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    Clinical Trial Results:
    A Phase II, 8-week-treatment, multicenter, randomized, double-blind, placebo-controlled, parallel group trial to evaluate the efficacy, tolerability and safety of orally administered BI 1358894 in patients with Post-Traumatic Stress Disorder (PTSD)

    Summary
    EudraCT number
    		 2021-003154-23
    Trial protocol
    		 SE   FI   PL   HR  
    Global end of trial date
    20 Nov 2023

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Dec 2024
    First version publication date
    01 Dec 2024
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    1402-0030
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT05103657
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Boehringer Ingelheim
    Sponsor organisation address
    Binger Strasse 173, Ingelheim am Rhein, Germany, 55216
    Public contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Scientific contact
    Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    16 Nov 2023
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Oct 2023
    Global end of trial reached?
    Yes
    Global end of trial date
    20 Nov 2023
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of this trial was to provide proof of concept (PoC) of orally administered BI 1358894 125 mg after eight weeks treatment in patients with PTSD compared to placebo.
    Protection of trial subjects
    A log of all patients enrolled into the trial (i.e. who have signed informed consent) was maintained in the Investigator Site File (ISF) irrespective of whether they had been treated with investigational drug or not. If retrospectively it was found that a patient has been randomized in error (=did not meet all inclusion criteria or met one or more exclusion criteria), the sponsor or delegate was to be contacted immediately. Based on an individual benefit-risk assessment a decision was to be made whether continued trial participation is possible or not. After premature trial drug discontinuation, patients were asked to further attend scheduled trial visits unless they withdrew consent to participate in the trial. The importance of continuing trial participation and the value of collecting data for all randomized patients was explained to the patients. Measures to control the withdrawal rate included careful patient selection, appropriate explanation of the trial requirements and procedures prior to trial enrolment, as well as the explanation of the options for early discontinuation and explanation of the consequences in case of withdrawals. The decision to discontinue trial treatment or withdraw consent to trial participation and the reason had to be documented in the patient files and case report form (CRF). If applicable, the requirements for adverse event (AE) collection reporting had to be consider. If new efficacy/safety information became available, Boehringer Ingelheim (BI) was to review the benefit-riskassessment and, if needed, pause or discontinue the trial treatment for all patients or take any other appropriate action to ensure the safety of the trial patients. Even if the trial treatment was discontinued, the patients remained in the trial and, given their agreement, were to undergo the procedures for early treatment discontinuation and follow-up as outlined in the flow charts.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    22 Dec 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Croatia: 31
    Country: Number of subjects enrolled
    Finland: 8
    Country: Number of subjects enrolled
    Germany: 43
    Country: Number of subjects enrolled
    Israel: 2
    Country: Number of subjects enrolled
    Mexico: 33
    Country: Number of subjects enrolled
    Poland: 21
    Country: Number of subjects enrolled
    Sweden: 19
    Country: Number of subjects enrolled
    United States: 516
    Worldwide total number of subjects
    673
    EEA total number of subjects
    122
    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)
    668
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a Phase II, 8-week-treatment, multicentre, randomised, double blind, placebocontrolled, parallel-group trial in patients with Post-Traumatic Stress Disorder (PTSD).

    Pre-assignment
    Screening details
    		 All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

    Period 1
    Period 1 title
    Randomised period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Investigator, Monitor, Carer, Subject, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients received orally, once daily for 8 consecutive weeks film-coated tablets of placebo matching BI 1358894. Placebo matching BI 1358894 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 BI 1358894 125 mg
    Arm description
    		 Patients received orally, once daily for 8 consecutive weeks 125 milligrams (mg) of BI 1358894. The dosage of 125 milligrams consisted of two film-coated tablets of 50 mg and 1 film-coated tablet of 25 mg. BI 135889 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		Placebo BI 1358894 125 mg
    Started
    160
    158
    Completed
    159
    157
    Not completed
    1
    1
         Not Treated
    1
    1
    Period 2
    Period 2 title
    Treatment period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Patients received orally, once daily for 8 consecutive weeks film-coated tablets of placebo matching BI 1358894. Placebo matching BI 1358894 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo matching BI 1358894
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received orally, once daily for 8 consecutive weeks film-coated tablets of placebo matching BI 1358894. Placebo matching BI 1358894 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.

