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    Clinical Trial Results:
    Interventional, randomised, double-blind, active-controlled, fixed-dose study of Lu AF35700 in patients with Treatment-resistant Schizophrenia

    Summary
    EudraCT number
    		 2014-003569-12
    Trial protocol
    		 ES   EE   FI   CZ   SK   BG   PL  
    Global end of trial date
    08 Oct 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    21 Sep 2019
    First version publication date
    21 Sep 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    16159A Daybreak
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02717195
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    H. Lundbeck A/S
    Sponsor organisation address
    Ottiliavej 9, Valby, Denmark, 2500
    Public contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, 45 36301311, lundbeckClinicalTrials@lundbeck.com
    Scientific contact
    LundbeckClinicalTrials@lundbeck.com, H. Lundbeck A/S, 45 36301311, 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
    08 Oct 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2018
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of 10 and 20 mg/day of Lu AF35700 on schizophrenia symptoms in patients with treatment-resistant schizophrenia (TRS)
    Protection of trial subjects
    The trial was conducted in accordance with the Declaration of Helsinki (2013) and ICH Good Clinical Practice (1996)
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    15 Mar 2016
    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: 33
    Country: Number of subjects enrolled
    Romania: 3
    Country: Number of subjects enrolled
    Slovakia: 15
    Country: Number of subjects enrolled
    Spain: 5
    Country: Number of subjects enrolled
    Bulgaria: 140
    Country: Number of subjects enrolled
    Czech Republic: 14
    Country: Number of subjects enrolled
    Estonia: 17
    Country: Number of subjects enrolled
    Finland: 3
    Country: Number of subjects enrolled
    Canada: 5
    Country: Number of subjects enrolled
    Mexico: 106
    Country: Number of subjects enrolled
    Russian Federation: 190
    Country: Number of subjects enrolled
    Serbia: 72
    Country: Number of subjects enrolled
    Ukraine: 79
    Country: Number of subjects enrolled
    United States: 416
    Worldwide total number of subjects
    1098
    EEA total number of subjects
    230
    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)
    1073
    From 65 to 84 years
    25
    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
    Prospective Confirmation (PC) Period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Prospective Confirmation (PC) Period - Risperidone
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4-6 mg/day, encapsulated tablets, orally

    Arm title
    		 PC period - Olanzapine
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olanzapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15-20 mg/day, encapsulated tablets, orally

    Number of subjects in period 1
    		Prospective Confirmation (PC) Period - Risperidone PC period - Olanzapine
    Started
    711
    387
    Completed
    421
    276
    Not completed
    290
    111
         Sponsor requested
    -
    1
         Technical error
    1
    -
         Change of place of residence
    1
    -
         Apato Abulcasis syndrome
    -
    1
         Subject took exclusionary medication
    -
    1
         Did not fulfill rand criteria for DBT
    189
    75
         Patient fraud with payment
    1
    -
         Lack of results for blood levels
    1
    -
         Low level of drug in the blood
    1
    -
         Duplicate subject
    1
    -
         Consent withdrawn by subject
    43
    12
         Patient decision
    5
    2
         Adverse event, non-fatal
    19
    7
         non compliance with IMP
    7
    -
         Investigator decision
    2
    1
         Lost to follow-up
    9
    4
         Positive Urine Drug Screen
    -
    1
         Enrolled but not treated
    3
    3
         Sub-therapeutic levels blood levels of Olanzapin
    1
    -
         Non-compliance with IMP
    -
    1
         Lack of efficacy
    2
    1
         Protocol deviation
    3
    1
         Non compliance with protocol
    1
    -
    Period 2
    Period 2 title
    Double-blind Treatment (DBT) period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 DBT, Lu AF35700 10 mg
    Arm description
    		 Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks. Lu AF35700: 10 mg/day, encapsulated tablets, orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Lu AF35700 10 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lu AF35700: 10 mg/day, encapsulated tablets, orally

    Arm title
    		 DBT, Lu AF35700 20 mg
    Arm description
    		 Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks. Lu AF35700: 20 mg/day, encapsulated tablets, orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    DBT, Lu AF35700 20 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Lu AF35700: 20 mg/day, encapsulated tablets, orally

