory behavior, P6- suspiciousness/ persecution, P7-hostility, G8-uncooperativeness: score: =>5, =>6 for 2 analysis separated by 3-7 days on any items if maximum score for PANSS:=<3 or 4, respectively. DB Intent-to-Treat (ITT) Analysis Set included subjects who were randomly assigned to PP6M/PP3M during DB Phase, received at least 1 dose of DB drug. Here,99999 refers that data is not collected for referred arm.
    End point type
    Primary
    End point timeframe
    At Month 12 of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    224
    478
    Units: Days
        median (confidence interval 95%)
    99999 (-99999 to +99999)
    99999 (-99999 to +99999)
    Statistical analysis title
    Statistical Analysis 1
    Comparison groups
    Double-blind (DB) PP6M v Double-blind (DB) PP3M
    Number of subjects included in analysis
    702
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority
    Method
    Parameter type
    Mean Percentage Difference
    Point estimate
    -2.9
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.8
         upper limit
    1.1

    Secondary: Changes From Baseline in the PANSS Total Score

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    End point title
    Changes From Baseline in the PANSS Total Score
    End point description
    The neuropsychiatric symptoms of schizophrenia were assessed using the 30-item PANSS scale, which provides a total score (sum of the scores for all 30 items) and scores for 3 subscales: the 7-item positive-symptom (P) subscale, the 7-item negative-symptom (N) subscale, and the 16-item general-psychopathology symptom (G) subscale. Each item is rated on a scale from 1 (absent) to 7 (extreme). The PANSS total score ranging from 30 (absent disease)-210 (more severe neuropsychiatric symptoms of schizophrenia). DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    220
    473
    Units: Units on a scale
        arithmetic mean (standard deviation)
    -1.6 ± 7.40
    -1.8 ± 8.92
    No statistical analyses for this end point

    Secondary: Changes From Baseline in the Clinical Global Impression – Severity (CGI-S) Total Score up to 12 Months of the DB Phase

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    End point title
    Changes From Baseline in the Clinical Global Impression – Severity (CGI-S) Total Score up to 12 Months of the DB Phase
    End point description
    The CGI-S total score is clinician rated and measures the clinical global impressions of severity of the subject’s psychosis on a 7-point scale, from “Not ill” to “Extremely Severe”. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    221
    475
    Units: Units on a scale
        arithmetic mean (standard deviation)
    0.0 ± 0.63
    0.0 ± 0.70
    No statistical analyses for this end point

    Secondary: Changes From Baseline in the Personal and Social Performance (PSP) Scale Total Score up to 12 Months of the DB Phase

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    End point title
    Changes From Baseline in the Personal and Social Performance (PSP) Scale Total Score up to 12 Months of the DB Phase
    End point description
    The PSP scale assesses the degree of dysfunction a subject exhibits within 4 domains of behavior: (a) socially useful activities, (b) personal and social relationships, (c) self-care, and (d) disturbing and aggressive behavior. The results of the assessment are converted to a numerical score from 1 to 100 points, functioning (91 to 100 points), good functioning (81 to 90 points), mild difficulties (71 to 80 points), etc, as shown in the Manual of Assessments. Scores from 31 to 70 points indicate varying degrees of difficulty, and scores below 30 points indicate functioning so poor that intensive support or supervision is needed. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    220
    473
    Units: Units on a scale
        arithmetic mean (standard deviation)
    1.1 ± 8.11
    1.0 ± 7.12
    No statistical analyses for this end point

    Secondary: Number of Subjects with Symptomatic Remission (SR) During the Double-Blind Phase (PANSS Total Score)