    Arm title
    		 BI 1358894 125 mg
    Arm description
    		 Patients received orally, once daily for 8 consecutive weeks 125 milligrams (mg) of BI 1358894. The dosage of 125 milligrams consisted of two film-coated tablets of 50 mg and 1 film-coated tablet of 25 mg. BI 135889 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.
    Arm type
    		 Experimental

    Investigational medicinal product name
    BI 1358894
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received orally, once daily for 8 consecutive weeks 125 milligrams (mg) of BI 1358894. The dosage of 125 milligrams consisted of two film-coated tablets of 50 mg and 1 film-coated tablet of 25 mg. BI 135889 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: Period 1 contains the randomised subjects. Baseline characteristics are reported for the subjects who started the treatment period i.e. treated subjects and not the randomised subjects.
    Number of subjects in period 2 [2]
    		Placebo BI 1358894 125 mg
    Started
    159
    157
    Completed
    133
    127
    Not completed
    26
    30
         Other reasons than listed
    9
    8
         Adverse event, non-fatal
    6
    14
         Perceived lack of efficacy
    1
    1
         Protocol deviation
    2
    2
         No reason available
    5
    4
         Burden of study procedures
    3
    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: Out of 673 screened subjects only 318 were randomised.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received orally, once daily for 8 consecutive weeks film-coated tablets of placebo matching BI 1358894. Placebo matching BI 1358894 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.

    Reporting group title
    BI 1358894 125 mg
    Reporting group description
    		 Patients received orally, once daily for 8 consecutive weeks 125 milligrams (mg) of BI 1358894. The dosage of 125 milligrams consisted of two film-coated tablets of 50 mg and 1 film-coated tablet of 25 mg. BI 135889 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.

    Reporting group values
    		 Placebo BI 1358894 125 mg Total
    Number of subjects
    		 159 157 316
    Age categorical
    Treated Set (TS): consisted of all patients that were randomised and had received at least one administration of trial drug. Patients were analysed according to the actual received treatment.
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 159 157 316
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age Continuous
    Treated Set (TS): consisted of all patients that were randomised and had received at least one administration of trial drug. Patients were analysed according to the actual received treatment.
    Units: years
        arithmetic mean (standard deviation)
    		 44.0 ( 12.9 ) 42.8 ( 12.4 ) -
    Sex: Female, Male
    Treated Set (TS): consisted of all patients that were randomised and had received at least one administration of trial drug. Patients were analysed according to the actual received treatment.
    Units: Participants
        Female
    		 101 111 212
        Male
    		 58 46 104
    Race (NIH/OMB)
    Treated Set (TS): consisted of all patients that were randomised and had received at least one administration of trial drug. Patients were analysed according to the actual received treatment.
    Units: Subjects
        American Indian or Alaska Native
    		 6 10 16
        Asian
    		 2 1 3
        Native Hawaiian or Other Pacific Islander
    		 0 0 0
        Black or African American
    		 46 26 72
        White
    		 102 119 221
        More than one race
    		 3 1 4
        Unknown or Not Reported
    		 0 0 0
    Ethnicity (NIH/OMB)
    Treated Set (TS): consisted of all patients that were randomised and had received at least one administration of trial drug. Patients were analysed according to the actual received treatment.
    Units: Subjects
        Hispanic or Latino
    		 29 35 64
        Not Hispanic or Latino
    		 130 122 252
        Unknown or Not Reported
    		 0 0 0
    CAPS−5 total severity score at baseline
    Clinician-administered Post Traumatic Stress Disorder (PTSD) Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (CAPS-5) is a 30-item clinician-administered structured interview that can be used to, make current (past month) diagnosis of PTSD and assess PTSD symptoms over the past week. The CAPS-5 as used in this trial has 20 items, each scored 0-4, to yield a score with a possible range of 0-80. Higher scores mean worse outcome. Study characteristic reported for the treated set (TS).
    Units: score on a scale
        arithmetic mean (standard deviation)
    		 41.3 ( 9.9 ) 42.0 ( 9.6 ) -

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received orally, once daily for 8 consecutive weeks film-coated tablets of placebo matching BI 1358894. Placebo matching BI 1358894 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.

