<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01703819</url>
  </required_header>
  <id_info>
    <org_study_id>C1201</org_study_id>
    <secondary_id>2012-002358-22</secondary_id>
    <nct_id>NCT01703819</nct_id>
  </id_info>
  <brief_title>Explorative Efficacy Profile of Neurexan® in an Experimental Acute Stress Setting in Healthy Subjects</brief_title>
  <acronym>NEUPRO-DB</acronym>
  <official_title>Efficacy Profile of Neurexan® in an Experimental Acute Stress Setting - an Explorative Double-blind Study in Healthy Probands</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Biologische Heilmittel Heel GmbH</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Biologische Heilmittel Heel GmbH</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study is to evaluate the efficacy of acutely dosed Neurexan using an&#xD;
      experimental stress test called the Trier Social Stress Test&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      An acute stress reaction is a biopsychological condition arising in response to an event&#xD;
      which is individually regarded as emotionally stressful. The onset of a stress response is&#xD;
      associated with specific physiological actions in the sympathetic nervous system, both&#xD;
      directly and indirectly through the release of adrenaline and to a lesser extent&#xD;
      noradrenaline from the medulla of the adrenal glands. These catecholamine hormones facilitate&#xD;
      immediate physical reactions by triggering increases in heart rate and breathing,&#xD;
      constricting blood vessels. The other major player in the acute stress response is the&#xD;
      hypothalamic-pituitary-adrenal axis.&#xD;
&#xD;
      Although stress has been described as a non-specific psychophysiological response to&#xD;
      environmental stimuli, it is possible to discern specific bodily stress responses caused by&#xD;
      specific emotional reactions to novel, ambivalent or uncontrollable situations and stimuli.&#xD;
      For example, social stress induces elevated cortisol levels, particularly if the stressor is&#xD;
      uncontrollable, unpredictable, and constitutes a social-evaluative threat due to the judgment&#xD;
      of others such as in the Trier Social Stress Test. Usually, the TSST induces a two-fold&#xD;
      increase in saliva cortisol with peaks around 10-20 min. after stress test termination. Also,&#xD;
      an average increase in heart rates of around 20 beats per minute (bpm) is observed during the&#xD;
      TSST. In addition, emotional states and feelings have been shown to be affected by this&#xD;
      stress test, such as marked increases in stress perception,anxiety and emotional insecurity&#xD;
      as well as decreases in mood, calmness and feeling awake.&#xD;
&#xD;
      Preliminary results indicate that Neurexan® may improve coping abilities in stressful&#xD;
      situations. This study aims to investigate the effect of Neurexan® on subjectively perceived&#xD;
      nervousness and tension during an acute stressful situation and to characterize the efficacy&#xD;
      profile of Neurexan®.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 2012</start_date>
  <completion_date type="Actual">April 2013</completion_date>
  <primary_completion_date type="Actual">April 2013</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Acute Stress Measured by Tension</measure>
    <time_frame>-210 minutes to +100 minutes</time_frame>
    <description>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&#xD;
= &quot;not at all&quot; to 100 = &quot;highly&quot;. The measurements started with first intake of Neurexan or Placebo 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.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Acute Stress Measured by Nervousness</measure>
    <time_frame>-210 minutes to +100 minutes</time_frame>
    <description>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&#xD;
= &quot;not at all&quot; to 100 = &quot;highly&quot;. The measurements started with first intake of Neurexan or Placebo 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.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in Saliva Alpha Amylase</measure>
    <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
    <description>The stress biomarkers plasma and saliva cortisol, alpha amylase, 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Saliva Cortisol</measure>
    <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Plasma Adrenocorticotropic Hormone (ACTH)</measure>
    <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Plasma Cortisol</measure>
    <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Plasma Catecholamines (Epinephrine)</measure>
    <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Plasma Catecholamines (Norepinephrine)</measure>
