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    Clinical Trial Results:
    Multimodal Prevention of First Psychotic Episode – a 2x2-Factorial Randomized Trial investigating the efficacy of Acetylcysteine (ACC) and Integrated Preventive Psychological Intervention (IPPI) in Subjects Clinically at High Risk for Psychosis

    Summary
    EudraCT number
    		 2014-003076-22
    Trial protocol
    		 DE  
    Global end of trial date
    26 Jan 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    01 Apr 2026
    First version publication date
    01 Apr 2026
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    PSY-201401_ESPRIT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03149107
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Zentralinstitut für Seelische Gesundheit
    Sponsor organisation address
    J5, Mannheim, Germany, 68159
    Public contact
    Dr. rer. nat. Christine Fuhrmann, Studienzentrale des Studienzentrum Bonn (SZB), 0049 22816046, Studienzentrale-SZB@ukbonn.de
    Scientific contact
    Dr. rer. nat. Christine Fuhrmann, Studienzentrale des Studienzentrum Bonn (SZB), 0049 22816046, Studienzentrale-SZB@ukbonn.de
    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
    23 Mar 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    26 Jan 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    26 Jan 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate individual and combined preventive effects of a pharmaceutical intervention with glutamatergic, neuroprotective and anti-inflammatory capabili-ties (ACC) and an integrated preventive psychologcial intervention (IPPI) on transition rates to psychosis, on progression of symptoms and on improvement of social functioning.
    Protection of trial subjects
    N-Acetylcystein is already well known as a safe and well-tolerable agent. The integrated psychological preventive intervention (IPPI) developed for this study considers the heterogeneous demands of subjects clinically at risk for psychosis by targeting three major needs: stress management, symptom management and social cognition. Thus, besides effects on symptomatic risk indicators and a significant lowering of transition rates, an improvement of psychosocial functioning can be expected. The control condition, Psychological Stress Management (PSM), offers another treatment approach based on the vulnerability-stress-coping model of psychosis development, one of the leading concepts in the field of schizophrenia research (Gispen-de Wied & Jansen, 2002). Thus, even in the control condition, a useful treatment is offered.
    Background therapy
    		 -
    Evidence for comparator
    		 Regarding psychological treatments, cognitive behavioral therapy (CBT) has been compared in five studies to a supportive treatment (standard counseling (PSM)) as usual (PMID: 17440198). Three of these studies reported significant reductions of TR, one (presumably underpowered) study a trend, one suffered from methodological problems hampering the discrimination of preventive effects. The most successful relative reduction was achieved in a trial conducted by Cologne, Bonn, Düsseldorf and Munich. This randomized trial compared a 12-month manual-based psychological intervention with a supportive counseling. TR was reduced by 81% to 3.2% during the intervention period. However, unfortunately, this TR showed not to be stable: 12 months after stopping the intervention (i.e. 24 months after baseline), it nearly doubled to 6.3%, equaling a nearly two-hundred times higher incidence rate than observed in the general population. Furthermore, it was an open-label study and the treatment period was too long with regard to convenience: more than a third of the participants took part in less than 50% of the sessions. Thus, an advancing of this approach is required with regard to (i) long-term sustainability of preventive effects beyond the phase of active intervention, (ii) methodology and (iii) convenience.
    Actual start date of recruitment
    15 Aug 2016
    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
    Germany: 46
    Worldwide total number of subjects
    46
    EEA total number of subjects
    46
    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)
    46
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment period: 46 months at 11 sites in Germany First patient in to last patient out: 52 months Participants were recruited via the center´s early detection facilities and either self-referred or referred via practitioners in stationary or ambulant settings.

    Pre-assignment
    Screening details
    		 Participants were recruited via the center’s early detection facilities and either self-referred or referred via practitioners in stationary or ambulant settings. Further details on inclusion and exclusion criteria, as well as trial design and recruitment, can be found in the publication (see tab "more information").