    Reporting group title
    BI 1358894 125 mg
    Reporting group description
    		 Patients received orally, once daily for 8 consecutive weeks 125 milligrams (mg) of BI 1358894. The dosage of 125 milligrams consisted of two film-coated tablets of 50 mg and 1 film-coated tablet of 25 mg. BI 135889 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.
    Reporting group title
    Placebo
    Reporting group description
    		 Patients received orally, once daily for 8 consecutive weeks film-coated tablets of placebo matching BI 1358894. Placebo matching BI 1358894 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.

    Reporting group title
    BI 1358894 125 mg
    Reporting group description
    		 Patients received orally, once daily for 8 consecutive weeks 125 milligrams (mg) of BI 1358894. The dosage of 125 milligrams consisted of two film-coated tablets of 50 mg and 1 film-coated tablet of 25 mg. BI 135889 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.

    Primary: Change from baseline in Clinician-Administered Post Traumatic Stress Disorder (PTSD) Scale for DSM-5 (CAPS-5) total severity score at Week 8

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    End point title
    		 Change from baseline in Clinician-Administered Post Traumatic Stress Disorder (PTSD) Scale for DSM-5 (CAPS-5) total severity score at Week 8
    End point description
    CAPS-5 is a 30-item clinician-administered structured interview that can be used to, make current (past month) diagnosis of PTSD and assess PTSD symptoms over the past week. Each of the 20 symptom items in the CAPS-5 is rated from 0 (absent) to 4 (extreme/incapacitating) with a single severity score combining information about frequency/amount and intensity which is yield by summing each item scores and ranges from 0 to 80 with higher scores indicating higher symptom severity. Least Squares (LS) means and confidence intervals were estimated by restricted maximum likelihood (REML)−based mixed model repeated measures (MMRM) including the fixed categorical covariates of treatment, and the stratification indicator of presence of significant childhood trauma (yes vs. no), the continuous fixed covariate of baseline CAPS−5 total severity score, time since index event (in years) and the treatment−by−visit interaction. Patient is considered as random. Unstructured covariance matrix was used.
    End point type
    Primary
    End point timeframe
    The MMRM model is a longitudinal analysis and it incorporated CAPS-5 measurements from baseline, Week 4, and Week 8. The data represents the Least Squares Mean at Week 8.
    End point values
    		 Placebo BI 1358894 125 mg
    Number of subjects analysed
    148 [1]
    151 [2]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -17.19 (-19.56 to -14.81)
    -17.13 (-19.52 to -14.74)
    Notes
    [1] - Endpoint is reported for the full analysis set.
    [2] - Endpoint is reported for the full analysis set.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Least Squares (LS) means differences and confidence intervals were estimated by REML−based MMRM including the fixed categorical covariates of treatment, and the stratification indicator of presence of significant childhood trauma (yes vs. no), the continuous fixed covariate of baseline CAPS−5 total severity score, time since index event (in years) and the treatment−by−visit interaction. Patient is considered as random. Unstructured covariance matrix was used.
    Comparison groups
    Placebo v BI 1358894 125 mg
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 other [3]
    P-value
    		 = 0.9726
    Method
    		 Mixed Models for repeated measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.06
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.31
         upper limit
    		 3.43
    Notes
    [3] - Least Squares mean of "BI 1358894 125 mg" - Least Square mean of "Placebo".

    Secondary: CAPS-5 response, defined as ≥30% CAPS-5 reduction from baseline at Week 8