    Arm title
    		 DBT, Continued treatment from PC period
    Arm description
    		 Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period. Risperidone: 4-6 mg/day, encapsulated tablets, orally. Olanzapine: 15-20 mg/day, encapsulated tablets, orally
    Arm type
    		 Experimental

    Investigational medicinal product name
    Olanzapine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    15-20 mg/day, encapsulated tablets, orally

    Investigational medicinal product name
    Risperidone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    4-6 mg/day, encapsulated tablets, orally

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Patients are randomized at the start of Period 2, therefor period 2 can be seen as the baseline period, whereas period 1 is a lead-in period.
    Number of subjects in period 2 [2]
    		DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period
    Started
    235
    232
    230
    Completed
    198
    188
    200
    Not completed
    37
    44
    30
         Family circumstances
    -
    -
    1
         Change of place of residence
    -
    1
    1
         Patient missed required visits
    -
    1
    1
         Psychosocial issues
    1
    -
    -
         Needed antidepressant medication
    -
    -
    1
         Consent withdrawn by subject
    14
    13
    8
         Patient decision
    -
    2
    2
         Adverse event, non-fatal
    10
    11
    8
         Investigator decision
    -
    1
    1
         Lost to follow-up
    -
    3
    2
         Enrolled but not treated
    1
    -
    -
         Non-compliance with IMP
    4
    3
    2
         Lack of efficacy
    6
    9
    2
         Protocol deviation
    1
    -
    1
    Notes
    [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: It is correct that not all the patients that enrolled the study started the double bind treatment period which explains that the numbers are not the same.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DBT, Lu AF35700 10 mg
    Reporting group description
    		 Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks. Lu AF35700: 10 mg/day, encapsulated tablets, orally

    Reporting group title
    DBT, Lu AF35700 20 mg
    Reporting group description
    		 Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks. Lu AF35700: 20 mg/day, encapsulated tablets, orally

    Reporting group title
    DBT, Continued treatment from PC period
    Reporting group description
    		 Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period. Risperidone: 4-6 mg/day, encapsulated tablets, orally. Olanzapine: 15-20 mg/day, encapsulated tablets, orally

    Reporting group values
    		 DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period Total
    Number of subjects
    		 235 232 230 697
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 42.6 ± 12.14 42.3 ± 11.44 43.2 ± 11.19 -
    Gender categorical
    Units: Subjects
        Female
    		 91 94 89 274
        Male
    		 144 138 141 423
    Race
    Units: Subjects
        American Indian or Alaska Native
    		 0 1 0 1
        Asian
    		 1 0 1 2
        Native Hawaiian or Other Pacific Islander
    		 0 0 0 0
        Black or African American
    		 36 33 34 103
        White
    		 176 179 178 533
        More than one race
    		 0 0 0 0
        Unknown or Not Reported
    		 22 19 17 58
    PANNS total score
    Units: units on a scale
        arithmetic mean (standard deviation)
    		 96.96 ± 9.17 98.23 ± 9.29 98.40 ± 9.84 -

    End points

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    End points reporting groups
    Reporting group title
    Prospective Confirmation (PC) Period - Risperidone
    Reporting group description
    		 -

    Reporting group title
    PC period - Olanzapine
    Reporting group description
    		 -
    Reporting group title
    DBT, Lu AF35700 10 mg
    Reporting group description
    		 Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks. Lu AF35700: 10 mg/day, encapsulated tablets, orally

    Reporting group title
    DBT, Lu AF35700 20 mg
    Reporting group description
    		 Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period, 10 weeks. Lu AF35700: 20 mg/day, encapsulated tablets, orally

    Reporting group title
    DBT, Continued treatment from PC period
    Reporting group description
    		 Eligible patients from PC Period (based on criteria to which investigator and patient are blinded), will be randomly assigned (1:1:1) double-blind treatment in DBT Period,10 weeks. Patients in this arm will continue with same the treatment and dose as at last visit of PC Period. Risperidone: 4-6 mg/day, encapsulated tablets, orally. Olanzapine: 15-20 mg/day, encapsulated tablets, orally

    Primary: Change From Randomization to Week 10 in Positive and Negative Syndrome Scale (PANSS) Total Score