    Period 1
    Period 1 title
    Trial participation (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 NAC + IPPI
    Arm description
    		 Acetylcysteine 500 mg capsules, Dose: 2000 mg/d (2 x 2 capsules/day), Mode of application: oral intake, 1000 mg (2 capsules) BID, Duration of treatment: 26 weeks + IPPI (Intergrated Preventive Psychological Intervention): IPPI has been applied weekly for the first 20 weeks (sessions 1 to 20, weeks 0 to 19), a booster and closure session (session 21) have taken place at week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    N-Acetylcysteine
    Investigational medicinal product code
    NAC
    Other name
    ACC
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    Dose: 2000 mg/d (2 x 2 capsules/day), Mode of application: oral intake, 1000 mg (2 capsules) BID

    Arm title
    		 PLC + PSM
    Arm description
    		 Placebo (PLC), Dose: 4 (2 x 2) capsules/day, Mode of Application: oral intake, 2 capsules BID, Duration of Treatment: 26 weeks + PSM (Psychological Stress Management) has been applied bi-weekly (sessions 1 to 10, weeks 0 to 18), a booster and closure session (session 11) have taken place at week 24.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PLC
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 2 capsules/day

    Arm title
    		 PLC + IPPI
    Arm description
    		 Placebo (PLC), Dose: 4 (2 x 2) capsules/day, Mode of Application: oral intake, 2 capsules BID, Duration of Treatment: 26 weeks + IPPI (Integrated Preventive Psychological Intervention): IPPI was applied weekly for the first 20 weeks (sessions 1 to 20, weeks 0 to 19), a booster and closure session (session 21) have taken place at week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PLC
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 2 capsules/day

    Arm title
    		 NAC + PSM
    Arm description
    		 N-Acetylcysteine 500 mg capsules, Dose: 2000 mg/d (2 x 2 capsules/day), Mode of application: oral intake, 1000 mg (2 capsules) BID, Duration of treatment: 26 weeks + PSM (Psychological Stress Management) has been applied bi-weekly (sessions 1 to 10, weeks 0 to 18), a booster and closure session (session 11) have taken place at week 24.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    PLC
    Other name
    Pharmaceutical forms
    Capsule, soft
    Routes of administration
    Oral use
    Dosage and administration details
    2 x 2 capsules/day

    Number of subjects in period 1
    		NAC + IPPI PLC + PSM PLC + IPPI NAC + PSM
    Started
    11
    11
    13
    11
    Completed
    11
    11
    13
    11

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    NAC + IPPI
    Reporting group description
    		 Acetylcysteine 500 mg capsules, Dose: 2000 mg/d (2 x 2 capsules/day), Mode of application: oral intake, 1000 mg (2 capsules) BID, Duration of treatment: 26 weeks + IPPI (Intergrated Preventive Psychological Intervention): IPPI has been applied weekly for the first 20 weeks (sessions 1 to 20, weeks 0 to 19), a booster and closure session (session 21) have taken place at week 24.

    Reporting group title
    PLC + PSM
    Reporting group description
    		 Placebo (PLC), Dose: 4 (2 x 2) capsules/day, Mode of Application: oral intake, 2 capsules BID, Duration of Treatment: 26 weeks + PSM (Psychological Stress Management) has been applied bi-weekly (sessions 1 to 10, weeks 0 to 18), a booster and closure session (session 11) have taken place at week 24.

    Reporting group title
    PLC + IPPI
    Reporting group description
    		 Placebo (PLC), Dose: 4 (2 x 2) capsules/day, Mode of Application: oral intake, 2 capsules BID, Duration of Treatment: 26 weeks + IPPI (Integrated Preventive Psychological Intervention): IPPI was applied weekly for the first 20 weeks (sessions 1 to 20, weeks 0 to 19), a booster and closure session (session 21) have taken place at week 24.

    Reporting group title
    NAC + PSM
    Reporting group description
    		 N-Acetylcysteine 500 mg capsules, Dose: 2000 mg/d (2 x 2 capsules/day), Mode of application: oral intake, 1000 mg (2 capsules) BID, Duration of treatment: 26 weeks + PSM (Psychological Stress Management) has been applied bi-weekly (sessions 1 to 10, weeks 0 to 18), a booster and closure session (session 11) have taken place at week 24.