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    End point title
    Number of Subjects with Symptomatic Remission (SR) During the Double-Blind Phase (PANSS Total Score)
    End point description
    Achieving Remission: For single observations, transitory SE defined as simultaneous score of mild/less (≤3 points) on PANSS items: positive items P1,P2,P3; negative items N1 (blunted affect), N4 (social withdrawal), N6 (lack of spontaneity); general-psychopathology items G5 (mannerisms/ posturing),G9 (unusual thought content). For multiple observations, durable symptomatic remission is defined as meeting those remission criteria for a 6-month period. DB ITT included all subjects who were randomly assigned to treatment group of either PP6M or PP3M, received at least 1 dose of DB study drug.
    End point type
    Secondary
    End point timeframe
    12 months of DB-phase (up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    224
    478
    Units: Subjects
        number (not applicable)
    157
    317
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Satisfaction With Participants in Social Roles (SPSR) Total Score

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    End point title
    Change From Baseline in the Satisfaction With Participants in Social Roles (SPSR) Total Score
    End point description
    The Patient-Reported Outcomes Measurement Information System (PROMIS) group developed and evaluated the Satisfaction With Participation in Social Roles (SPSR) with funding from the US National Institutes of Health (NIH) and other academic and research grants. The SPSR asked subjects to consider the past 7 days and to rate 8 items on 5-point Likert scales, with higher scores representing higher satisfaction. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    70
    154
    Units: Units on a scale
        arithmetic mean (standard deviation)
    0.9 ± 7.15
    0.6 ± 6.58
    No statistical analyses for this end point

    Secondary: Changes From Baseline in the Treatment Satisfaction Questionnaire for Medication (TSQM-9) Score

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    End point title
    Changes From Baseline in the Treatment Satisfaction Questionnaire for Medication (TSQM-9) Score
    End point description
    The 9-item abbreviated treatment satisfaction questionnaire for medication (TSQM-9) was found to be a reliable and valid measure to assess treatment satisfaction in naturalistic study designs.5 Items are scored on 5- or 7-point Likert scales, with higher scores representing higher satisfaction. Subjects are asked to consider the time frame of the last 2 to 3 weeks, or since the last time the medication was used. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    121
    279
    Units: Units on a scale
        arithmetic mean (standard deviation)
    2.5 ± 19.29
    0.5 ± 20.02
    No statistical analyses for this end point

    Secondary: Changes From Baseline in the Simpson-Angus Rating Scale (SAS) Total Score

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    End point title
    Changes From Baseline in the Simpson-Angus Rating Scale (SAS) Total Score
    End point description
    The SAS rates 10 items for general extrapyramidal symptoms (EPS) on a 5-point scale from 0 (normal) to 4 (extreme), including gait, arm dropping, shoulder shaking, elbow rigidity, wrist rigidity, leg pendulousness, head rotation, Glabellar tap, tremor, and salivation. The SAS global score is the average score (total sum of item scores divided by the number of items) and ranges between 0 and 4. Negative change in score indicates improvement. Higher scores denote more severe condition of EPS. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    220
    477
    Units: Units on a scale
        median (full range (min-max))
    0.00 (-0.6 to 2.1)
    0.00 (-0.6 to 1.5)
    No statistical analyses for this end point

    Secondary: Number of Subjects With Symptoms of Akathisia Assesses Using Barnes Akathisia Rating Scale (BARS) Score

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    End point title
    Number of Subjects With Symptoms of Akathisia Assesses Using Barnes Akathisia Rating Scale (BARS) Score
    End point description
    The BARS assesses akathisia via 1 objective rating and 2 subjective ratings (awareness of restlessness and reported distress related to restlessness); each is scored from 0 to 3 points. It also assesses akathisia via 1 global clinical rating scored from 0 to 5 points. For all items, anchors are provided for each value and higher scores indicate worse akathisia. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    221
    477
    Units: Subjects
        Absent
    212
    451
        Questionable
    7
    19
        Mild Akathisia
    2
    6
        Moderate Akathisia
    0
    1
        Marked Akathisia
    0
    0
        Severe Akathisia
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Abnormal Involuntary Movement Scale (AIMS) Total Score