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    End point title
    		 CAPS-5 response, defined as ≥30% CAPS-5 reduction from baseline at Week 8
    End point description
    Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (CAPS-5) is a 30-item clinician-administered structured interview that can be used to, make current (past month) diagnosis of PTSD and assess PTSD symptoms over the past week. Each of the 20 symptom items in the CAPS-5 is rated from 0 (absent) to 4 (extreme/incapacitating) with a single severity score combining information about frequency/amount and intensity which is yield by summing each item scores and ranges from 0 to 80 with higher scores indicating higher symptom severity. Number of participants with ≥30% CAPS-5 reduction from baseline at Week 8 is reported. This endpoint is reported for the full analysis set which consisted of all patients in the treated set (TS) that had a baseline and at least one evaluable post-baseline measurement for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    At baseline and at 8 weeks after start of treatment.
    End point values
    		 Placebo BI 1358894 125 mg
    Number of subjects analysed
    129
    129
    Units: Participants
    77
    77
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Logistic regression was adjusted for fixed factors of treatment and presence of significant childhood trauma (yes vs. no).
    Comparison groups
    Placebo v BI 1358894 125 mg
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 other [4]
    P-value
    		 = 0.9945
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.002
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.608
         upper limit
    		 1.65
    Notes
    [4] - BI 1358894 125 mg vs. Placebo

    Secondary: CAPS-5 response, defined as ≥50% CAPS-5 reduction from baseline at Week 8

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    End point title
    		 CAPS-5 response, defined as ≥50% CAPS-5 reduction from baseline at Week 8
    End point description
    Clinician-Administered PTSD Scale for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (CAPS-5) is a 30-item clinician-administered structured interview that can be used to, make current (past month) diagnosis of PTSD and assess PTSD symptoms over the past week. Each of the 20 symptom items in the CAPS-5 is rated from 0 (absent) to 4 (extreme/incapacitating) with a single severity score combining information about frequency/amount and intensity which is yield by summing each item scores and ranges from 0 to 80 with higher scores indicating higher symptom severity. Number of participants with ≥50% CAPS-5 reduction from baseline at Week 8 is reported. This endpoint is reported for the full analysis set which consisted of all patients in the treated set (TS) that had a baseline and at least one evaluable post-baseline measurement for the primary endpoint.
    End point type
    Secondary
    End point timeframe
    At baseline and at 8 weeks after start of treatment.
    End point values
    		 Placebo BI 1358894 125 mg
    Number of subjects analysed
    129
    129
    Units: Participants
    53
    50
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Logistic regression was adjusted for fixed factors of treatment and presence of significant childhood trauma (yes vs. no).
    Comparison groups
    Placebo v BI 1358894 125 mg
    Number of subjects included in analysis
    258
    Analysis specification
    Pre-specified
    Analysis type
    		 other [5]
    P-value
    		 = 0.7167
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.912
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.552
         upper limit
    		 1.504
    Notes
    [5] - BI 1358894 125 mg vs. Placebo

    Secondary: Change from baseline on the PTSD Checklist for DSM-5 (PCL-5) total score at Week 8

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    End point title
    		 Change from baseline on the PTSD Checklist for DSM-5 (PCL-5) total score at Week 8
    End point description
    The PTSD Checklist for Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (PCL-5) is a 20-item patient-reported assessment designed to measure the presence and severity of PTSD symptoms in the past month. Items on the PCL-5 correspond with DSM-5 criteria for PTSD. Each item is rated on a five point Likert scale, from 0 (not at all) to 4 (extremely) yielding a total score from 0-80 with higher scores indicating higher severity of the symptoms. Least Square (LS) means and confidence intervals were estimated by restricted maximum likelihood (REML)−based mixed model repeated measures (MMRM) including the fixed categorical covariates of treatment, and the stratification indicator of presence of significant childhood trauma (yes vs. no), the continuous fixed covariate of baseline CAPS−5 total severity score, time since index event (in years) and the treatment−by−visit interaction. Patient is considered as random. Unstructured covariance matrix was used.
    End point type
    Secondary
    End point timeframe
    The MMRM model is a longitudinal analysis and it incorporated PCL-5 measurements from baseline, Week 4, and Week 8. The data represents the Least Squares Mean at Week 8.
    End point values
    		 Placebo BI 1358894 125 mg
    Number of subjects analysed
    148 [6]
    151 [7]
    Units: units on a scale
        least squares mean (confidence interval 95%)
    -19.21 (-21.80 to -16.61)
    -18.55 (-21.12 to -15.98)
    Notes
    [6] - Endpoint is reported for the full analysis set.
    [7] - Endpoint is reported for the full analysis set.
    Statistical analysis title
    		 Statistical analysis 1
    Statistical analysis description
    Least Square (LS) means differences and confidence intervals were estimated by REML−based MMRM including the fixed categorical covariates of treatment, and the stratification indicator of presence of significant childhood trauma (yes vs. no), the continuous fixed covariate of baseline CAPS−5 total severity score, time since index event (in years) and the treatment−by−visit interaction. Patient is considered as random. Unstructured covariance matrix was used.
    Comparison groups
    Placebo v BI 1358894 125 mg
    Number of subjects included in analysis
    299
    Analysis specification
    Pre-specified
    Analysis type
    		 [8]
    P-value
    		 = 0.723
    Method
    		 Mixed Models for Repeated Measures
    Parameter type
    		 Mean difference (net)
    Point estimate
    0.66
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3
         upper limit
    		 4.32
    Notes
    [8] - Least Square mean of "BI 1358894 125 mg" - Least Square mean of "Placebo".

