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    Clinical Trial Results:
    Interventional, randomised, double-blind, parallel-group, placebo-controlled, flexible-dose study of brexpiprazole as adjunctive treatment to paroxetine or sertraline in adult patients suffering from post-traumatic stress disorder (PTSD)

    Summary
    EudraCT number
    		 2012-004982-41
    Trial protocol
    		 EE   IT   FI   SE   PL  
    Global end of trial date
    30 Oct 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Nov 2016
    First version publication date
    12 Nov 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14865A
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01987960
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    H. Lundbeck A/S
    Sponsor organisation address
    Ottiliavej 9, Valby, Denmark, 2200
    Public contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, LundbeckClinicalTrials@lundbeck.com
    Scientific contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, LundbeckClinicalTrials@lundbeck.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
    30 Oct 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Oct 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Oct 2015
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of brexpiprazole up to 1-3 mg/day as adjunctive treatment to paroxetine or sertraline on PTSD symptoms
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2008) and ICH Good Clinical Practice (1996)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    12 Dec 2013
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 51
    Country: Number of subjects enrolled
    Sweden: 21
    Country: Number of subjects enrolled
    Finland: 41
    Country: Number of subjects enrolled
    France: 8
    Country: Number of subjects enrolled
    Italy: 6
    Country: Number of subjects enrolled
    United States: 186
    Country: Number of subjects enrolled
    South Africa: 27
    Country: Number of subjects enrolled
    Estonia: 19
    Country: Number of subjects enrolled
    Mexico: 19
    Country: Number of subjects enrolled
    Serbia: 25
    Country: Number of subjects enrolled
    Argentina: 14
    Worldwide total number of subjects
    417
    EEA total number of subjects
    146
    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)
    415
    From 65 to 84 years
    2
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects who met each of the inclusion and none of the exclusion criteria were eligible to participate in the study

    Period 1
    Period 1 title
    Period 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Arm title
    		 Placebo and PAR/SER
    Arm description
    		 Placebo adjunct to open-label treatment with a commercially available approved treatment for PTSD (Paroxetine/Sertraline (PAR/SER))
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily, tablets, orally

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 or 100mg/day; tablets, orally; The dose of sertraline was increased from 50mg/day to 150mg/day during the first 2 weeks. Further dose increase to 200mg/day was allowed until the Week 4 Visit. In case of tolerability issues, the dose could be decreased to 100, 150, or 200mg/day until the Week 8 Visit in steps of 50mg/day per week

    Investigational medicinal product name
    Paroxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 or 30mg/day; tablets, orally; From 20mg/day to 30mg/day during the first week. Further dose increase to 40mg/day was allowed until the Week 4 Visit. In case of tolerability issues, the dose could be decreased to 20 or 30 mg/day until the Week 8 Visit in steps of 10mg/day per week.

    Number of subjects in period 1
    		Placebo and PAR/SER
    Started
    417
    Completed
    231
    Not completed
    186
         non-compliance with IMP
    6
         Consent withdrawn by subject
    21
         Withdrawal of consent before treatmnet
    4
         Adverse event, non-fatal
    24
         aministrative or other reason
    75
         Lost to follow-up
    40
         Lack of efficacy
    4
         Protocol deviation
    12
    Period 2
    Period 2 title
    Period 2
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo and PAR/SER
    Arm description
    		 Randomized placebo adjunct to open-label treatment with a commercially available approved treatment for PTSD (PAR/SER)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily, tablets, orally

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 or 100mg/day; tablets, orally; The dose of sertraline was increased from 50mg/day to 150mg/day during the first 2 weeks. Further dose increase to 200mg/day was allowed until the Week 4 Visit. In case of tolerability issues, the dose could be decreased to 100, 150, or 200mg/day until the Week 8 Visit in steps of 50mg/day per week

    Investigational medicinal product name
    Paroxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 or 30mg/day; tablets, orally; From 20mg/day to 30mg/day during the first week. Further dose increase to 40mg/day was allowed until the Week 4 Visit. In case of tolerability issues, the dose could be decreased to 20 or 30 mg/day until the Week 8 Visit in steps of 10mg/day per week.

    Arm title
    		 Brexpiprazole and PAR/SER
    Arm description
    		 Randomized brexpiprazole adjunct to open-label treatment with a commercially available approved treatment for PTSD (PAR/SER)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Brexpiprazole
    Investigational medicinal product code
    Other name
    Rexulti
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1mg/day for one week, followed by 2mg/day for 3 weeks. Thereafter the dose was flexible and could be adjusted from 1 to 3 mg/day.