    <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Natural Killer (NK) Cells (Subgroup)</measure>
    <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
    <description>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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Blood Pressure</measure>
    <time_frame>-15 minutes, 0 minutes, +15 minutes, +45 minutes</time_frame>
    <description>Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording.&#xD;
The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Heart Rate</measure>
    <time_frame>-15 minutes, 0 minutes, +15 minutes, +45 minutes</time_frame>
    <description>Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording.&#xD;
The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>State Anxiety and Stress Perception Measured by STAI-X1</measure>
    <time_frame>-90 minutes, +15 minutes, +100 minutes</time_frame>
    <description>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 the stress test and were repeated at 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 =&quot;not at all&quot; to 4 =&quot;very true&quot;. 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.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Psychological Questionnaire (Modified Somatic SCL90)</measure>
    <time_frame>-210 minutes, +100 minutes</time_frame>
    <description>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 &quot;now&quot;. The corresponding items from SCL90 were: 1, 4, 12, 27, 40, 42, 48, 49, 52, 53, 56, 58 and the introductory question: &quot;How much do you currently suffer from&quot; (&quot;Wie sehr leiden Sie momentan unter:&quot;). 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.</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">66</enrollment>
  <condition>Acute Stress Reaction</condition>
  <arm_group>
    <arm_group_label>Neurexan®</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Neurexan®</intervention_name>
    <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes</description>
    <arm_group_label>Neurexan®</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Lactose monohydrate, magnesium stearate.</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Provide written informed consent&#xD;
&#xD;
          2. Healthy male or female&#xD;
&#xD;
          3. age between 31 to 59 years&#xD;
&#xD;
          4. Fluent in German language.&#xD;
&#xD;
          5. Ability to understand the explanations and instructions given by the study physician&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. allergies to ingredients of Neurexan® (Passiflora incarnata, Avena sativa, Coffea&#xD;
             arabica, Zincum isovalerianicum, lactose monohydrate, magnesium stearate) or Placebo&#xD;
&#xD;
          2. lactose intolerance&#xD;
&#xD;
          3. use of any psychological stress-management intervention within the last 4 weeks&#xD;
&#xD;
          4. sick leave for any reason&#xD;
&#xD;
          5. participation in any other clinical study 3 months prior to Screening Visit&#xD;
&#xD;
          6. current or recent (3 months prior to Screening Visit) history of substance abuse or&#xD;
             drug dependence including nicotine and alcohol (as verified in the respective IDCL&#xD;
             list)&#xD;
&#xD;
          7. smokers&#xD;
&#xD;
          8. alcohol intake within last 24 hours (before Baseline Visit V3)&#xD;
&#xD;
          9. shift workers or work regularly during night time&#xD;
&#xD;
         10. use of any psychotropic medication or suffering from severe psychiatric illness&#xD;
             needing acute intervention&#xD;
&#xD;
         11. BMI &gt; 30 kg/m2&#xD;
&#xD;
         12. currently pregnant (verified by urine pregnancy test) or lactating&#xD;
&#xD;
         13. participation in a previous TSST study&#xD;
&#xD;
         14. high chronic stress as verified with the TICS-SSCS (a score of ≥ 23 on the screening&#xD;
             scale for chronic stress meets the criterion of being chronically stressed)&#xD;
&#xD;
         15. major mental disorder as verified with the IDCL (depressive episode, panic disorder,&#xD;
             social phobia, obsessive-compulsory disorder; alcohol dependency; schizophrenia and&#xD;
             mania.)&#xD;
&#xD;
         16. employee of the Sponsor, one of the investigators or the CRO&#xD;
&#xD;
         17. use of any concomitant medication except contraceptives&#xD;
&#xD;
         18. any somatic disease or other condition the Investigator or their duly assigned&#xD;
             representatives believes may affect the ability of the individual to complete the&#xD;
             study or the interpretation of the study results&#xD;
&#xD;
         19. Individuals whose ability to speak for themselves lacks or can be doubted&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>31 Years</minimum_age>