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    End point title
    Change From Baseline in the Abnormal Involuntary Movement Scale (AIMS) Total Score
    End point description
    Dyskinesia was assessed using the AIMS. The AIMS is included in the Early Clinical Development Evaluation Unit Assessment Manual from the United States National Institute of Mental Health (NIMH). The AIMS rates 9 items about dyskinesia on scale as 0 = none, 1 = minimal, 2 = mild, 3 = moderate, and 4 = severe. It rates 1 item about the subject's awareness of abnormal movements as 0 = no awareness; 1 = aware, no distress; 2 = aware, mild distress; 3 = aware, moderate distress; and 4 = aware, severe distress. It has 2 yes/no questions about dental status. Negative change in score indicates improvement. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    221
    477
    Units: Units on a scale
        median (full range (min-max))
    0.0 (-3 to 2)
    0.0 (-7 to 14)
    No statistical analyses for this end point

    Secondary: Number of Subjects Based on Columbia Suicide Severity Rating Scale (C-SSRS) Total Score

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    End point title
    Number of Subjects Based on Columbia Suicide Severity Rating Scale (C-SSRS) Total Score
    End point description
    The C-SSRS is a clinical interview which provides a summary of both ideation and behavior that can be administered during any evaluation or risk assessment to identify the level and type of suicidality present. It can also be used during treatment to monitor for clinical worsening. The C-SSRS Baseline Version assesses suicidal behavior and ideation over a lifetime, and the C-SSRS "since last visit" version assesses those parameters over an interval. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to endpoint (12 Months of DB Phase [Up to 16 months])
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    224
    478
    Units: Subjects
        Baseline (0 No event)
    221
    477
        Baseline (1 Wish to be dead)
    3
    0
        Baseline (2 Non-specific suicidal thought)
    0
    1
        Baseline (3 Suicidal ideation-no intent)
    0
    0
        Baseline (4 Ideation with intent, no plan)
    0
    0
        Baseline (5 Ideation with plan/intent)
    0
    0
        Baseline (6 Preparatory acts/behavior)
    0
    0
        Baseline (7 Aborted attempt)
    0
    0
        Baseline (8 Interrupted attempt)
    0
    0
        Baseline (9 Actual attempt)
    0
    0
        End Point (0 No event)
    218
    471
        End Point (1 Wish to be dead)
    1
    1
        End Point (2 Non-specific suicidal thought)
    0
    0
        End Point (3 Suicidal ideation-no intent)
    0
    1
        End Point (4 Ideation with intent, no plan)
    1
    0
        End Point (5 Ideation with plan/intent)
    1
    2
        End Point (6 Preparatory acts/behavior)
    0
    0
        End Point (7 Aborted attempt)
    0
    0
        End Point (8 Interrupted attempt)
    0
    0
        End Point (9 Actual attempt)
    0
    1
        End Point (10 Suicide)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-emergent Abnormal Electrocardiogram (ECG) Values During DB Phase

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    End point title
    Number of Subjects With Treatment-emergent Abnormal Electrocardiogram (ECG) Values During DB Phase
    End point description
    Number of subjects with clinically significant abnormalities in ECG measurements were reported. Double-blind Safety analysis set (DB Safety) includes all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the Double-blind Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint. Less than equal to (=<) and greater than equal to (>=).
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    220
    474
    Units: Subjects
        Heart Rate value =<50
    5
    9
        Heart Rate value =>100
    20
    36
        PR Duration value >= 210
    3
    8
        QRS Duration value =< 50
    0
    0
        QRS Duration value => 120
    1
    2
        QT Duration value =< 200
    0
    0
        QT Duration value => 500
    0
    0
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Body Weight During DB Phase

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    End point title
    Change From Baseline in the Body Weight During DB Phase
    End point description
    Change from baseline in body weight was reported. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    219
    473
    Units: Kilogram per meter^2 (kg/m^2)
        arithmetic mean (standard deviation)
    0.3 ± 1.78
    0.0 ± 1.72
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Waist Circumference During DB Phase

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    End point title
    Change From Baseline in the Waist Circumference During DB Phase
    End point description
    Change from baseline in Weight Circumference was reported. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    219
    473
    Units: Centimeter (cm)
        arithmetic mean (standard deviation)
    0.82 ± 5.137
    0.37 ± 5.157
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Weight During DB Phase