    Investigational medicinal product name
    Paroxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 or 30mg/day; tablets, orally; From 20mg/day to 30mg/day during the first week. Further dose increase to 40mg/day was allowed until the Week 4 Visit. In case of tolerability issues, the dose could be decreased to 20 or 30 mg/day until the Week 8 Visit in steps of 10mg/day per week.

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 or 100mg/day; tablets, orally; The dose of sertraline was increased from 50mg/day to 150mg/day during the first 2 weeks. Further dose increase to 200mg/day was allowed until the Week 4 Visit. In case of tolerability issues, the dose could be decreased to 100, 150, or 200mg/day until the Week 8 Visit in steps of 50mg/day per week

    Arm title
    		 Placebo and PAR/SER
    Arm description
    		 Continuation of treatment with placebo adjunct to open-label treatment with a commercially available approved treatment for PTSD (PAR/SER) from Period 1
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Once daily, tablets, orally

    Investigational medicinal product name
    Paroxetine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    20 or 30mg/day; tablets, orally; From 20mg/day to 30mg/day during the first week. Further dose increase to 40mg/day was allowed until the Week 4 Visit. In case of tolerability issues, the dose could be decreased to 20 or 30 mg/day until the Week 8 Visit in steps of 10mg/day per week.

    Investigational medicinal product name
    Sertraline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    50 or 100mg/day; tablets, orally; The dose of sertraline was increased from 50mg/day to 150mg/day during the first 2 weeks. Further dose increase to 200mg/day was allowed until the Week 4 Visit. In case of tolerability issues, the dose could be decreased to 100, 150, or 200mg/day until the Week 8 Visit in steps of 50mg/day per week

    Number of subjects in period 2 [1]
    		Placebo and PAR/SER Brexpiprazole and PAR/SER Placebo and PAR/SER
    Started
    17
    23
    190
    Completed
    12
    14
    119
    Not completed
    5
    9
    71
         non-compliance with IMP
    -
    -
    1
         Consent withdrawn by subject
    -
    1
    9
         Adverse event, non-fatal
    -
    1
    7
         Administrative or other reason
    5
    7
    43
         Lost to follow-up
    -
    -
    5
         Protocol deviation
    -
    -
    6
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: 1 patient completed period 1, but didn't receive treatment in period 2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo and PAR/SER
    Reporting group description
    		 Placebo adjunct to open-label treatment with a commercially available approved treatment for PTSD (Paroxetine/Sertraline (PAR/SER))

    Reporting group values
    		 Placebo and PAR/SER Total
    Number of subjects
    		 417 417
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 417 417
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.53 ± 11.62 -
    Gender categorical
    Units: Subjects
        Female
    		 255 255
        Male
    		 162 162
    Subject analysis sets

    Subject analysis set title
    Period 2: Placebo adjunct to open-label treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Period 2: Placebo adjunct to open-label treatment

    Subject analysis set title
    Period 2: Brexpiprazole adjunct to open-label treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Period 2: Brexpiprazole adjunct to open-label treatment

    Subject analysis sets values
    		 Period 2: Placebo adjunct to open-label treatment Period 2: Brexpiprazole adjunct to open-label treatment
    Number of subjects
    17
    23
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    17
    23
        From 65-84 years
    0
    0
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    42.9 ± 11.8
    47.6 ± 10.4
    Gender categorical
    Units: Subjects
        Female
    10
    11
        Male
    7
    12

    End points

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    End points reporting groups
    Reporting group title
    Placebo and PAR/SER
    Reporting group description
    		 Placebo adjunct to open-label treatment with a commercially available approved treatment for PTSD (Paroxetine/Sertraline (PAR/SER))
    Reporting group title
    Placebo and PAR/SER
    Reporting group description
    		 Randomized placebo adjunct to open-label treatment with a commercially available approved treatment for PTSD (PAR/SER)

    Reporting group title
    Brexpiprazole and PAR/SER
    Reporting group description
    		 Randomized brexpiprazole adjunct to open-label treatment with a commercially available approved treatment for PTSD (PAR/SER)

    Reporting group title
    Placebo and PAR/SER
    Reporting group description
    		 Continuation of treatment with placebo adjunct to open-label treatment with a commercially available approved treatment for PTSD (PAR/SER) from Period 1

    Subject analysis set title
    Period 2: Placebo adjunct to open-label treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Period 2: Placebo adjunct to open-label treatment

    Subject analysis set title
    Period 2: Brexpiprazole adjunct to open-label treatment
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Period 2: Brexpiprazole adjunct to open-label treatment