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    "All-Cause Mortality" "Serious Adverse Events" and "Other Adverse Events": From first administration of BI 1358894 or placebo to last administration of BI 1358894 or placebo + 4 weeks of residual effect period, up to 13 weeks.
    Adverse event reporting additional description
    Treated Set (TS): consisted of all patients that were randomised and had received at least one administration of trial drug. Patients were analysed according to the actual received treatment.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    BI 135889 125mg
    Reporting group description
    		 Patients received orally, once daily for 8 consecutive weeks 125 milligrams (mg) of BI 1358894. The dosage of 125 milligrams consisted of two film-coated tablets of 50 mg and 1 film-coated tablet of 25 mg. BI 135889 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.

    Reporting group title
    Placebo
    Reporting group description
    		 Patients received orally, once daily for 8 consecutive weeks film-coated tablets of placebo matching BI 1358894. Placebo matching BI 1358894 was administered with water and in a consistent way, i.e. either with or without food every morning at approximately the same time.

    Serious adverse events
    		 BI 135889 125mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 157 (7.64%)
    10 / 159 (6.29%)
         number of deaths (all causes)
    0
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Endometrial adenocarcinoma
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Toxicity to various agents
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 1
    Vascular disorders
    Deep vein thrombosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hypertension
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Amnesia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Encephalopathy
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Haematochezia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Depression
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Panic attack
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicidal ideation
         subjects affected / exposed
    4 / 157 (2.55%)
    4 / 159 (2.52%)
         occurrences causally related to treatment / all
    4 / 8
    1 / 5
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Muscular weakness
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rhabdomyolysis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cellulitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Wound infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 BI 135889 125mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    106 / 157 (67.52%)
    88 / 159 (55.35%)
    Vascular disorders
    Venous thrombosis limb
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Orthostatic hypotension
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Hypotension
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Hypertension
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Hot flush
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    2
    Haematoma
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    10 / 157 (6.37%)
    2 / 159 (1.26%)
         occurrences all number
    11
    2
    Chills
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Feeling jittery
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Inflammation
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Influenza like illness
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Malaise
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Non-cardiac chest pain
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Oedema
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Oedema peripheral
         subjects affected / exposed
    4 / 157 (2.55%)
    0 / 159 (0.00%)
         occurrences all number
    6
    0
    Pain
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Pre-existing condition improved
         subjects affected / exposed
    3 / 157 (1.91%)
    3 / 159 (1.89%)
         occurrences all number
    6
    3
    Pyrexia
         subjects affected / exposed
    2 / 157 (1.27%)
    3 / 159 (1.89%)
         occurrences all number
    2
    3
    Thirst
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Asthenia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Social circumstances
    Physical assault
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Caregiver
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Impaired driving ability
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Reproductive system and breast disorders
    Uterine polyp
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Sexual dysfunction
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Polymenorrhoea
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 159 (1.26%)
         occurrences all number
    0
    3
    Intermenstrual bleeding
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Heavy menstrual bleeding
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Erectile dysfunction
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Dysmenorrhoea
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 159 (1.26%)
         occurrences all number
    2
    2
    Breast tenderness
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Respiratory, thoracic and mediastinal disorders
    Rhinitis allergic
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    2
    Oropharyngeal pain
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Nasal congestion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Lower respiratory tract congestion
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Hiccups
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Epistaxis
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 159 (1.26%)
         occurrences all number
    0
    3
    Dyspnoea
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Cough
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Psychiatric disorders
    Anhedonia
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Abnormal dreams
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 159 (0.63%)