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    End point title
    Change From Baseline in the Weight During DB Phase
    End point description
    Change from baseline in weight was reported. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    219
    473
    Units: Kilogram (kg)
        arithmetic mean (standard deviation)
    0.96 ± 5.103
    0.10 ± 4.959
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Vital Signs (Pulse Rate) During DB Phase

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    End point title
    Change From Baseline in the Vital Signs (Pulse Rate) During DB Phase
    End point description
    Change from baseline vital signs (pulse rate) were reported. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    219
    473
    Units: beats/minute
    arithmetic mean (standard deviation)
        Supine Pulse Rate
    1.2 ± 11.57
    0.6 ± 11.56
        Standing Pulse Rate
    2.6 ± 12.28
    0.9 ± 12.60
        Pulse Rate(Standing-Supine)
    1.5 ± 8.85
    0.2 ± 8.31
    No statistical analyses for this end point

    Secondary: Change From Baseline in the Vital Signs (Systolic Blood pressure [SBP] and Diastolic Blood Pressure [DBP]) During DB Phase

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    End point title
    Change From Baseline in the Vital Signs (Systolic Blood pressure [SBP] and Diastolic Blood Pressure [DBP]) During DB Phase
    End point description
    Change from baseline vital signs including SBP and DBP (supine/standing) were reported. DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    219
    473
    Units: Millimetre of mercury (mmHg)
    arithmetic mean (standard deviation)
        Supine SBP
    -0.3 ± 13.14
    0.6 ± 9.96
        Standing SBP
    0.8 ± 12.08
    1.3 ± 10.40
        SBP (Standing-Supine)
    1.0 ± 9.83
    0.6 ± 7.32
        Supine DBP
    0.1 ± 9.25
    -0.4 ± 7.49
        Standing DBP
    0.3 ± 9.39
    0.4 ± 7.48
        DBP (Standing-Supine)
    0.2 ± 7.79
    0.7 ± 6.43
    No statistical analyses for this end point

    Secondary: Change From Baseline Positive and Negative Syndrome Scale (PANSS) Subscales During DB Phase

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    End point title
    Change From Baseline Positive and Negative Syndrome Scale (PANSS) Subscales During DB Phase
    End point description
    The neuropsychiatric symptoms of schizophrenia were assessed using the 30-item PANSS scale, which provides a total score (sum of the scores for all 30 items) and scores for 3 subscales: the 7-item positive-symptom (P) subscale, the 7-item negative-symptom (N) subscale, and the 16-item general-psychopathology symptom (G) subscale. Each item was rated on a scale from 1 (absent) to 7 (extreme). DB ITT Analysis Set included all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the DB Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint.
    End point type
    Secondary
    End point timeframe
    Baseline (DB) to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    220
    473
    Units: Units on a scale
    arithmetic mean (standard deviation)
        Positive Subscale Score
    -0.1 ± 2.82
    -0.1 ± 3.30
        Negative Subscale Score
    -0.6 ± 2.61
    -0.7 ± 2.70
        General Psychopathology Subscale Score
    -0.9 ± 4.18
    -1.0 ± 4.86
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Clinically Significant Abnormal Laboratory Values in Chemistry During DB Phase

