Explorative Open Label Study of Efficacy Profile of Neurexan® in Experimental Acute Stress Setting in Healthy Subjects

Study Overview
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Brief Summary
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The purpose of this study is to explore the efficacy of acutely dosed Neurexan using an experimental stress test called the Trier Social Stress Test

Detailed Description
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An acute stress reaction is a biopsychological condition arising in response to an event which is individually regarded as emotionally stressful. The onset of a stress response is associated with specific physiological actions in the sympathetic nervous system, both directly and indirectly through the release of adrenaline and to a lesser extent noradrenaline from the medulla of the adrenal glands. These catecholamine hormones facilitate immediate physical reactions by triggering increases in heart rate and breathing, constricting blood vessels. The other major player in the acute stress response is the hypothalamic-pituitary-adrenal axis. Although stress has been described as a non-specific psychophysiological response to environmental stimuli, it is possible to discern specific bodily stress responses caused by specific emotional reactions to novel, ambivalent or uncontrollable situations and stimuli. For example, social stress induces elevated cortisol levels, particularly if the stressor is uncontrollable, unpredictable, and constitutes a social-evaluative threat due to the judgment of others such as in the Trier Social Stress Test). Usually, the TSST induces a two-fold increase in saliva cortisol with peaks around 10-20 min. after stress test termination. Also, an average increase in heart rates of around 20 beats per minute (bpm) is observed during the TSST. In addition, emotional states and feelings have been shown to be affected by this stress test, such as marked increases in stress perception,anxiety and emotional insecurity as well as decreases in mood, calmness and feeling awake. Preliminary results indicate that Neurexan® may improve coping abilities in stressful situations. This study aims to investigate the effect of Neurexan® on subjectively perceived nervousness and tension during an acute stressful situation and to characterize the efficacy profile of Neurexan®.

Official Title
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Efficacy Profile of Neurexan® in an Experimental Acute Stress Setting - an Explorative Open-Label Study in Healthy Probands

Conditions
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Acute Stress Reaction

Intervention / Treatment
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* Drug: Neurexan®


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Provide written informed consent Healthy male or female age between 31 to 59 years Fluent in German language. Ability to understand the explanations and instructions given by the study physician Exclusion Criteria: allergies to ingredients of Neurexan® (Passiflora incarnata, Avena sativa, Coffea arabica, Zincum isovalerianicum, lactose monohydrate, magnesium stearate) lactose intolerance use of any psychological stress-management intervention within the last 4 weeks sick leave for any reason participation in any other clinical study 3 months prior to Screening Visit current or recent (3 months prior to Screening Visit) history of substance abuse or drug dependence including nicotine and alcohol (as verified in the respective IDCL list) smokers alcohol intake within last 24 hours (before Baseline Visit V3) shift workers or work regularly during night time use of any psychotropic medication or suffering from severe psychiatric illness needing acute intervention BMI > 30 kg/m2 currently pregnant (verified by urine pregnancy test) or lactating participation in a previous TSST study high chronic stress as verified with the TICS-SSCS (a score of ≥ 23 on the screening scale for chronic stress meets the criterion of being chronically stressed) major mental disorder as verified with the IDCL (depressive episode, panic disorder, social phobia, obsessive-compulsory disorder; alcohol dependency; schizophrenia and mania.) employee of the Sponsor, one of the investigators or the CRO use of any concomitant medication except contraceptives any somatic disease or other condition the Investigator or their duly assigned representatives believes may affect the ability of the individual to complete the study or the interpretation of the study results Individuals whose ability to speak for themselves lacks or can be doubted

Ages Eligible for Study
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Minimum Age: 31 Years
Maximum Age: 59 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neurexan®<br>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes | Drug: Neurexan®<br>* 0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes<br>|
| No Intervention: No intervention<br>no tablet intake and subjects will undergo the natural course | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Acute Stress Measured by Nervousness | Tension and nervousness were self-assessed by the participants on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) before and after a stress test. The VAS is used to determine the subjective impression of tension and nervousness on a 10 cm bipolar visual scale ranging from 0 = not at all to 100 = highly. The measurements started with first intake of Neurexan or Natural Course and were repeated until 100 minutes after the end of the stress test. The total stress was then summarized with the Area under the curve (AUC) method. | -210 minutes to +100 minutes | 
| Acute Stress Measured by Tension | Tension and nervousness were self-assessed by the participants on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) before and after a stress test. The VAS is used to determine the subjective impression of tension and nervousness on a 10 cm bipolar visual scale ranging from 0 = not at all to 100 = highly. The measurements started with first intake of Neurexan or Natural Course and were repeated until 100 minutes after the end of the stress test. The total stress was then summarized with the Area under the curve (AUC) method. | -210 minutes to +100 minutes | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Changes in Plasma Catecholamines (Epinephrine) | The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test. | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 
| Changes in Plasma Catecholamines (Norepinephrine) | The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test. | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 
| Changes in Natural Killer (NK) Cells (Subgroup) | The Natural Killer Cells as immune cells and stress biomarkers were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test. | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 
| Changes in Blood Pressure | Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording. The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test. | -15 minutes, 0 minutes, +15 minutes, +45 minutes | 
| Changes in Heart Rate | Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording. The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test. | -15 minutes, 0 minutes, +15 minutes, +45 minutes | 
| Changes in Saliva Cortisol | The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test. | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 
| Changes in Plasma Cortisol | The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test. | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 
| Changes in Plasma Adrenocorticotropic Hormone (ACTH) | The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test. | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 
| Changes in Saliva Alpha Amylase | The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test. | -60 minute, +15 minute , + 45 minute, +100 minute | 
| State Anxiety and Stress Perception Measured by STAI-X1 | State anxiety and stress perception were measured by State-Trait Anxiety Inventory X1 before and after a stress test. The measurements took place 90 minutes before stress test and were repeated 15 and 100 minutes after the end of the stress test. The German version of the State-Trait-Anxiety Inventory was used and differentiates between temporary/emotional state anxiety versus personality trait anxiety. The two scales with 20 items each assess (1) anxiety as a trait (STAI-X2) and (2) anxiety as a state (STAI-XI). Answers are given in a 4-point rating scale ranging from 1 =not at all to 4 =very true. For analysis of each, STAI-scale single scores were summed up to one total score, representing the state and trait anxiety. Score range is 20-80 and higher scores indicate a higher anxiety. | -90 minutes, +15 minutes, +100 minutes | 
| Psychological Questionnaire (Modified Somatic SCL90) | The SCL90 has 90 items with dimensions like depression, somatization, obsessive-compulsive disorder, social insecurity, anxiety, phobic anxiety, aggression/hostility, paranoid ideation, psychoticism and each item in a subscale ranged from 0 to 4. The lower range values are favorable outcomes and higher are worse outcomes. The modified somatic SCL90 uses the SCL90 somatization items, but instead of a 7 day timeframe asks for now. The corresponding items from SCL90 were: 1, 4, 12, 27, 40, 42, 48, 49, 52, 53, 56, 58 and the introductory question: How much do you currently suffer from (Wie sehr leiden Sie momentan unter:). The median of the average Modified Somatic SCL90 score is reported. The average score was calculated at each time point as the sum score divided by the number of non-missing individual question results for subjects with no more than 2 missing responses. The lower values in the range represent favorable outcomes while the higher values represent worse outcomes. | -210 minutes, +100 minutes | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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physiological stress response, Neurexan, acute stress reaction, stress, stress perception