         occurrences all number
    2
    1
    Affect lability
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Agitation
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Initial insomnia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Insomnia
         subjects affected / exposed
    4 / 157 (2.55%)
    1 / 159 (0.63%)
         occurrences all number
    6
    1
    Intentional self-injury
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    2
    Irritability
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Libido decreased
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 159 (0.63%)
         occurrences all number
    2
    1
    Listless
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    3
    0
    Middle insomnia
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 159 (0.63%)
         occurrences all number
    2
    1
    Mood swings
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Nervousness
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Nightmare
         subjects affected / exposed
    2 / 157 (1.27%)
    3 / 159 (1.89%)
         occurrences all number
    3
    4
    Panic attack
         subjects affected / exposed
    4 / 157 (2.55%)
    1 / 159 (0.63%)
         occurrences all number
    4
    1
    Post-traumatic stress disorder
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Anxiety
         subjects affected / exposed
    2 / 157 (1.27%)
    4 / 159 (2.52%)
         occurrences all number
    2
    6
    Apathy
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Confusional state
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Depersonalisation/derealisation disorder
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Depressed mood
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Depression
         subjects affected / exposed
    4 / 157 (2.55%)
    1 / 159 (0.63%)
         occurrences all number
    6
    1
    Depressive symptom
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Euphoric mood
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Illusion
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Restlessness
         subjects affected / exposed
    4 / 157 (2.55%)
    1 / 159 (0.63%)
         occurrences all number
    6
    1
    Sleep disorder
         subjects affected / exposed
    2 / 157 (1.27%)
    3 / 159 (1.89%)
         occurrences all number
    3
    3
    Sleep talking
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Somnambulism
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Investigations
    Weight increased
         subjects affected / exposed
    11 / 157 (7.01%)
    3 / 159 (1.89%)
         occurrences all number
    11
    3
    Hepatic enzyme increased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Alanine aminotransferase increased
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 159 (0.63%)
         occurrences all number
    2
    1
    Amylase increased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Blood creatine phosphokinase MB increased
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Blood creatine phosphokinase increased
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 159 (0.63%)
         occurrences all number
    3
    1
    Blood creatinine increased
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    2
    Blood thyroid stimulating hormone decreased
         subjects affected / exposed
    2 / 157 (1.27%)
    2 / 159 (1.26%)
         occurrences all number
    3
    2
    Blood thyroid stimulating hormone increased
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 159 (0.63%)
         occurrences all number
    2
    1
    C-reactive protein increased
         subjects affected / exposed
    1 / 157 (0.64%)
    6 / 159 (3.77%)
         occurrences all number
    1
    8
    Crystal urine present
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    2
    Gamma-glutamyltransferase increased
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Heart rate increased
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Lipase increased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Platelet count decreased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Weight decreased
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    White blood cell count decreased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Neutrophil count decreased
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Arthropod bite
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Contusion
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Intentional product misuse
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Limb injury
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    2
    Muscle strain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Post-traumatic neck syndrome
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Road traffic accident
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Sedation complication
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Stress fracture
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Sunburn
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Tooth fracture
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Traumatic haemorrhage
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Ligament sprain
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    2
    1
    Congenital, familial and genetic disorders
    Hyperexplexia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Cardiac disorders
    Palpitations
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Wolff-Parkinson-White syndrome
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    12 / 157 (7.64%)
    8 / 159 (5.03%)
         occurrences all number
    12
    13
    Headache
         subjects affected / exposed
    34 / 157 (21.66%)
    20 / 159 (12.58%)
         occurrences all number
    66
    34
    Amnesia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Brain fog
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Circadian rhythm sleep disorder
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    2
    Clumsiness