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    End point title
    Number of Subjects With Treatment-Emergent Clinically Significant Abnormal Laboratory Values in Chemistry During DB Phase
    End point description
    Number of subjects with clinically significant abnormal laboratory values in chemistry included alanine aminotransferase, albumin, alkaline phosphatase, aspartate aminotransferase, bicarbonate, bilirubin, calcium, chloride, cholesterol, creatinine, gamma glutamyl transferase (GGT), glucose, high-density lipoproteins (HDL) cholesterol, low density lipoproteins (LDL) cholesterol, lactate dehydrogenase,phosphate, potassium, protein, sodium, triglycerides, urate, urea nitrogen were reported. Double-Blind Safety analysis set (DB Safety) includes all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the Double-blind Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint. Here 'n' (number analyzed) included all evaluable subjects who were analyzed at specified categories. Abnormally Low (ABL) and Abnormally High (ABH).
    End point type
    Secondary
    End point timeframe
    Up to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    216
    464
    Units: Subjects
        Alanine Aminotransferase (U/L) ABH (n= 216, 464)
    0
    1
        Albumin (g/L) ABL (n= 216, 464)
    0
    0
        Albumin (g/L) ABH (n= 216, 464)
    0
    0
        Alkaline Phosphatase (U/L) ABH (n= 216, 464)
    0
    0
        Aspartate Aminotransferase (U/L) ABH (n= 216, 464)
    0
    0
        Bicarbonate (mmol/L) ABL (n= 216, 461)
    0
    3
        Bicarbonate (mmol/L) ABH (n= 216, 461)
    0
    0
        Bilirubin (umol/L) ABH (n= 208, 447)
    0
    1
        Calcium (mmol/L) ABL (n= 216, 464)
    0
    0
        Calcium (mmol/L) ABH (n= 216, 464)
    0
    0
        Chloride (mmol/L) ABL (n= 216, 463)
    4
    5
        Chloride (mmol/L) ABH (n= 216, 463)
    0
    0
        Cholesterol (mmol/L) ABH (n= 216, 463)
    2
    4
        Creatinine (umol/L) ABH (n= 216, 464)
    0
    0
        Gamma Glutamyl Transferase (U/L) ABH (n= 216, 464)
    0
    2
        Glucose (mmol/L) ABL (n= 216, 464)
    1
    0
        Glucose (mmol/L) ABH (n= 216, 464)
    1
    5
        HDL Cholesterol (mmol/L) ABL (n= 216, 463)
    18
    40
        LDL Cholesterol (mmol/L) ABL (n= 216, 463)
    33
    44
        LDL Cholesterol (mmol/L) ABH (n= 216, 463)
    9
    22
        Lactate Dehydrogenase (U/L) ABH (n= 215, 456)
    0
    1
        Phosphate (mmol/L) ABL (n= 216, 464)
    1
    8
        Phosphate (mmol/L) ABH (n= 216, 464)
    0
    0
        Potassium (mmol/L) ABL (n= 216, 463)
    0
    0
        Potassium (mmol/L) ABH (n= 216, 463)
    0
    0
        Protein (g/L) ABL (n= 216, 464)
    0
    1
        Sodium (mmol/L) ABL (n= 216, 463)
    1
    0
        Sodium (mmol/L) ABH (n= 216, 463)
    0
    0
        Triglycerides (mmol/L) ABH (n= 216, 463)
    4
    6
        Urate (umol/L) ABL (n= 215, 463)
    0
    0
        Urate (umol/L) ABH (n= 215, 463)
    1
    4
        Urea Nitrogen (mmol/L) ABH (n= 215, 464)
    0
    0
    No statistical analyses for this end point

    Secondary: Number of Subjects With Treatment-Emergent Clinically Significant Abnormal Laboratory Values in Hematology During DB Phase