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    End point title
    		 Change From Randomization to Week 10 in Positive and Negative Syndrome Scale (PANSS) Total Score
    End point description
    Positive and Negative Syndrome Scale (PANSS) total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia.
    End point type
    Primary
    End point timeframe
    From Randomization to Week 10
    End point values
    		 DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period
    Number of subjects analysed
    201
    189
    202
    Units: units on a scale
        least squares mean (standard error)
    -10.01 ± 0.96
    -8.22 ± 0.98
    -9.90 ± 0.97
    Statistical analysis title
    		 Superiority Lu AF35700 10mg vs Continued Treatment
    Statistical analysis description
    Only patients randomized to receive double-blind treatment in the DBT Period are analyzed. Overall Number of Participants Analyzed is number of patients in the FAS with a week 10 observation.
    Comparison groups
    DBT, Lu AF35700 10 mg v DBT, Continued treatment from PC period
    Number of subjects included in analysis
    403
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.9196 [2]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.12
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.37
         upper limit
    		 2.13
    Notes
    [1] - The mean changes from Randomization in PANSS total score was analysed using a MMRM approach. The model included the fixed, categorical effects of treatment, country, week, treatment-by-week interaction, PC Period treatment, PC Period treatment-by-week interaction, and the continuous covariates of Randomization score and Randomization score-by-week interaction with an unstructured covariance structure to model the within-patient errors.
    [2] - Multiplicity adjustment was planned for the testing of the primary endpoint, but was not applied since all p-values > 0.05
    Statistical analysis title
    		 Superiority Lu AF35700 20mg vs Continued Treatment
    Statistical analysis description
    Only patients randomized to receive double-blind treatment in the DBT Period are analysed. Overall Number of Participants Analysed is number of patients in the FAS with a week 10 observation.
    Comparison groups
    DBT, Lu AF35700 20 mg v DBT, Continued treatment from PC period
    Number of subjects included in analysis
    391
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.1474 [4]
    Method
    		 Mixed Models Repeared Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.59
         upper limit
    		 3.94
    Notes
    [3] - The mean changes from Randomization in PANSS total score was analyzed using a MMRM approach. The model included the fixed, categorical effects of treatment, country, week, treatment-by-week interaction, PC Period treatment, PC Period treatment-by-week interaction, and the continuous covariates of Randomization score and Randomization score-by-week interaction with an unstructured covariance structure to model the within-patient errors.
    [4] - Multiplicity adjustment was planned for the testing of the primary endpoint, but was not applied since all p-values > 0.05

    Secondary: Change From Randomization to Week 10 in PSP Total Personal and Social Performance (PSP) Total Score

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    End point title
    		 Change From Randomization to Week 10 in PSP Total Personal and Social Performance (PSP) Total Score
    End point description
    PSP is a clinician-rated scale designed and validated to measure a patient’s current level of social functioning. It consists of 4 items: socially useful activities, personal and social relationships, self-care, and disturbing and aggressive behaviours. Each items were assessed on a 6-point scale, from 1 (absent) to 6 (very severe). PSP score was calculated as sum of all the items on the scale and ranged from 4 to 100. A higher score represents more severe functional impairment.
    End point type
    Secondary
    End point timeframe
    From Randomization to Week 10
    End point values
    		 DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period
    Number of subjects analysed
    204
    197
    203
    Units: units on a scale
        least squares mean (standard error)
    4.90 ± 0.96
    3.23 ± 0.98
    3.94 ± 0.98
    Statistical analysis title
    		 Lu AF35700 10 mg vs Continued Treatment
    Comparison groups
    DBT, Lu AF35700 10 mg v DBT, Continued treatment from PC period
    Number of subjects included in analysis
    407
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.2998 [6]
    Method
    		 Mixed Models Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.86
         upper limit
    		 2.78
    Notes
    [5] - The mean changes from Randomization in PSP score was analysed using a MMRM approach. The model included the fixed, categorical effects of treatment, country, week, treatment-by-week interaction, PC Period treatment, PC Period treatment-by-week interaction, and the continuous covariates of Randomization score and Randomization score-by-week interaction with an unstructured covariance structure to model the within-patient errors.
    [6] - Multiplicity adjustment was planned for the testing of the primary endpoint, but was not applied since all p-values > 0.05
    Statistical analysis title
    		 Lu AF35700 20 mg vs Continued Treatment
    Statistical analysis description
    The mean changes in PSP score was analysed using an MMRM approach. The model included the fixed, categorical effects of treatment , country, week, treatment-by-week interaction, PC Period treatment , PC Period treatment-by-week interaction, and the continuous covariates of Randomization score and Randomization score-by-week interaction with an unstructured covariance structure to model the within-patient errors.
    Comparison groups
    DBT, Lu AF35700 20 mg v DBT, Continued treatment from PC period
    Number of subjects included in analysis
    400
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.4478 [7]
    Method
    		 Mixed Model Repeated Measures
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.71
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.54
         upper limit
    		 1.12
    Notes
    [7] - Multiplicity adjustment was planned for the testing of the primary endpoint, but was not not applied since all p-values>0.05

