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    Clinical Trial Results:
    Dose-dependent effects of propranolol on extinction learning and return of fear

    Summary
    EudraCT number
    		 2018-003409-25
    Trial protocol
    		 BE  
    Global end of trial date
    16 Jun 2021

    Results information
    Results version number
    		 v2(current)
    This version publication date
    22 Sep 2022
    First version publication date
    19 Mar 2022
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    In the previous version, US expectancy data had not been treated for missing values (unlike our other outcome measures). We treated the data, repeated the analysis, and provide the new results here. It should be noted that the pattern of results did not change.

    Trial information

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    Trial identification
    Sponsor protocol code
    S61887
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    KU Leuven
    Sponsor organisation address
    Tiensestraat 102 bus 3712, Leuven, Belgium, 3000
    Public contact
    Prof. Dr. Tom Beckers, KU Leuven, +32 016326134, tom.beckers@kuleuven.be
    Scientific contact
    Prof. Dr. Tom Beckers, KU Leuven, +32 016326134, tom.beckers@kuleuven.be
    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
    11 Oct 2021
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    In our previous study (2016-002392-10; S59302), we found evidence that 40 mg oral administration of Propranolol HCl 60 min prior to extinction training attenuates fear responding and facilitates extinction. Propranolol administration did not prevent the return of fear, however, we did not test for return of fear in absence of the drug. The main aim of the present study is to investigate whether propranolol has a dose-dependent effect on extinction learning, and whether this further prevents the return of fear, in absence of the drug.
    Protection of trial subjects
    During all testing days, the experimenter remained in an adjacent room and had one-way visual contact with the subjects at all times. Subjects were informed that they could stop the experiment at any point, without giving reason and without being penalized. At the end of the experiment, we provided the subjects with the contact details of several support services in case they needed further assistance after completion of the experiment or had the urge to talk to somebody (other than the researchers) about it. These people were prepared to talk to the subjects immediately or get back to them (e.g., contact by e-mail). Contact information included clinical psychologists from within, as well as from outside our department, the student health services, and a call center where you can speak to someone anonymously.
    Background therapy
    		 None.
    Evidence for comparator
    		 We used a placebo, a commonly used comparator. Placebos were used as they did not contain any active substance that could exert effects upon consumption. Placebo pills were manufactured to be perceptually matched to the active drug (Propranolol). All medication was packaged in the same neutral package that was only labeled with a subject number. Labelling was done by the university hospital pharmacy. These steps were taken as to maintain a double-blind experimental procedure, thus preventing any undue influence on the results from expectations/demands of the subjects or the researcher.
    Actual start date of recruitment
    04 Mar 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Belgium: 152
    Worldwide total number of subjects
    152
    EEA total number of subjects
    152
    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)
    152
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Healthy, adult subjects were recruited from 04/03/2019 until 16/06/2021 through a database of potential research participants, managed by the KU Leuven Faculty of Psychology and Educational Sciences (Experiment Management System, EMS, accessible at psykuleuven.sona-systems.com).

    Pre-assignment
    Screening details
    		 Subjects were screened on Days 1 and 2, before being assigned to the arms of the study. Day 1 screening: 1) Medical exclusion criteria, 2) The Anxiety Sensitivity Index questionnaire (ASI), and 3) Non-differentiation between CS+ and CS-, on the last block of acquisition, in FPS. Day 2 screening: Medical exclusion criteria. See pre-assignment period

    Pre-assignment period milestones
    Number of subjects started
    		 152
    Number of subjects completed
    		 73

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Medical exclusion criteria (Day 2): 3
    Reason: Number of subjects
    		 Participant cancelled appointment: 3
    Reason: Number of subjects
    		 Screening questionnaire cutoff (ASI): 11
    Reason: Number of subjects
    		 Medical exclusion criteria (Day 1): 20
    Reason: Number of subjects
    		 Non-differentiation CS+/CS- (end of Day 1): 42
    Period 1
    Period 1 title
    Overall period
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    An external collaborator not involved in the study randomized subjects into three groups matched on age, gender, trait anxiety (STAI-T), and anxiety sensitivity (ASI).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 80 mg Propranolol
    Arm description
    		 In this arm, subjects were administered 80 mg Propranolol on Day 2 of the experiment, 60 minutes prior to extinction learning.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol EG - 80 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered 2 tablets of 40 mg Propranolol EG simultaneously, for a combined dose of 80 mg.