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Cold-stimulus headache
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Coordination abnormal
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Disturbance in attention
         subjects affected / exposed
    3 / 157 (1.91%)
    3 / 159 (1.89%)
         occurrences all number
    4
    3
    Drug withdrawal headache
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    2
    Hypoaesthesia
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Lethargy
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    Migraine
         subjects affected / exposed
    5 / 157 (3.18%)
    2 / 159 (1.26%)
         occurrences all number
    6
    3
    Psychogenic seizure
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Sedation
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 159 (1.26%)
         occurrences all number
    1
    2
    Somnolence
         subjects affected / exposed
    6 / 157 (3.82%)
    3 / 159 (1.89%)
         occurrences all number
    7
    3
    Syncope
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Taste disorder
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Tension headache
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Tremor
         subjects affected / exposed
    2 / 157 (1.27%)
    1 / 159 (0.63%)
         occurrences all number
    2
    1
    Carpal tunnel syndrome
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Blood and lymphatic system disorders
    Lymphadenopathy
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    Neutrophilia
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Leukocytosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Hyperacusis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Tinnitus
         subjects affected / exposed
    3 / 157 (1.91%)
    0 / 159 (0.00%)
         occurrences all number
    4
    0
    Eye disorders
    Dry eye
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Eye irritation
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Eye pruritus
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Ocular hyperaemia
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Vision blurred
         subjects affected / exposed
    2 / 157 (1.27%)
    2 / 159 (1.26%)
         occurrences all number
    2
    2
    Visual impairment
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    7 / 157 (4.46%)
    15 / 159 (9.43%)
         occurrences all number
    8
    15
    Toothache
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    3
    0
    Abdominal discomfort
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Abdominal distension
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    3 / 157 (1.91%)
    2 / 159 (1.26%)
         occurrences all number
    6
    2
    Acid peptic disease
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Constipation
         subjects affected / exposed
    5 / 157 (3.18%)
    3 / 159 (1.89%)
         occurrences all number
    6
    3
    Diarrhoea
         subjects affected / exposed
    5 / 157 (3.18%)
    6 / 159 (3.77%)
         occurrences all number
    6
    7
    Dry mouth
         subjects affected / exposed
    3 / 157 (1.91%)
    1 / 159 (0.63%)
         occurrences all number
    3
    1
    Dyspepsia
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    Flatulence
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Gastrointestinal disorder
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Gastrooesophageal reflux disease
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Irritable bowel syndrome
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Vomiting
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 159 (1.26%)
         occurrences all number
    2
    2
    Hepatobiliary disorders
    Bile duct stone
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Acne
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Rosacea
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Rash
         subjects affected / exposed
    1 / 157 (0.64%)
    3 / 159 (1.89%)
         occurrences all number
    1
    3
    Pruritus
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    Night sweats
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Neurodermatitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Mechanical urticaria
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Hyperhidrosis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Dry skin
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Dermatitis allergic
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Dermatitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Dermal cyst
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Renal and urinary disorders
    Ureterolithiasis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Proteinuria
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Haematuria
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Micturition urgency
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Pollakiuria
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hypothyroidism
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    6 / 157 (3.82%)
    3 / 159 (1.89%)
         occurrences all number
    8
    4
    Back pain
         subjects affected / exposed
    1 / 157 (0.64%)
    2 / 159 (1.26%)
         occurrences all number
    2
    2
    Exostosis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Muscle spasms
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    Myalgia
         subjects affected / exposed
    5 / 157 (3.18%)
    1 / 159 (0.63%)
         occurrences all number
    5
    1
    Neck pain
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Pain in extremity
         subjects affected / exposed
    0 / 157 (0.00%)
    3 / 159 (1.89%)
         occurrences all number
    0
    3
    Spinal pain
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Temporomandibular joint syndrome
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Infections and infestations
    Gastroenteritis
         subjects affected / exposed
    2 / 157 (1.27%)
    2 / 159 (1.26%)
         occurrences all number
    2
    3
    Acarodermatitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Bronchitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    COVID-19
         subjects affected / exposed
    1 / 157 (0.64%)
    4 / 159 (2.52%)
         occurrences all number
    1
    4
    Cellulitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Cystitis
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    2
    1
    Dacryocystitis
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Ear infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Eye infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Fungal infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Gastroenteritis viral
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Infected bite
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Influenza
         subjects affected / exposed
    0 / 157 (0.00%)
    2 / 159 (1.26%)
         occurrences all number
    0
    2
    Mycoplasma infection
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Nasopharyngitis
         subjects affected / exposed
    7 / 157 (4.46%)
    5 / 159 (3.14%)
         occurrences all number
    11
    8
    Parainfluenzae virus infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Pharyngitis
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Pneumonia
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Sinusitis
         subjects affected / exposed
    3 / 157 (1.91%)
    4 / 159 (2.52%)
         occurrences all number
    3
    4
    Streptococcal infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Tooth abscess
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Tooth infection
         subjects affected / exposed
    2 / 157 (1.27%)
    0 / 159 (0.00%)
         occurrences all number
    2
    0
    Upper respiratory tract infection
         subjects affected / exposed
    1 / 157 (0.64%)
    1 / 159 (0.63%)
         occurrences all number
    1
    1
    Urinary tract infection
         subjects affected / exposed
    5 / 157 (3.18%)
    5 / 159 (3.14%)
         occurrences all number
    5
    5
    Urinary tract infection bacterial
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Viral infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Vulvovaginal mycotic infection
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Groin abscess
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Increased appetite
         subjects affected / exposed
    8 / 157 (5.10%)
    2 / 159 (1.26%)
         occurrences all number
    8
    2
    Decreased appetite
         subjects affected / exposed
    1 / 157 (0.64%)
    5 / 159 (3.14%)
         occurrences all number
    1
    5
    Diabetes mellitus
         subjects affected / exposed
    0 / 157 (0.00%)
    1 / 159 (0.63%)
         occurrences all number
    0
    1
    Fluid retention
         subjects affected / exposed
    3 / 157 (1.91%)
    1 / 159 (0.63%)
         occurrences all number
    3
    1
    Food craving
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Glucose tolerance impaired
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (0.00%)
         occurrences all number
    1
    0
    Hypertriglyceridaemia
         subjects affected / exposed
    5 / 157 (3.18%)
    1 / 159 (0.63%)
         occurrences all number
    5
    1
    Obesity
         subjects affected / exposed
    1 / 157 (0.64%)
    0 / 159 (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? Yes
    Date
    Amendment
    03 May 2022
    Global amendment 1 included the following changes toin the protocol: Addition of pregnancy test at End of Study (EOS) Inclusion of pregnancy test at V1A; Addition of counseling about the need of contraception and of information about the risk of medication-induced birth deficits; Sexual abstinence as contraceptive method no longer allowed; Added required reiteration that woman of childbearing potential (WOCBP) had to use appropriate methods of contraception; Description of a pivotal embryo-fetal development study in Goettingen minipigs added which had identified embryofetal development toxicity at relevant human exposure levels; Added how the risk for teratogenicity was to be mitigated; The permitted use of nonbenzodiazepine-. non-Z-drug hypnotics during the trial was changed from a dose equivalent to ≤1.0 mg lorazepam per day to the lowest dose of the compound as noted in the Summary of Product Characteristic (or SmPC).
    26 Sep 2022
    Global amendment 2 included the following changes to the protocol: Added that the fulfillment of the inclusion criterion no. 7 the use of required regarding contraception by WOCBP had to be confirmed by the investigator; Added that the investigator had to obtain the confirmation of the required use of contraception from WOCBP at all visits; Added that the investigator had to ensure that the patient understood the contraception requirements for the trial and could reliably comply with contraception use during the trial; Guidance in the event the requirements for contraception were not met; Added that due to results from a Drug-Drug Interaction (DDI) trial restrictions to sensitive substrates of CYP2B6 were no longer needed; Restriction for sensitive substrates of CYP2B6 removed; The order of assessments was made more flexible.
    18 Jan 2023
    Global amendment 3 included the following changes to the protocol: Added description of assessment and categorization of index traumatic events.
    09 Jun 2023
    Global amendment 4 included the following changes to the protocol: The exception of “in situ carcinoma” in exclusion criterion no. 18 was more precisely defined as “in situ carcinoma of uterine cervix”; Added local erythrocyte sedimentation rate (ESR) (ESR) assessment and that the ESR testing results were not intended to be used as safety parameter or for medical management decisions; For medical management decisions of safety relevant inflammation parameter, the C-Reactive Protein (CRP) test was to be used.

    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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    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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