    Secondary: Change From Randomization to Week 10 in Global Clinical Impression - Severity of Illness (CGI-S) Score

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    End point title
    		 Change From Randomization to Week 10 in Global Clinical Impression - Severity of Illness (CGI-S) Score
    End point description
    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). Higher scores indicate worsening.
    End point type
    Secondary
    End point timeframe
    From Randomization to Week 10
    End point values
    		 DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period
    Number of subjects analysed
    232
    231
    228
    Units: units on a scale
        least squares mean (standard error)
    -0.59 ± 0.06
    -0.54 ± 0.06
    -0.57 ± 0.06
    No statistical analyses for this end point

    Secondary: Response at Week 10, Defined as ≥20% Reduction in PANSS Total Score, PANSS (Positive and Negative Syndrome Scale) Total Score ≤70, CGI-S (Clinical Global Impression Scale - Severity of Illness) Score <4

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    End point title
    		 Response at Week 10, Defined as ≥20% Reduction in PANSS Total Score, PANSS (Positive and Negative Syndrome Scale) Total Score ≤70, CGI-S (Clinical Global Impression Scale - Severity of Illness) Score <4
    End point description
    PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement. The Clinical Global Impression scale - severity of illness (CGI-S) is administered by the investigator. The patient is rated on a 7-point scale ranging from 1 (Normal - not at all ill) to 7 (among the most extremely ill patients). A reduction in scale indicates improvement.
    End point type
    Secondary
    End point timeframe
    From Randomization to Week 10
    End point values
    		 DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period
    Number of subjects analysed
    201
    189
    202
    Units: participants
    21
    18
    12
    No statistical analyses for this end point

    Secondary: Response at Week 10, Defined as ≥20% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization

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    End point title
    		 Response at Week 10, Defined as ≥20% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization
    End point description
    PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.
    End point type
    Secondary
    End point timeframe
    From Randomization to Week 10
    End point values
    		 DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period
    Number of subjects analysed
    201
    189
    202
    Units: participants
    82
    59
    77
    No statistical analyses for this end point

    Secondary: Response at Week 10, Defined as ≥30% Reduction in PANSS Total Score From Randomization

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    End point title
    		 Response at Week 10, Defined as ≥30% Reduction in PANSS Total Score From Randomization
    End point description
    Positive and Negative Syndrome Scale (PANSS) total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.
    End point type
    Secondary
    End point timeframe
    From Randomization to Week 10
    End point values
    		 DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period
    Number of subjects analysed
    201
    189
    202
    Units: participants
    42
    30
    45
    No statistical analyses for this end point

    Secondary: Response at Week 10, Defined as ≥40% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization

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    End point title
    		 Response at Week 10, Defined as ≥40% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization
    End point description
    PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.
    End point type
    Secondary
    End point timeframe
    From Randomization to Week 10
    End point values
    		 DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period
    Number of subjects analysed
    201
    189
    202
    Units: participants
    23
    15
    16
    No statistical analyses for this end point

    Secondary: Response at Week 10, Defined as ≥50% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization

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    End point title
    		 Response at Week 10, Defined as ≥50% Reduction in Positive and Negative Syndrome Scale (PANSS) Total Score From Randomization
    End point description
    PANSS total score administered by the investigator. It included 3 sub-scales with a total of 30 items that evaluated the Positive Symptoms subscale, the Negative Symptoms subscale, the General Psychopathology subscale. Each item is rated from 1 (symptom not present) to 7 (symptom extremely severe). PANSS total score was calculated as sum of all the items on the scale and ranged from 30 to 210. A higher score corresponded to a worse severity of schizophrenia. A reduction in score indicates improvement.
    End point type
    Secondary
    End point timeframe
    From Randomization to Week 10
    End point values
    		 DBT, Lu AF35700 10 mg DBT, Lu AF35700 20 mg DBT, Continued treatment from PC period
    Number of subjects analysed
    201
    189
    202
    Units: participants
    10
    4
    6
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    22 weeks
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Prospective Confirmation (PC) Period - Risperidone
    Reporting group description
    		 -

    Reporting group title
    PC period - Olanzapine
    Reporting group description
    		 -

    Reporting group title
    DBT Lu AF35700, 10 mg
    Reporting group description
    		 -

    Reporting group title
    DBT Lu AF35700, 20 mg
    Reporting group description
    		 -

    Reporting group title
    DBT period, continued treatment from PC period
    Reporting group description
    		 -

    Serious adverse events
    		 Prospective Confirmation (PC) Period - Risperidone PC period - Olanzapine DBT Lu AF35700, 10 mg DBT Lu AF35700, 20 mg DBT period, continued treatment from PC period
    Total subjects affected by serious adverse events
         subjects affected / exposed
    14 / 708 (1.98%)
    7 / 384 (1.82%)
    6 / 234 (2.56%)
    5 / 232 (2.16%)
    5 / 230 (2.17%)
         number of deaths (all causes)
    0
    0
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    0
    1
    Investigations
    Electrocardiogram abnormal
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    0 / 234 (0.00%)
    1 / 232 (0.43%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Intentional overdose
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Vascular disorders
    Hypertensive emergency
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    1 / 234 (0.43%)
    0 / 232 (0.00%)
    0 / 230 (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
    Myocardial infarction
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    1 / 234 (0.43%)
    0 / 232 (0.00%)
    0 / 230 (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
    Sinus tachycardia
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    1 / 234 (0.43%)
    0 / 232 (0.00%)
    0 / 230 (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
    Surgical and medical procedures
    Psychosocial support
         subjects affected / exposed
    1 / 708 (0.14%)
    0 / 384 (0.00%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    0 / 230 (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
    Nervous system disorders
    Multiple sclerosis
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    1 / 230 (0.43%)
         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
    Presyncope
         subjects affected / exposed
    0 / 708 (0.00%)
    1 / 384 (0.26%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
    0 / 0
    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
    Vascular stent thrombosis
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    1 / 234 (0.43%)
    0 / 232 (0.00%)
    0 / 230 (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
    Social circumstances
    Social stay hospitalisation
         subjects affected / exposed
    1 / 708 (0.14%)
    1 / 384 (0.26%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    1 / 234 (0.43%)
    0 / 232 (0.00%)
    0 / 230 (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
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    0 / 234 (0.00%)
    1 / 232 (0.43%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 708 (0.14%)
    0 / 384 (0.00%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    0 / 230 (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
    Pulmonary thrombosis
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    1 / 230 (0.43%)
         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 / 1
    Psychiatric disorders
    Acute psychosis
         subjects affected / exposed
    1 / 708 (0.14%)
    0 / 384 (0.00%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    0 / 230 (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
    Hallucination
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    1 / 234 (0.43%)
    0 / 232 (0.00%)
    0 / 230 (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
    Paranoia
         subjects affected / exposed
    2 / 708 (0.28%)
    1 / 384 (0.26%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 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
    Psychotic disorder
         subjects affected / exposed
    1 / 708 (0.14%)
    1 / 384 (0.26%)
    0 / 234 (0.00%)
    1 / 232 (0.43%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
    0 / 0
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Schizophrenia
         subjects affected / exposed
    5 / 708 (0.71%)
    1 / 384 (0.26%)
    1 / 234 (0.43%)
    2 / 232 (0.86%)
    2 / 230 (0.87%)
         occurrences causally related to treatment / all
    1 / 5
    0 / 2
    0 / 1
    0 / 2
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    2 / 708 (0.28%)
    1 / 384 (0.26%)
    2 / 234 (0.85%)
    0 / 232 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    2 / 3
    0 / 1
    1 / 2
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 708 (0.00%)
    0 / 384 (0.00%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    1 / 230 (0.43%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Type 2 diabetes mellitus
         subjects affected / exposed
    0 / 708 (0.00%)
    1 / 384 (0.26%)
    0 / 234 (0.00%)
    0 / 232 (0.00%)
    0 / 230 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    3 / 3
    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
    		 Prospective Confirmation (PC) Period - Risperidone PC period - Olanzapine DBT Lu AF35700, 10 mg DBT Lu AF35700, 20 mg DBT period, continued treatment from PC period
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    60 / 708 (8.47%)
    45 / 384 (11.72%)
    20 / 234 (8.55%)
    40 / 232 (17.24%)
    25 / 230 (10.87%)
    Investigations
    Weight increased
         subjects affected / exposed
    5 / 708 (0.71%)
    1 / 384 (0.26%)
    8 / 234 (3.42%)
    19 / 232 (8.19%)
    11 / 230 (4.78%)
         occurrences all number
    5
    1
    8
    19
    11
    Nervous system disorders
    Akathisia
         subjects affected / exposed
    36 / 708 (5.08%)
    8 / 384 (2.08%)
    3 / 234 (1.28%)
    5 / 232 (2.16%)
    4 / 230 (1.74%)
         occurrences all number
    37
    8
    4
    5
    4
    Headache
         subjects affected / exposed
    24 / 708 (3.39%)
    16 / 384 (4.17%)
    11 / 234 (4.70%)
    15 / 232 (6.47%)
    10 / 230 (4.35%)
         occurrences all number
    25
    18
    12
    16
    11
    Somnolence
         subjects affected / exposed
    34 / 708 (4.80%)
    30 / 384 (7.81%)
    3 / 234 (1.28%)
    9 / 232 (3.88%)
    4 / 230 (1.74%)
         occurrences all number
    35
    31
    3
    9
    4