    Arm title
    		 40 mg Propranolol
    Arm description
    		 In this arm, subjects were administered 40 mg Propranolol on Day 2 of the experiment, 60 minutes prior to extinction learning.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Propranolol EG - 40 mg
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered 1 tablet of 40 mg Propranolol EG and 1 placebo tablet simultaneously.

    Arm title
    		 Placebo
    Arm description
    		 In this arm, subjects were administered placebo on Day 2 of the experiment, 60 minutes prior to extinction learning.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Subjects were orally administered 2 placebo tablets, simultaneously.

    Number of subjects in period 1 [1]
    		80 mg Propranolol 40 mg Propranolol Placebo
    Started
    25
    24
    24
    Completed
    24
    24
    24
    Not completed
    1
    0
    0
         Excluded for not following instructions
    1
    -
    -
    Notes
    [1] - 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: 152 subjects were originally recruited. 79 subjects were excluded during the pre-assignment period (see Subject disposition). 73 subjects were thus included in the baseline period.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    80 mg Propranolol
    Reporting group description
    		 In this arm, subjects were administered 80 mg Propranolol on Day 2 of the experiment, 60 minutes prior to extinction learning.

    Reporting group title
    40 mg Propranolol
    Reporting group description
    		 In this arm, subjects were administered 40 mg Propranolol on Day 2 of the experiment, 60 minutes prior to extinction learning.

    Reporting group title
    Placebo
    Reporting group description
    		 In this arm, subjects were administered placebo on Day 2 of the experiment, 60 minutes prior to extinction learning.

    Reporting group values
    		 80 mg Propranolol 40 mg Propranolol Placebo Total
    Number of subjects
    		 25 24 24 73
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 25 24 24 73
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 21 19 20 60
        Male
    		 4 5 4 13

    End points

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    End points reporting groups
    Reporting group title
    80 mg Propranolol
    Reporting group description
    		 In this arm, subjects were administered 80 mg Propranolol on Day 2 of the experiment, 60 minutes prior to extinction learning.

    Reporting group title
    40 mg Propranolol
    Reporting group description
    		 In this arm, subjects were administered 40 mg Propranolol on Day 2 of the experiment, 60 minutes prior to extinction learning.

    Reporting group title
    Placebo
    Reporting group description
    		 In this arm, subjects were administered placebo on Day 2 of the experiment, 60 minutes prior to extinction learning.

    Primary: Fear-potentiated startle responding

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    End point title
    		 Fear-potentiated startle responding [1]
    End point description
    Values reported have been standardized, as is commonly done in this measure. To standardize the data, means and standard deviations from the first day were used to calculate within-participant z-scores. It is the z-scores that are reported below.
    End point type
    Primary
    End point timeframe
    Fear-potentiated startle responding was measured throughout the experiment, but to assess the end point, we used the first trial during the retention testing phase on day 3 of the experiment.
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: See attached chart/documents for the statistical analysis.
    End point values
    		 80 mg Propranolol 40 mg Propranolol Placebo
    Number of subjects analysed
    24
    24
    24
    Units: microvolts
    arithmetic mean (standard deviation)
        CS+
    0.342 ( 1.136 )
    0.593 ( 1.072 )
    0.522 ( 0.989 )
        CS-
    -0.113 ( 0.915 )
    0.356 ( 1.142 )
    0.645 ( 1.106 )
        NA
    -1.006 ( 0.807 )
    -0.728 ( 1.141 )
    -0.873 ( 0.895 )
    Attachments
    		 FPS - Memory retention analysis
    No statistical analyses for this end point