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    End point title
    Number of Subjects With Treatment-Emergent Clinically Significant Abnormal Laboratory Values in Hematology During DB Phase
    End point description
    Number of subjects with clinically significant abnormal laboratory values in hematology included hemoglobin (Hb), hematocrit (Hct), red blood cell (RBC) count, white blood cell (WBC) count with differential, platelets, hemoglobin A1c. Double-blind Safety analysis set (DB Safety) includes all subjects who were randomly assigned to treatment group of either PP6M or PP3M during the Double-blind Phase and received at least 1 dose of DB study drug. Here 'N' (number of subjects analyzed), included all subjects who were evaluable for this endpoint. Here 'n' (number analyzed) included all evaluable subjects who were analyzed at specified categories. Abnormally Low (ABL) and Abnormally High (ABH).
    End point type
    Secondary
    End point timeframe
    Up to 12 Months of DB Phase (Up to 16 months)
    End point values
    Double-blind (DB) PP3M Double-blind (DB) PP6M
    Number of subjects analysed
    215
    459
    Units: Subjects
        Basophils ABL (n=215,459)
    0
    0
        Eosinophils ABL (n=215,459)
    1
    1
        Erythrocytes ABL (n=215,459)
    1
    0
        Erythrocytes ABH (n=215,459)
    0
    0
        Hematocrit ABL (n=215,457)
    0
    1
        Hematocrit ABH (n=215,457)
    0
    0
        Hemoglobin (g/L) ABL (n=215,459)
    1
    0
        Hemoglobin (g/L) ABH (n=215,459)
    0
    0
        Leukocytes ABL (n=215,459)
    0
    0
        Leukocytes ABH (n=215,459)
    2
    4
        Lymphocytes ABL (n=215,459)
    0
    2
        Lymphocytes ABH (n=215,459)
    1
    1
        Monocytes ABH (n=215,459)
    0
    0
        Neutrophils ABL (n=215,459)
    1
    0
        Neutrophils ABH (n=215,459)
    0
    0
        Platelets ABL (n=214,458)
    0
    0
        Platelets ABH (n=214,458)
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 2.5 Years
    Adverse event reporting additional description
    OL Safety set included all subjects who received at least 1 dose of OL study drug (excluding the first study subjects if re-screened), both transition and maintenance phases. DB Safety set included all subjects who were randomly assigned to treatment group either PP6M or PP3M during DB Phase and received at least 1 dose of DB study drug.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    22.1
    Reporting groups
    Reporting group title
    Open Label (OL) PP1M/PP3M (4 Months)
    Reporting group description
    Subjects previously treated with oral antipsychotics, or injectable risperidone, or a moderate or higher dose of PP1M with previous initiation but without previous stabilization (where stabilization was defined as at least 3 months of injections with the last 2 doses being the same strength) received 1 to 5 intramuscular (IM) injections of paliperidone palmitate 1-month (PP1M) 50 to 150 milligrams equivalent (mg eq.) to achieve stability during Open-label (OL) transition phase and to initiate the OL maintenance phase. Subjects received single dose of IM injections of PP1M as 100 or 150 mg eq. or paliperidone palmitate 3-month (PP3M) as 350 or 525 mg eq was administered during the OL-maintenance Phase. Open-label phase duration was of 4 Months (OL-transition of 1 month and OL-maintenance of 3 months).

    Reporting group title
    Double-blind (DB) Phase PP3M
    Reporting group description
    Subjects received four doses of PP3M (350 or 525 mg eq.) IM injection for up to 12 months (one dose every 3 month) during DB phase.

    Reporting group title
    Double-blind (DB) Phase PP6M
    Reporting group description
    Subjects received two doses of PP6M (700 or 1000 mg eq.) IM injection for 12 months (one dose every 6 months), during the DB Phase. To maintain blinding, subjects who were assigned to treatment with PP6M in this arm, received IM injections of matching placebo at the 3-month time points between their 6-month doses of PP6M drug.

    Reporting group title
    Follow-up (FU) Phase PP3M
    Reporting group description
    Subjects who have received at least 1 dose of PP3M (350 or 525 mg eq.) IM injection during double-blind phase but then have relapsed or have met other relevant conditions for withdrawal or discontinuation can participate in the Follow-up phase PP3M (350 or 525 mg eq.) IM injection for up to 12 months for evaluating efficacy and safety.

