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    The EU Clinical Trials Register currently displays   43871   clinical trials with a EudraCT protocol, of which   7290   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2015-001802-32
    Sponsor's Protocol Code Number:C1501
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-05-20
    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 ConcernedGermany - BfArM
    A.2EudraCT number2015-001802-32
    A.3Full title of the trial
    Neuronal correlates of Neurexan® action in mildly to moderately stressed probands - a randomized, placebo-controlled, double-blind, cross-over trial of mode of action and response prediction by functional magnetic resonance imaging MRI
    Neuronale Korrelate der Wirkung von Neurexan® bei leicht bis mäßig gestressten Probanden – Eine randomisierte, Placebo-kontrollierte, doppelblinde, Cross-over Studie zur Wirkungsweise und Vorhersagbarkeit des Ansprechens mittels funktioneller Magnetresonanztomographie (MRT)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    In this clinical trial the effect of Neurexan® on the brain response will be explored by functional magnetic resonance imaging in male healthy volunteers under mild to moderate stress exposures. For this purpose, the volunteers will receive Neurexan® on one day and placebo on another day in a cross-over method.
    Bei der vorliegenden klinischen Prüfung wird bei männlichen gesunden Probanden unter gering- bis mittelgradigen Stressexpositionen der Wirkmechanismus von Neurexan® auf die Gehirnfunktion untersucht mittels funktioneller Magnetresonanztomographie. Dazu wird den Probanden in einem Cross-Over Verfahren an einem Untersuchungstag Neurexan® und an einem anderen Untersuchungstag ein Placebo verabreicht.
    A.3.2Name or abbreviated title of the trial where available
    NEURIM
    A.4.1Sponsor's protocol code numberC1501
    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 SponsorBiologische Heilmittel Heel GmbH
    B.1.3.4CountryGermany
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportBiologische Heilmittel Heel GmbH
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBiologische Heilmittel Heel GmbH
    B.5.2Functional name of contact pointDr. Istvan Zatik
    B.5.3 Address:
    B.5.3.1Street AddressDr.-Reckeweg-Str. 2-4
    B.5.3.2Town/ cityBaden-Baden
    B.5.3.3Post code76532
    B.5.3.4CountryGermany
    B.5.4Telephone number004972215013192
    B.5.5Fax number00497221501660
    B.5.6E-mailistvan.zatik@heel.com
    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 Neurexan®
    D.2.1.1.2Name of the Marketing Authorisation holderBiologische Heilmittel Heel GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameNeurexan®
    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.3.9.1CAS number 8001000-82-6
    D.3.9.3Other descriptive namePASSIFLORA INCARNATA D2
    D.3.9.4EV Substance CodeSUB46861
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0,6 mg to per 1 tablet
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 8001001-41-0
    D.3.9.3Other descriptive nameAVENA SATIVA D2
    D.3.9.4EV Substance CodeSUB44627
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0,6 mg to per 1 tablet
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.3Other descriptive nameZINCUM ISOVALERIANICUM TRIT. D4
    D.3.9.4EV Substance CodeSUB48467
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0,6 mg to per 1 tablet
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 8000050-74-0
    D.3.9.3Other descriptive nameARABICA COFFEE BEAN
    D.3.9.4EV Substance CodeSUB121485
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number0,6 mg to per 1 tablet
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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
    mildly to moderately stressed probands
    gering- bis mittelgradig gestresste Probanden
    E.1.1.1Medical condition in easily understood language
    mildly to moderately stressed probands
    gering- bis mittelgradig gestresste Probanden
    E.1.1.2Therapeutic area Psychiatry and Psychology [F] - Behaviours [F01]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.0
    E.1.2Level SOC
    E.1.2Classification code 10022891
    E.1.2Term Investigations
    E.1.2System Organ Class 10022891 - Investigations
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of this clinical trial is to explore the effect of Neurexan® on the brain response when participants undergo an emotional stressful condition in verum compared to placebo. The measures testing neuronal responses in the amygdala are assessed from functional MRI during resting state and while participants perform different tasks: an emotional paradigm (Hariri), stress induced task (Montreal Imaging Stress Task - MIST).