    Primary: Skin conductance response

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    End point title
    		 Skin conductance response [2]
    End point description
    Values reported have been standardized, as is commonly done in this measure. To standardize the data, means and standard deviations from the first day were used to calculate within-participant z-scores. It is the z-scores that are reported below.
    End point type
    Primary
    End point timeframe
    Skin conductance responding was measured throughout the experiment, but to assess the end point, we used the first trial during the retention testing phase on day 3 of the experiment.
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: See attached chart/documents for the statistical analysis.
    End point values
    		 80 mg Propranolol 40 mg Propranolol Placebo
    Number of subjects analysed
    24
    24
    24
    Units: microsiemens
    arithmetic mean (standard deviation)
        CS+
    0.353 ( 1.524 )
    0.548 ( 1.551 )
    0.636 ( 1.494 )
        CS-
    0.155 ( 1.577 )
    0.015 ( 1.321 )
    0.252 ( 1.499 )
    Attachments
    		 SCR - Memory retention analysis
    No statistical analyses for this end point

    Primary: US expectancies

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    End point title
    		 US expectancies [3]
    End point description
    End point type
    Primary
    End point timeframe
    Expectancies to receiving the US (i.e., shock to the wrist) were measured throughout the experiment, but to assess the end point, we used the first trial during the retention testing phase on day 3 of the experiment.
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: See attached chart/documents for the statistical analysis.
    End point values
    		 80 mg Propranolol 40 mg Propranolol Placebo
    Number of subjects analysed
    24
    24
    24
    Units: Arbitrary units on a scale (-5 to 5)
    arithmetic mean (standard deviation)
        CS+
    -0.167 ( 3.226 )
    -0.250 ( 2.878 )
    0.583 ( 2.749 )
        CS-
    -2.708 ( 2.422 )
    -2.667 ( 2.316 )
    -2.750 ( 2.625 )
    Attachments
    		 Untitled (Filename: US expectancies - Memory retention analysis.pdf)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The researcher had to report all serious adverse events immediately to the sponsor except for those that the protocol identifies as not requiring immediate reporting.
    Adverse event reporting additional description
    At the end of each testing day, subjects had to fill out an adverse events form which asked about possible adverse reactions during/following the experiment in general (e.g., dizziness, pain, strong negative feelings, etc.).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20
    Reporting groups
    Reporting group title
    40 mg Propranolol
    Reporting group description
    		 In this arm, subjects were administered 40 mg Propranolol on Day 2 of the experiment, 60 minutes prior to extinction learning.

    Reporting group title
    80 mg Propranolol
    Reporting group description
    		 In this arm, subjects were administered 80 mg Propranolol on Day 2 of the experiment, 60 minutes prior to extinction learning.

    Reporting group title
    Placebo
    Reporting group description
    		 In this arm, subjects were administered placebo on Day 2 of the experiment, 60 minutes prior to extinction learning.

    Serious adverse events
    		 40 mg Propranolol 80 mg Propranolol Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 40 mg Propranolol 80 mg Propranolol Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 24 (12.50%)
    3 / 25 (12.00%)
    3 / 24 (12.50%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 25 (4.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    1
    1
    Headache
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    General disorders and administration site conditions
    Pain
    Additional description: At the wrist; the unconditioned stimulus (US; 200-ms shock) was administered there.
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0
    Fatigue
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 25 (4.00%)
    0 / 24 (0.00%)
         occurrences all number
    0
    1
    0
    Ear and labyrinth disorders
    Difficulty hearing
    Additional description: Noise blasts (90dB) were presented through headphones during the experiment to elicit fear-potentiated startle responding.
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 25 (0.00%)
    1 / 24 (4.17%)
         occurrences all number
    1
    0
    1
    Psychiatric disorders
    Strong negative feelings
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 25 (0.00%)
    0 / 24 (0.00%)
         occurrences all number
    1
    0
    0

    More information

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

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    12 Mar 2020
    Covid-19 pandemic; labs were shut down and all research paused.
    09 Nov 2020

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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