    Reporting group title
    Follow-up (FU) Phase PP6M
    Reporting group description
    Subjects who received PP6M (700 or 1000 mg eq.) IM injection for up to 12 months for evaluating efficacy and safety

    Serious adverse events
    Open Label (OL) PP1M/PP3M (4 Months) Double-blind (DB) Phase PP3M Double-blind (DB) Phase PP6M Follow-up (FU) Phase PP3M Follow-up (FU) Phase PP6M
    Total subjects affected by serious adverse events
         subjects affected / exposed
    23 / 838 (2.74%)
    15 / 224 (6.70%)
    24 / 478 (5.02%)
    1 / 42 (2.38%)
    6 / 109 (5.50%)
         number of deaths (all causes)
    1
    2
    1
    0
    0
         number of deaths resulting from adverse events
    Vascular disorders
    Deep Vein Thrombosis
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Peripheral Artery Occlusion
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Mammoplasty
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Brain Neoplasm
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Lymphocytic Leukaemia
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Nasal Sinus Cancer
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Neoplasm Malignant
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion Spontaneous
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Death
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    Sudden Death
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute Psychosis
         subjects affected / exposed
    1 / 838 (0.12%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adjustment Disorder with Mixed Anxiety and Depressed Mood
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Adjustment Disorder with Mixed Disturbance of Emotion and Conduct
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Alcohol Withdrawal Syndrome
         subjects affected / exposed
    1 / 838 (0.12%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Behavioural Addiction
         subjects affected / exposed
    1 / 838 (0.12%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Completed Suicide
         subjects affected / exposed
    1 / 838 (0.12%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Depression
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hallucination, Auditory
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mental Disorder
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Mixed Anxiety and Depressive Disorder
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Panic Disorder
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic Disorder
         subjects affected / exposed
    3 / 838 (0.36%)
    2 / 224 (0.89%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 2
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychotic Symptom
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    6 / 838 (0.72%)
    1 / 224 (0.45%)
    8 / 478 (1.67%)
    0 / 42 (0.00%)
    2 / 109 (1.83%)
         occurrences causally related to treatment / all
    2 / 6
    0 / 1
    4 / 8
    0 / 0
    1 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal Ideation
         subjects affected / exposed
    3 / 838 (0.36%)
    2 / 224 (0.89%)
    1 / 478 (0.21%)
    1 / 42 (2.38%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    2 / 4
    1 / 2
    0 / 1
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide Attempt
         subjects affected / exposed
    2 / 838 (0.24%)
    0 / 224 (0.00%)
    2 / 478 (0.42%)
    0 / 42 (0.00%)
    1 / 109 (0.92%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    1 / 2
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Priapism
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Femur Fracture
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Limb Injury
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Radius Fracture
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial Fibrillation
         subjects affected / exposed
    1 / 838 (0.12%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Acute Respiratory Failure
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Chronic Obstructive Pulmonary Disease
         subjects affected / exposed
    2 / 838 (0.24%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 2
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Dyspnoea
         subjects affected / exposed
    1 / 838 (0.12%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary Embolism
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    Nervous system disorders
    Seizure
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal Obstruction
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholelithiasis
         subjects affected / exposed
    0 / 838 (0.00%)
    1 / 224 (0.45%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pelvi-Ureteric Obstruction
         subjects affected / exposed
    0 / 838 (0.00%)
    0 / 224 (0.00%)
    1 / 478 (0.21%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Rotator Cuff Syndrome
         subjects affected / exposed
    1 / 838 (0.12%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Infections and infestations
    Furuncle
         subjects affected / exposed
    1 / 838 (0.12%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 838 (0.12%)
    0 / 224 (0.00%)