    Reporting group values
    		 NAC + IPPI PLC + PSM PLC + IPPI NAC + PSM Total
    Number of subjects
    		 11 11 13 11 46
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 11 11 13 11 46
        From 65-84 years
    		 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 25.1 ( 4.5 ) 20.9 ( 3.9 ) 23.8 ( 6.2 ) 27.1 ( 5.9 ) -
    Gender categorical
    Units: Subjects
        Female
    		 3 5 6 4 18
        Male
    		 8 6 7 7 28
    Employment
    Units: Subjects
        unemployed
    		 0 1 1 3 5
        employed
    		 11 10 12 8 41
    Marital status
    Units: Subjects
        marital status (single)
    		 8 7 8 5 28
        marital status (not single)
    		 3 4 5 6 18
    Living situation
    Units: Subjects
        alone
    		 2 2 2 2 8
        not alone
    		 9 9 11 9 38
    Social Connections
    Units: Subjects
        min. 1/week
    		 10 9 11 8 38
        none
    		 1 2 2 3 8
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    		 76.3 ( 19.5 ) 69.1 ( 14.8 ) 67.3 ( 14.8 ) 79.2 ( 25.5 ) -
    Height
    Units: cm
        arithmetic mean (standard deviation)
    		 176.8 ( 9.8 ) 175.5 ( 8.9 ) 172.8 ( 8.2 ) 174.2 ( 11.3 ) -
    BMI
    Units: none
        arithmetic mean (standard deviation)
    		 24.4 ( 5.6 ) 22.4 ( 5.0 ) 22.4 ( 3.7 ) 25.9 ( 7.4 ) -
    Education
    Units: Years
        arithmetic mean (standard deviation)
    		 12.3 ( 1.3 ) 11.5 ( 1.2 ) 12.0 ( 1.2 ) 11.5 ( 1.9 ) -
    Population density
    Units: per square km
        arithmetic mean (standard deviation)
    		 2112.4 ( 1358.3 ) 1518.8 ( 1512.1 ) 1791.1 ( 1461.6 ) 2243.8 ( 1518.8 ) -
    Subject analysis sets

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Primary analysis set was based on the full analysis set, as derived from the intention-to-treat (IIT) principle. All randomized patients were inckuded. Patients who withdraw or showed protocol violations were included in the IIT population. Data of drop outs was analyzed using all available data.

    Subject analysis sets values
    		 Full analysis
    Number of subjects
    46
    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)
    46
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    24.2 ( 5.6 )
    Gender categorical
    Units: Subjects
        Female
    18
        Male
    28
    Employment
    Units: Subjects
        unemployed
    5
        employed
    41
    Marital status
    Units: Subjects
        marital status (single)
    28
        marital status (not single)
    18
    Living situation
    Units: Subjects
        alone
    8
        not alone
    38
    Social Connections
    Units: Subjects
        min. 1/week
    38
        none
    8
    Weight
    Units: kg
        arithmetic mean (standard deviation)
    72.8 ( 19.1 )
    Height
    Units: cm
        arithmetic mean (standard deviation)
    174.8 ( 9.4 )
    BMI
    Units: none
        arithmetic mean (standard deviation)
    23.7 ( 5.6 )
    Education
    Units: Years
        arithmetic mean (standard deviation)
    11.8 ( 1.4 )
    Population density
    Units: per square km
        arithmetic mean (standard deviation)
    1938.4 ( 1472.6 )

    End points

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    End points reporting groups
    Reporting group title
    NAC + IPPI
    Reporting group description
    		 Acetylcysteine 500 mg capsules, Dose: 2000 mg/d (2 x 2 capsules/day), Mode of application: oral intake, 1000 mg (2 capsules) BID, Duration of treatment: 26 weeks + IPPI (Intergrated Preventive Psychological Intervention): IPPI has been applied weekly for the first 20 weeks (sessions 1 to 20, weeks 0 to 19), a booster and closure session (session 21) have taken place at week 24.

    Reporting group title
    PLC + PSM
    Reporting group description
    		 Placebo (PLC), Dose: 4 (2 x 2) capsules/day, Mode of Application: oral intake, 2 capsules BID, Duration of Treatment: 26 weeks + PSM (Psychological Stress Management) has been applied bi-weekly (sessions 1 to 10, weeks 0 to 18), a booster and closure session (session 11) have taken place at week 24.

    Reporting group title
    PLC + IPPI
    Reporting group description
    		 Placebo (PLC), Dose: 4 (2 x 2) capsules/day, Mode of Application: oral intake, 2 capsules BID, Duration of Treatment: 26 weeks + IPPI (Integrated Preventive Psychological Intervention): IPPI was applied weekly for the first 20 weeks (sessions 1 to 20, weeks 0 to 19), a booster and closure session (session 21) have taken place at week 24.

    Reporting group title
    NAC + PSM
    Reporting group description
    		 N-Acetylcysteine 500 mg capsules, Dose: 2000 mg/d (2 x 2 capsules/day), Mode of application: oral intake, 1000 mg (2 capsules) BID, Duration of treatment: 26 weeks + PSM (Psychological Stress Management) has been applied bi-weekly (sessions 1 to 10, weeks 0 to 18), a booster and closure session (session 11) have taken place at week 24.