    Primary: Change From Randomisation in PTSD Symptoms Using CAPS-2 Total Score

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    End point title
    		 Change From Randomisation in PTSD Symptoms Using CAPS-2 Total Score [1]
    End point description
    Clinician-Administered PTSD Scale Part 2 (CAPS-2): 17 items in criteria B, C and D (Corresponding to CAPS-2) will be administered to provide a total score. They are rated on a 5 point scale for frequency from 0 (never or none) to 4 (daily or almost every day), and intensity from 0 (none) to 4 (extreme). The sum of the 17 items gives a toal score ranging from 0 to 136, with a higher score indicating greater symptom severity
    End point type
    Primary
    End point timeframe
    Baseline and Week 28
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Due to the low number of enrolled patients eligible for randomization and the sponsor's early termination of the study, the primary and secondary efficacy endpoints were not evaluated
    End point values
    		 Period 2: Placebo adjunct to open-label treatment Period 2: Brexpiprazole adjunct to open-label treatment
    Number of subjects analysed
    0 [2]
    0 [3]
    Units: score
        number (not applicable)
    Notes
    [2] - Endpoints were not evaluated see "limitation section"
    [3] - Endpoints were not evaluated see "limitation section"
    No statistical analyses for this end point

    Secondary: Change From Randomisation in Global Clinical Impression Using CGI-S Score

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    End point title
    		 Change From Randomisation in Global Clinical Impression Using CGI-S Score
    End point description
    Clinical Global Impression - Severity of Illness (CGI-S) The CGI-S provides the clinician’s impression of the patient’s current state of mental illness. The clinician uses his or her clinical experience of this patient population to rate the severity of the patient’s current mental illness on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients).
    End point type
    Secondary
    End point timeframe
    Baseline and Week 28
    End point values
    		 Period 2: Placebo adjunct to open-label treatment Period 2: Brexpiprazole adjunct to open-label treatment
    Number of subjects analysed
    0 [4]
    0 [5]
    Units: score
        number (not applicable)
    Notes
    [4] - Endpoints were not evaluated see "limitation section"
    [5] - Endpoints were not evaluated see "limitation section"
    No statistical analyses for this end point

    Secondary: Change From Randomisation in Functioning Using SDS Score

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    End point title
    		 Change From Randomisation in Functioning Using SDS Score
    End point description
    Sheehan Disability Scale (SDS) The SDS is a series of patient self-rated, 10-point visual analogue scales designed to measure the extent to which the patient’s life is impaired by panic, anxiety, phobic or depressive symptoms. There are verbal descriptors for the points on the scales as well as numerical scores that provide more precise levels of the verbal descriptors. The patient rates the extent to which his or her 1) work, 2) social life or leisure activities, and 3) home life or family responsibilities are impaired by his or her symptoms, with a higher score indicating greater symptom severity
    End point type
    Secondary
    End point timeframe
    Baseline and Week 28
    End point values
    		 Period 2: Placebo adjunct to open-label treatment Period 2: Brexpiprazole adjunct to open-label treatment
    Number of subjects analysed
    0 [6]
    0 [7]
    Units: Score
        number (not applicable)
    Notes
    [6] - Endpoints were not evaluated see "limitation section"
    [7] - Endpoints were not evaluated see "limitation section"
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    First dose to follow-up
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    16.1
    Reporting groups
    Reporting group title
    Placebo adjunct to open-label treatment
    Reporting group description
    		 Placebo + PAR/SER

    Reporting group title
    Brexpiprazole adjunct to open-label treatment
    Reporting group description
    		 Brex + PAR/SER

    Serious adverse events
    		 Placebo adjunct to open-label treatment Brexpiprazole adjunct to open-label treatment
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 17 (0.00%)
    0 / 23 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Placebo adjunct to open-label treatment Brexpiprazole adjunct to open-label treatment
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    8 / 17 (47.06%)
    3 / 23 (13.04%)
    Injury, poisoning and procedural complications
    Accidental overdose
         subjects affected / exposed
    1 / 17 (5.88%)
    2 / 23 (8.70%)
         occurrences all number
    1
    3
    Tendon rupture
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Eye disorders
    Conjunctivitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Reproductive system and breast disorders
    Galactorrhoea
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Hyperhidrosis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 17 (5.88%)
    1 / 23 (4.35%)
         occurrences all number
    1
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0
    Metabolism and nutrition disorders
    Hypercholesterolaemia
         subjects affected / exposed
    1 / 17 (5.88%)
    0 / 23 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    27 Aug 2015
    The study was terminated 27th of August 2015 due to challenges with patient eligibility; the decision to terminate was not based on any safety concerns. Last patient last visit was 30th of October 2015 (the date of last protocol-specified contact with any patient)
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    As the study was terminated limited efficacy and safety data were collected from the randomized patients. As a result no efficacy analyses were performed in accordance with the ICH E3 and thus not reported in the abbreviated clinical study report.
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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