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    Summary
    EudraCT Number:2018-003409-25
    Sponsor's Protocol Code Number:S61887
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-10-02
    Trial results View results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2018-003409-25
    A.3Full title of the trial
    Dose-dependent effects of propranolol on extinction learning and return of fear
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Dose-dependent effects of propranolol on extinction learning and return of fear
    A.3.2Name or abbreviated title of the trial where available
    WipeOutFear_Extinction
    A.4.1Sponsor's protocol code numberS61887
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorKU Leuven
    B.1.3.4CountryBelgium
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportEuropean Research Council
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationKU Leuven
    B.5.2Functional name of contact pointPI Tom Beckers
    B.5.3 Address:
    B.5.3.1Street AddressTiensestraat 102 bus 3712
    B.5.3.2Town/ cityLeuven
    B.5.3.3Post code3000
    B.5.3.4CountryBelgium
    B.5.4Telephone number+32016326134
    B.5.6E-mailtom.beckers@kuleuven.be
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Propranolol EG (Eurogenerics NV) - 40 mg
    D.2.1.1.2Name of the Marketing Authorisation holderEurogenerics NV - Brussels
    D.2.1.2Country which granted the Marketing AuthorisationBelgium
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePropranolol
    D.3.2Product code C07AA05
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNPROPRANOLOL HYDROCHLORIDE
    D.3.9.1CAS number 318-98-9
    D.3.9.4EV Substance CodeSUB04091MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Experimental study with healthy participants recruited from the general population; no vulnerable individuals or clinical groups will be involved. Our objective is to test whether propranolol administration has a dose-dependent effect on the facilitation of extinction learning and subsequent return of fear.
    E.1.1.1Medical condition in easily understood language
    Experimental study with healthy participants recruited from the general population; no vulnerable individuals or clinical groups will be involved.
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Psychological processes [F02]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary objectives of the trial
    Our secondary objective is to investigate how the effective connectivity between neural regions-of-interest changes during fear extinction, and the dose-dependent effect of propranolol on these connections.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Healthy participants 18-40 years old.
    E.4Principal exclusion criteria
    We will exclude pregnant women, people with cardiovascular conditions, lung problems, neurologic conditions (e.g., epilepsy, seizures, convulsions), serious psychiatric conditions (depression, mania, psychosis, anxiety disorder) in the past or the present, or other serious medical conditions, people with pace-makers or other electronic implants, people with (uncorrected) hearing impairments, people with pain, injury or other medical conditions at the hands or wrists, and people who have been advised by their physician to keep away from stressful situations.
    Specific exclusion criteria also apply for the administration of propranolol. Those include a history of low blood pressure, dizziness, or
    fainting, inability to perform moderate exercise, cardiac problems in first-degree relative, a history of diabetes, liver or kidney problems,
    metabolic acidosis, excessive production of thyroid hormone, circulatory problems, current use of medication that acts on the cardiac system,
    antihypertensive drugs, migraine medication, blood sugar level depression medication, gastric acid blinding drugs, anti-inflammatory agents, antidepressants, antipsychotics, anxiolytics, asthma medication, drugs against dizziness, migraine, tuberculosis, or psoriasis, known allergy for propranolol, current systolic blood pressure below 90 or diastolic blood pressure below 60, current heart rate at rest below 60. We will also exclude all participants with a score of 26 or above on the Anxiety Sensitivity Index (questionnaire).
    E.5 End points
    E.5.1Primary end point(s)
    Our primary endpoint (study part A) is to test whether the administration of propranolol prior to extinction attenuates the conditioned fear responses [fear-potentiated startle (FPS) and skin conductance (SCR)] during extinction (relative to a group that receives placebo prior to extinction), and subsequently prevents the return of fear (i.e., spontaneous recovery and reinstatement) the next day (in absence of the drug). In our previous study (2016-002392-10; S59302), we found an attenuation of FPS CS+/CS- responding (effect significantly stronger for CS+ responding) during extinction in a group that received 40 mg propranolol 60 min prior to extinction. We did not find any effects on reinstatement, yet, we tested for reinstatement while the drug was still active. We predict a similar CS+/CS- attenuation during extinction for the groups that receive propranolol, but we expect to observe a stronger decline in conditioned responding in the group that receives 80 mg propranolol. It has been suggested that drug administration induces an internal drug state which gets integrated within the initial memory trace (Gisquet-Verrier et al., 2015). While we do not expect that 40 mg propranolol induces such a potent internal state, we do expect that 80 mg propranolol will induce such a state. Thereby, when testing for return of fear in absence of the drug, we believe that the 80 mg group will show a return of fear (due to a dissimilar state during extinction and testing), as will the placebo group (due to not having any drug intervention). We hypothesize that the 40 mg group will not show a return of fear, based on the assumption of similar internal states during extinction and during testing, as well as previous findings reported by Kroes et al. (2016). We expect these findings to agree between FPS and SCR measures, but we do not expect any differences between the conditions in US-expectancy ratings (in line with previous studies reporting that propranolol administration does not affect declarative memory, i.e., Kindt et al., 2009).
    E.5.1.1Timepoint(s) of evaluation of this end point
    Three day protocol with an evaluation of the extinction learning on day 2 and a final evaluation test (for return of fear) on day 3. Placebo/propranolol will be administered on day 2.
    E.5.2Secondary end point(s)
    In study Part B, we aim to replicate the findings for US-expectancy and SCR of study Part A in a second sample. Due to practical constraints FPS will not be measured. We will use Dynamic Causal Modelling (DCM) to quantify the directed influence between two anatomically defined regions-of-interest, specifically the vmPFC and amygdala. We expect that the vmPFC will have a greater influence over the activity in the amygdala during extinction and return of fear, than acquisition. We will then compare whether the strength of the influence from the vmPFC to the amygdala is related to the strength of propranolol administration.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Three day protocol with an evaluation of the extinction learning on day 2 and a final evaluation test (for return of fear) on day 3. Placebo/propranolol will be administered on day 2.
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial3
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA2
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    E.8.8 Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months6
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months6
    E.8.9.2In all countries concerned by the trial days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 144
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers Yes
    F.3.2Patients No
    F.3.3Specific vulnerable populations No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state72
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 144
    F.4.2.2In the whole clinical trial 144
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    We will provide all subjects with contact details of several support services (including a therapist and clinical psychologist, a medical doctor, and the student counselor of our university) in case they need further assistance after the experiment or have the urge to talk to somebody (other than the researchers) about it. These people will be prepared to talk to the subjects immediately or get back to them (e.g., contact by e-mail).
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2018-10-18
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2018-11-08
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-06-16
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