    Subject analysis set title
    Full analysis
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Primary analysis set was based on the full analysis set, as derived from the intention-to-treat (IIT) principle. All randomized patients were inckuded. Patients who withdraw or showed protocol violations were included in the IIT population. Data of drop outs was analyzed using all available data.

    Primary: Overall Event free survival - combined intervention

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    End point title
    		 Overall Event free survival - combined intervention
    End point description
    event = transition to psychosis - Details see attached publication Wasserthal et al. 2024, doi 10.1093
    End point type
    Primary
    End point timeframe
    after 18 Months (after treatment and follow Up phase)
    End point values
    		 NAC + IPPI PLC + PSM PLC + IPPI NAC + PSM
    Number of subjects analysed
    11
    11
    13
    11
    Units: %
    arithmetic mean (standard deviation)
        Overall Event free survival - combined interventio
    72.7 ( 13.4 )
    39.0 ( 17.4 )
    56.1 ( 15.3 )
    72.7 ( 13.4 )
    Statistical analysis title
    		 event free survival probability after 18 months
    Statistical analysis description
    NAC+IPPI vs. PLC+PSM
    Comparison groups
    PLC + PSM v NAC + IPPI
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.674
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.707
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.141
         upper limit
    		 3.549
    Statistical analysis title
    		 event free survival probability after 18 months
    Statistical analysis description
    NAC+PSM vs. PLC+PSM
    Comparison groups
    NAC + PSM v PLC + PSM
    Number of subjects included in analysis
    22
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.73
    Method
    		 Logrank
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.785
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.197
         upper limit
    		 3.119
    Statistical analysis title
    		 event free survival probability after 18 months
    Statistical analysis description
    PLC+IPPI vs. PLC+PSM
    Comparison groups
    PLC + IPPI v PLC + PSM
    Number of subjects included in analysis
    24
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.814
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.815
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.149
         upper limit
    		 4.457

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Timeframe for AE
    Adverse event reporting additional description
    AE additional description
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    1 IPPI+ACC
    Reporting group description
    		 -