    E.2.2Secondary objectives of the trial
    The secondary objectives are:
    Explore the effect of Neurexan® on:
    • association of electroencephalogram (EEG) and heart rate variability (HRV) with amygdala activation and connectivity
    • morning cortisol as a predictor of subjective (VAS, STAI) and objective stress response in MRI
    • change in state anxiety and stress perception measured by State-Trait Anxiety Inventory (STAI) and Visual Analogue Scale (VAS)
    • change in cortisol and amygdala response predicted by individual differences, e.g., personality, childhood traumatic experiences, copying style, self-esteem, somatic symptoms (SCL-90)
    • change in saliva (cortisol, alpha-amylase) under stress conditions.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male
    2. Age between ≥31 to ≤59 years
    3. Fluent in German language
    4. Nonsmoker
    5. Able to understand the explanations and instructions given by the study physician
    6. Willing to adhere to the prohibitions and restrictions specified in this protocol
    7. Healthy or medically stable on the basis of clinical laboratory tests, physical examination, medical history, vital signs performed at Screening Visit
    8. Magnetic Resonance Imaging (MRI) compatible
    9. Participants must have signed a written informed consent document prior to any study procedure indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study
    10. Trier Inventory for Chronic Stress (TICS) Score ≥ 9 and ≤ 36
    11. Perceived Stress Scale (PSS) > 9
    E.4Principal exclusion criteria
    1. Current or past history of psychotic features or a diagnosis of any psychiatric disorder as defined in the Diagnostic and Statistical Manual of Mental Disorder 4th edition (DSM-IV) Axis I (recurrent major depression, panic disorder, social phobia, obsessive-compulsory disorder; alcohol dependency; schizophrenia and mania)
    2. History of depressive episodes during the last 3 months prior to Screening Visit
    3. Use of any psychotropic medication or suffering from severe psychiatric illness during the last 3 months prior to Screening Visit
    4. Intake of prescription drugs for sleeping disorders or nervousness within one month prior to Screening Visit
    5. Intake of over the counter (OTC) medication for the treatment of sleeping disorders or nervousness within the last (one) week prior to Screening Visit
    6. High chronic stress as verified with the TICS-SSCS (> 36)
    7. Low chronic stress as verified with the TICS-SSCS (< 9) and PSS ≤ 9
    8. Participants with Blood Pressure (BP) ≥ 160/100 at on day 0 and randomization
    9. Participants with treated hypertension
    10. Known allergies and/or hypersensitivity to ingredients of Neurexan® (Passiflora incarnata, Avena sativa, Coffea arabica, Zincum isovalerianicum, lactose monohydrate, magnesium stearate) or Placebo (Lactose monohydrate, magnesium stearate)
    11. Known Lactose intolerance
    12. Use of any psychological stress-management intervention within the last 4 weeks prior to Screening Visit
    13. History of substance, drug, including nicotine, or alcohol abuse within the preceding 3 months prior to Screening Visit
    14. Alcohol, drug, nicotine intake within the last 24 hours before day 0 and randomization confirmed by positive screening tests
    15. Body Mass Index (BMI) > 30 kg/m2
    16. Works regularly nights shifts
    17. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic or hematologic disease as defined by clinical screening interview
    18. Any somatic disease or other condition the Investigator or their duly assigned representatives believes could affect the ability of the individual to complete the study or the interpretation of the study results
    19. Participants with medical illness that may have influenced brain morphology and/or physiology (e.g. uncontrolled hypertension, diabetes)
    20. Participants with a history of one or more seizures without a clear and resolved aetiology
    21. Participants with claustrophobia
    22. Participants with tinnitus
    23. Clinically significant acute illness within 7 days prior to randomization
    24. Presence of metallic (ferromagnetic) implants (heart pacemaker, aneurysm clips), tattoos or piercings
    25. Have received an experimental drug or used an experimental medical device (participation in any other clinical trial) within the last 30 days before study inclusion
    26. Participants whose ability to speak for themselves lacks or can be doubted
    E.5 End points
    E.5.1Primary end point(s)
    Primary endpoints:
    Brain responses in pre-selected areas
    1. Reduced amygdala responsiveness measured by negative face to form contrasts in the Hariri task (Hariri et. al.., 2000: Hariri et. al., 2003) after verum versus placebo condition.
    2. Reduced functional connectivity density (FCD) in amygdala after verum versus placebo condition during rest.
    3. Reduced whole brain functional connectivity of amygdala after verum versus placebo condition during rest.
    4. Reduced local resting state activity of amygdala after verum versus placebo condition.
    5. Increased effective connectivity from frontal cortex to amygdala during Hariri experiment after verum versus placebo condition.
    6. Reduced stress network activation during stress (MIST) in verum relative to placebo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The fMRI and the EEG and the questionnaires will be done on Day 1 and Day 2. Day 1 will take place 7-35 days after the screening visit (=Day 0). Day 2 will take place 7-35 days after Day 1.
    E.5.2Secondary end point(s)
    Secondary endpoints:
    1. Normalized EEG frontal frequency changes associated with normalized HRV in verum relative to placebo conditions.
    2. High morning cortisol and alpha-amylase level predicts increased subjective stress response (VAS, STAI-XI), effect which is reversed in verum but not in placebo condition.
    3. Reduced subjects stress perception as assessed with STAI-XI, VAS after MIST task in verum relative to placebo condition.
    4. Personality traits assessed with TCI predicted stress response.
    E.5.2.1Timepoint(s) of evaluation of this end point
    The fMRI and the EEG and the questionnaires will be done on Day 1 and Day 2. Day 1 will take place 7-35 days after the screening visit (=Day 0). Day 2 will take place 7-35 days after Day 1.
    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 No
    E.6.4Safety No
    E.6.5Efficacy No
    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 Yes
    E.6.13.1Other scope of the trial description
    The scope of the clinical trial is to explore the effect of Neurexan® on the brain response when participants undergo an emotional stressful condition in verum compared to placebo.
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    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 No
    E.8.1.6Cross over Yes
    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 trial2
    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 No
    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
    After the second day of scanning (DAY2) of the last proband the study will end (end of study = DAY2).
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months9
    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: 40
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female No
    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 state40
    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)
    Not applicable because only healthy probands will be included in this clinical trial.
    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 Decision2015-08-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-07-29
    P. End of Trial
    P.End of Trial StatusCompleted
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    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
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