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    13 May 2016
    PA1: A urine dipstick pregnancy test at Baseline was added. Definition of a completer was changed to: “a subject who has completed the treatment period including any following follow up activities is considered to have completed the study”. Ethics: text was changed to ensure that only patients who were able to consent for themselves were included in the study. Treatment regimen: wording was clarified on how switch should occur to avoid accidental overdosing. Post-study access to IMP(s): information regarding extension Study 16159B was added. Safety follow-up Visit (Visit 13): error corrected; it was specified that AEs ongoing after the end of the treatment period will be followed up at the Safety Follow-up Visit, and that no new non SAEs will be captured after the end of the treatment period. Error corrected; B basophils added to Panel 3. Genotyping: update in according with the analysis kit used by Covance Department of Genomics. Additional alleles added for test.
    30 Sep 2016
    PA2: Study population: the period for treatment with an adequate (previously same) antipsychotic dose prior to screening has been reduced from 6 weeks to 2 weeks. Exclusion Criterion 13: guidance added for evaluation of treatment improvement in the last 2 years prior to Screening. CYP1A2 inhibitors were added as concomitant medication not permitted during the study.
    04 Oct 2016
    PA3: It was added that the analysis of PK assessments in the DBT Period will also include Lu AF36152, risperidone, 9 OH risperidone, and olanzapine. Exclusion criterion 25: the criterion defining unstable co-morbid diabetes were changed to reflect the disease in a patient with schizophrenia. Exclusion criterion 26 was deleted; patients with schizophrenia who meet the laboratory test criteria for co-morbid diabetes will not be excluded from participating in the study. Treatment regimen: time of dosing at each visit, including changing in dosing times, was more clearly defined. Assessments: complete description of questionnaires used for assessment of the PANSS (PANSS informant data is specified). It was specified that prolactin test results 250 g / L must be followed up. Limiting of re-sampling. Statistical Methodology: analysis of subgroups was added.

    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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