    Reporting group title
    2 IPPI+PLC
    Reporting group description
    		 -

    Reporting group title
    3 PSM+ACC
    Reporting group description
    		 -

    Reporting group title
    4 PSM+PLC
    Reporting group description
    		 -

    Serious adverse events
    		 1 IPPI+ACC 2 IPPI+PLC 3 PSM+ACC 4 PSM+PLC
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    General disorders and administration site conditions
    Disease prodromal stage
    Additional description: Disease prodromal stage
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Psychiatric disorders
    Acute stress disorder
    Additional description: Acute stress disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 1 IPPI+ACC 2 IPPI+PLC 3 PSM+ACC 4 PSM+PLC
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    7 / 11 (63.64%)
    8 / 13 (61.54%)
    4 / 11 (36.36%)
    5 / 11 (45.45%)
    Vascular disorders
    Circulatory collapse
    Additional description: Circulatory collapse
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    General disorders and administration site conditions
    Adverse drug reaction
    Additional description: Adverse drug reaction
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Asthenia
    Additional description: Asthenia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Fatigue
    Additional description: Fatigue
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    2
    Immune system disorders
    Seasonal allergy
    Additional description: Seasonal allergy
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Cough
    Additional description: Cough
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Dry throat
    Additional description: Dry throat
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Oropharyngeal pain
    Additional description: Oropharyngeal pain
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Psychiatric disorders
    Abnormal dreams
    Additional description: Abnormal dreams
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 13 (7.69%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
         occurrences all number
    2
    1
    1
    3
    Attention deficit hyperactivity disorder
    Additional description: Attention deficit hyperactivity disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Depressive symptom
    Additional description: Depressive symptom
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Indifference
    Additional description: Indifference
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Insomnia
    Additional description: Insomnia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    1
    0
    1
    Libido increased
    Additional description: Libido increased
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    2
    Restlessness
    Additional description: Restlessness
         subjects affected / exposed
    1 / 11 (9.09%)
    2 / 13 (15.38%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    2
    0
    0
    Sleep disorder
    Additional description: Sleep disorder
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Tension
    Additional description: Tension
         subjects affected / exposed
    2 / 11 (18.18%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    2
    1
    0
    2
    Terminal insomnia
    Additional description: Terminal insomnia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Thinking abnormal
    Additional description: Thinking abnormal
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Investigations
    Blood bilirubin increased
    Additional description: Blood bilirubin increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Blood cannabinoids increased
    Additional description: Blood cannabinoids increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Hepatic enzyme increased
    Additional description: Hepatic enzyme increased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    1 / 11 (9.09%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Urine cannabinoids increased
    Additional description: Urine cannabinoids increased
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    White blood cell count decreased
    Additional description: White blood cell count decreased
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Cardiac disorders
    Palpitations
    Additional description: Palpitations
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Nervous system disorders
    Advanced sleep phase
    Additional description: Advanced sleep phase
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    Disturbance in attention
    Additional description: Disturbance in attention
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
         occurrences all number
    2
    1
    1
    2
    Dizziness postural
    Additional description: Dizziness postural
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    1
    0
    0
    1
    Headache
    Additional description: Headache
         subjects affected / exposed
    2 / 11 (18.18%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    2
    0
    0
    0
    Memory impairment
    Additional description: Memory impairment
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    2 / 11 (18.18%)
         occurrences all number
    1
    0
    1
    2
    Mental impairment
    Additional description: Mental impairment
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Sedation
    Additional description: Sedation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tension headache
    Additional description: Tension headache
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Blood and lymphatic system disorders
    Lymphopenia
    Additional description: Lymphopenia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Eye disorders
    Accommodation disorder
    Additional description: Accommodation disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Aptyalism
    Additional description: Aptyalism
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Constipation
    Additional description: Constipation
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Diarrhoea
    Additional description: Diarrhoea
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    2 / 11 (18.18%)
         occurrences all number
    0
    1
    0
    2
    Dyspepsia
    Additional description: Dyspepsia
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Gastrooesophageal reflux disease
    Additional description: Gastrooesophageal reflux disease
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Nausea
    Additional description: Nausea
         subjects affected / exposed
    1 / 11 (9.09%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    1
    0
    0
    Saliva altered
    Additional description: Saliva altered
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Alopecia
    Additional description: Alopecia
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Hyperhidrosis
    Additional description: Hyperhidrosis
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Photosensitivity reaction
    Additional description: Photosensitivity reaction
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Pigmentation disorder
    Additional description: Pigmentation disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pruritus
    Additional description: Pruritus
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Rash
    Additional description: Rash
         subjects affected / exposed
    0 / 11 (0.00%)
    2 / 13 (15.38%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    2
    0
    0
    Renal and urinary disorders
    Micturition disorder
    Additional description: Micturition disorder
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    0
    1
    Infections and infestations
    Influenza
    Additional description: Influenza
         subjects affected / exposed
    1 / 11 (9.09%)
    0 / 13 (0.00%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Nasopharyngitis
    Additional description: Nasopharyngitis
         subjects affected / exposed
    0 / 11 (0.00%)
    0 / 13 (0.00%)
    1 / 11 (9.09%)
    1 / 11 (9.09%)
         occurrences all number
    0
    0
    1
    1
    Norovirus infection
    Additional description: Norovirus infection
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Pneumonia
    Additional description: Pneumonia
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Skin candida
    Additional description: Skin candida
         subjects affected / exposed
    0 / 11 (0.00%)
    1 / 13 (7.69%)
    0 / 11 (0.00%)
    0 / 11 (0.00%)
         occurrences all number
    0
    1
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 Aug 2016
    Amendment 1: update from initially approved protocol version 3 to version 4. Changes: Correction of an error in the list of stress training sessions/laboratory assessments now max. 28 days old instead of 3 months
    04 Apr 2017
    Amendment 3: approval of protocol version 6, changes from version 4 to version 5: details of new PIs/deputy PIs added, changes from version 5 to 6: deletion of 3 inclusion criteria, Pregnancy tests now explicitly permitted through blood tests .
    15 Aug 2017
    Amendment 4: protocol version 6 to version 7: changes of PIs
    18 Jul 2018
    Amendment 5: protocol version 7 to version 8: Deletion of various test procedures that were not previously evaluated in the eCRF / Adjustments to visits / Deletions and changes to exclusion criteria
    23 Jul 2019
    Amendment 6: protocol version 9 submitted, protocol version 10 approved. Changes from version 8 to 9: Follow-up Phase now only optional for 12 months / Introduction of a futility parameter / Addition of inclusion criterion 5 / Adjustment of the end date as part of the cost-neutral extension change of PIs Changes from version 9 to 10: Additions at the suggestion of the BfArM: only the DSMB has access to unblinded data after futility analysis, early termination date corrected to June 30, 2019.
    18 Feb 2020
    Amendment 7: protocol version 10 to version 11, changes: Change to an exclusion criterion, change of sponsor representative adjustment of trial medication label

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/30784233
    http://www.ncbi.nlm.nih.gov/pubmed/39144108
    For support, Contact us.
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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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