    0 / 478 (0.00%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Open Label (OL) PP1M/PP3M (4 Months) Double-blind (DB) Phase PP3M Double-blind (DB) Phase PP6M Follow-up (FU) Phase PP3M Follow-up (FU) Phase PP6M
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    127 / 838 (15.16%)
    52 / 224 (23.21%)
    125 / 478 (26.15%)
    1 / 42 (2.38%)
    5 / 109 (4.59%)
    Investigations
    Weight Increased
         subjects affected / exposed
    8 / 838 (0.95%)
    17 / 224 (7.59%)
    40 / 478 (8.37%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences all number
    8
    17
    40
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    16 / 838 (1.91%)
    12 / 224 (5.36%)
    32 / 478 (6.69%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences all number
    25
    16
    61
    0
    0
    General disorders and administration site conditions
    Injection Site Pain
         subjects affected / exposed
    72 / 838 (8.59%)
    9 / 224 (4.02%)
    37 / 478 (7.74%)
    0 / 42 (0.00%)
    0 / 109 (0.00%)
         occurrences all number
    123
    10
    57
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    22 / 838 (2.63%)
    13 / 224 (5.80%)
    22 / 478 (4.60%)
    1 / 42 (2.38%)
    4 / 109 (3.67%)
         occurrences all number
    22
    16
    27
    1
    4
    Upper Respiratory Tract Infection
         subjects affected / exposed
    19 / 838 (2.27%)
    9 / 224 (4.02%)
    24 / 478 (5.02%)
    0 / 42 (0.00%)
    1 / 109 (0.92%)
         occurrences all number
    21
    9
    48
    0
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    21 Mar 2018
    a) Clarified text (1) on the version of Columbia Suicide Severity Rating Scale (C-SSRS) to be used at the screening and baseline visits, and all other visits; (2) vital signs to be collected every 3 months (Q3) during Double-blind (DB) Phase; (3) on the frequency of pre study Risperdal injections, and that subjects taking branded LAI of risperidone or paliperidone palmitate (PP) were permitted to enter the Transition Phase of the study. b) Added text (1) to maximize patient safety, exclude clinically unstable patients, and align with the R092670PSY3011 protocol; (2) to modify exclusion criterion #10 to minimize risk of fetal exposure to study drug; (3) to include risperidone 3 mg/day as a valid alternative at an equivalent dose in countries for which the paliperidone ER/prolonged-release (PR) formulations was not available; (3) to provide clearer guidance on timing of the end-of phase (EOP) visit; (4) to update Attachment 1 "Guidelines for the Intramuscular Injection of Paliperidone Palmitate or Placebo During the DB Phase" with clear instructions regarding the administration of injection; (5) to add exclusion criterion #26 excluding subjects with severe renal impairment per FDA request for clarification; (6) to add a formula to clarify the calculation of percent change of PANSS total score. c) Modified text (1) to remove renal insufficiency as part of exclusion criterion #7; (2) to limit participation in the Transition Phase to subjects taking INVEGA SUSTENNA or XEPLION PP1M formulations (3) to modify text to prevent the risk of unblinding study treatment while collecting prolactin samples for clinical laboratory testing; (4) to remove controlling stratification by the maintenance dose level in the primary efficacy analysis. Two hundred sixteen subjects were enrolled in the study under the original protocol and 464 subjects were enrolled under the first protocol amendment.
    28 Sep 2018
    a) Revised the number of pre-randomization injections of PP1M from a total of 6 (i.e., 5-month duration) to a total of 5 (i.e., 4-month duration) required before subjects were randomized to either PP3M or PP6M (paliperidone palmitate [PP] treatment group in the Double-blind Phase. This change was applied to subjects in the study’s Open-label phases being treated with PP1M after the PP3M pre-randomization target was met, since these subjects were randomized directly from PP1M treatment. b) Updated and clarified supporting text, figures, and tables for consistency and to correct conflicting portions of the protocol that inadvertently increased the minimum duration of PP1M treatment from 4 months to 5 months. c) Removed text related to optional salivary biomarkers research. Fourteen subjects were enrolled under the second global protocol amendment
    11 Feb 2019
    a) To align with the primary endpoint, the duration of the Double-blind Phase was limited to 12 months by eliminating the double-blind extension period. b) The estimated number of subjects entering the Transition/Maintenance Phases was increased from a target sample size of 765 to 840 to match dropout/enrollment rates and to meet the randomization target of 549 subjects in the Double-blind Phase. c) Modified Inclusion Criterion 11 to clarify the method of contraception in criterion 10 was applicable to female partners of male study subjects. d) Removed collection of blood biomarkers from the protocol. The third global amendment was implemented after all subjects had been enrolled.

    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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