Neuronal Correlates of Neurexan® Action in Mildly to Moderately Stressed Probands

Study Overview
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Brief Summary
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The purpose of this study is to explore the effect of Neurexan® on the brain response when participants undergo an emotional stressful condition in verum compared to placebo.

Detailed Description
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A randomized placebo-controlled, double-blind, two-period crossover study with an explorative design. 40 healthy males aged 31-59 years will be included in the study. Participant allocation to either Neurexan® or Placebo at study start is randomized with a ratio of 1:1, i.e. 20 Neurexan® first to 20 Placebo first individuals. Participants receive totally three tablets of either Neurexan® or Placebo per treatment period orally.

Official Title
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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

Conditions
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Acute Stress Reaction

Intervention / Treatment
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* Drug: Neurexan®
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male Age between ≥31 to ≤59 years Fluent in German language Nonsmoker Able to understand the explanations and instructions given by the study physician Willing to adhere to the prohibitions and restrictions specified in this protocol Healthy on the basis of clinical laboratory tests, physical examination, medical history, vital signs performed at Screening Visit Magnetic Resonance Imaging (MRI) compatible 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 Trier Inventory for Chronic Stress (TICS) Score ≥ 9 and ≤ 36 Perceived Stress Scale (PSS) > 9 Exclusion Criteria: 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) History of depressive episodes during the last 3 months prior to Screening Visit Use of any psychotropic medication or suffering from severe psychiatric illness during the last 3 months prior to Screening Visit Intake of prescription drugs for sleeping disorders or nervousness within one month prior to Screening Visit Intake of over the counter (OTC) medication for the treatment of sleeping disorders or nervousness within the last (one) week prior to Screening Visit High chronic stress as verified with the TICS-SSCS (> 36) Low chronic stress as verified with the TICS-SSCS (< 9) and PSS ≤ 9 Participants with Blood Pressure (BP) ≥ 160/100 on day 0 and at randomization Participants with treated hypertension 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) Known Lactose intolerance Use of any psychological stress-management intervention within the last 4 weeks prior to Screening Visit History of substance, drug, including nicotine, or alcohol abuse within the preceding 3 months prior to Screening Visit Alcohol, drug, nicotine intake within the last 24 hours before day 0 and at randomization - confirmed by positive screening tests Body Mass Index (BMI) > 30 kg/m2 Works regularly nights shifts Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic or hematologic disease as defined by clinical screening interview 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 Participants with medical illness that may have influenced brain morphology and/or physiology (e.g. uncontrolled hypertension, diabetes) Participants with a history of one or more seizures without a clear and resolved aetiology Participants with claustrophobia Participants with tinnitus Clinically significant acute illness within 7 days prior to randomization Presence of metallic (ferromagnetic) implants (heart pacemaker, aneurysm clips), tattoos or piercings 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 Participants 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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Male

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: Crossover Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Neurexan®<br>0.6 mg / tablet, 3 tablets, 40-60 minutes before the second MRI Intervention: Drug: Neurexan® | Drug: Neurexan®<br>* There are two experimental conditions; in one condition participants receive Neurexan® and the second condition they receive Placebo for oral administration (three tablets) in a cross over design. In the experimantal arm participants will receive verum on DAY1/PERIOD 1 and will receive placebo on DAY2/PERIOD 2.<br>|
| Placebo Comparator: Placebo<br>3 tablets, 40-60 minutes before the second MRI | Other: Placebo<br>* There are two experimental conditions; in one condition participants receive Neurexan® and the second condition they receive Placebo for oral administration (three tablets) in a cross over design. In the comparator arm participants will receive placebo on DAY1/PERIOD 1 and will receive verum on DAY2/PERIOD 2.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Primary Outcome 1: Effect of drug, driven by significantly smaller amygdala activations in the contrast (negative faces vs forms) in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates. | Day 1 and Day 2 | 
| Reduced functional connectivity density (FCD) in amygdala after verum versus placebo condition during rest. | Primary Outcome 2: Interaction of time and drug, driven by significantly greater reductions of amygdala functional connectivity density (FCD) in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates. | Day 1 and Day 2 | 
| Reduced whole brain functional connectivity of amygdala after verum versus placebo condition during rest. | Primary Outcome 3: Interaction of time and drug, driven by significantly greater changes (smaller and greater, two sided effects because of inclusion of top down and bottom up processes in different regions) of amygdala seeded connectivities in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the whole brain. | Day 1 and Day 2 | 
| Reduced local resting state activity of amygdala after verum versus placebo condition. | Primary Outcome 4: Interaction of time and drug, driven by significantly greater reductions of amygdala ALFF in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates. | Day 1 and Day 2 | 
| Increased effective connectivity from frontal cortex to amygdala during Hariri experiment after verum versus placebo condition. | Primary Outcome 5: Influence of drug on directed connectivity in an effective connectivity model (DCM) from ventral prefrontal cortex (vPFC) towards amygdala, driven by positive effects of verum on directed negative effective (top down) connectivity from vPFC to amygdala. Significance for the modulating effect of drug on effective connectivity is accepted for a p level of 0.05, for a winning model selected based on Bayesian information criterion (BIC) across all subjects and scans (verum and placebo) (Sladky et al 2013). | Day 1 and Day 2 | 
| Reduced stress network activation during stress (MIST) in verum relative to placebo. | Primary Outcome 6: Effect of drug, driven by significantly smaller activations in anterior cingulate cortex, medio-orbitofrontal cortex, hippocampus, amygdala, and hypothalamus in the contrast (hard vs easy) in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates. | Day 1 and Day 2 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Normalized EEG frontal frequency changes associated with normalized HRV in verum relative to placebo conditions. |  | Day 1 and Day 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. | Individual cortisol and alpha-amylase level at 8 timepoints during the MRI visits, VAS (tensions and nervousness) at 7 timepoints, and STAI-X1 at 6 timepoints will be computed as the area under the curve. The relation between change in cortisol, VAS (tension and nervousness) and personality traits (TCI), coping to stress (ABI, FKK), self-esteem (Rosenberg Self-Esteem), and childhood traumatic experiences (CTQ) will be investigated by the use of non-parametric correlations analysis. Changes in subject reported outcome instruments and stress response by morning cortisol and alpha amylase will be evaluated within the framework of formal crossover analyses. Due to unknown distributions, the analysis will be of nonparametric nature. | Day 1 and Day 2 | 
| Reduced subjects stress perception as assessed with STAI-XI, VAS after MIST task in verum relative to placebo condition. | The analysis is already described under point Outcome 8 and Outcome 10 of secondary outcome measures. | Day 1 and Day 2 | 
| Personality traits assessed with TCI predicted stress response. | It will be investigated how personality traits (TCI), anxiety level (STAI), depressive symptoms (BDI-II), self-esteem, subject's coping strategies as well as cognitive processes predict stress response and the relation with Neurexan® efficiency. Regression analyses will be conducted on resting state functional connectivity in placebo and verum conditions. These exploratory analyses are hypothesis generating in order to confine follow up investigations. | Screening Visit |