    <maximum_age>59 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Manfred Schedlowski, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Institut für Medizinische Psychologie und Verhaltensimmunbiologie Universitätsklinikum Essen</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Institut fur Medizinische Psychologie und Verhaltensimmunbiologie Universitatsklinikum Essen</name>
      <address>
        <city>Essen</city>
        <zip>45122</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Klinische Psychologie und Psychotherapie, Fachbereich Psychologie, Universität Marburg</name>
      <address>
        <city>Marburg</city>
        <zip>35032</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
  </location_countries>
  <reference>
    <citation>McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007 Jul;87(3):873-904. doi: 10.1152/physrev.00041.2006.</citation>
    <PMID>17615391</PMID>
  </reference>
  <reference>
    <citation>Elsenbruch S, Lucas A, Holtmann G, Haag S, Gerken G, Riemenschneider N, Langhorst J, Kavelaars A, Heijnen CJ, Schedlowski M. Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome. Am J Gastroenterol. 2006 Oct;101(10):2300-7. doi: 10.1111/j.1572-0241.2006.00837.x. Epub 2006 Sep 4.</citation>
    <PMID>16952284</PMID>
  </reference>
  <reference>
    <citation>Kirschbaum C, Pirke KM, Hellhammer DH. The 'Trier Social Stress Test'--a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28(1-2):76-81. doi: 10.1159/000119004.</citation>
    <PMID>8255414</PMID>
  </reference>
  <reference>
    <citation>Hellhammer J, Schubert M. The physiological response to Trier Social Stress Test relates to subjective measures of stress during but not before or after the test. Psychoneuroendocrinology. 2012 Jan;37(1):119-24. doi: 10.1016/j.psyneuen.2011.05.012.</citation>
    <PMID>21689890</PMID>
  </reference>
  <reference>
    <citation>Schult J, Hero T, Hellhammer J. Effects of powdered fertilized eggs on the stress response. Clin Nutr. 2010 Apr;29(2):255-60. doi: 10.1016/j.clnu.2009.09.004. Epub 2009 Oct 17.</citation>
    <PMID>19837490</PMID>
  </reference>
  <reference>
    <citation>Mason JW. A review of psychoendocrine research on the pituitary-adrenal cortical system. Psychosom Med. 1968 Sep-Oct;30(5):Suppl:576-607. No abstract available.</citation>
    <PMID>4303377</PMID>
  </reference>
  <reference>
    <citation>Weiss JM. Somatic effects of predictable and unpredictable shock. Psychosom Med. 1970 Jul-Aug;32(4):397-408. doi: 10.1097/00006842-197007000-00008. No abstract available.</citation>
    <PMID>5535207</PMID>
  </reference>
  <reference>
    <citation>Pawlak CR, Jacobs R, Mikeska E, Ochsmann S, Lombardi MS, Kavelaars A, Heijnen CJ, Schmidt RE, Schedlowski M. Patients with systemic lupus erythematosus differ from healthy controls in their immunological response to acute psychological stress. Brain Behav Immun. 1999 Dec;13(4):287-302. doi: 10.1006/brbi.1999.0553.</citation>
    <PMID>10600217</PMID>
  </reference>
  <reference>
    <citation>Schedlowski M, Hosch W, Oberbeck R, Benschop RJ, Jacobs R, Raab HR, Schmidt RE. Catecholamines modulate human NK cell circulation and function via spleen-independent beta 2-adrenergic mechanisms. J Immunol. 1996 Jan 1;156(1):93-9.</citation>
    <PMID>8598500</PMID>
  </reference>
  <reference>
    <citation>Schmid-Ott G, Jacobs R, Jager B, Klages S, Wolf J, Werfel T, Kapp A, Schurmeyer T, Lamprecht F, Schmidt RE, Schedlowski M. Stress-induced endocrine and immunological changes in psoriasis patients and healthy controls. A preliminary study. Psychother Psychosom. 1998;67(1):37-42. doi: 10.1159/000012257.</citation>
    <PMID>9491439</PMID>
  </reference>
  <verification_date>February 2015</verification_date>
  <study_first_submitted>October 8, 2012</study_first_submitted>
  <study_first_submitted_qc>October 10, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 11, 2012</study_first_posted>
  <results_first_submitted>August 1, 2014</results_first_submitted>
  <results_first_submitted_qc>February 9, 2015</results_first_submitted_qc>
  <results_first_posted type="Estimate">February 11, 2015</results_first_posted>
  <last_update_submitted>February 9, 2015</last_update_submitted>
  <last_update_submitted_qc>February 9, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">February 11, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>acute stress reaction</keyword>
  <keyword>stress</keyword>
  <keyword>stress perception</keyword>
  <keyword>physiological stress response</keyword>
  <keyword>Neurexan</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Fractures, Stress</mesh_term>
    <mesh_term>Stress Disorders, Traumatic, Acute</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Recruitment was carried out in 2 outpatient clinics in Germany (Marburg and Essen).</recruitment_details>
      <pre_assignment_details>All 66 healthy participants were enrolled and none of them was excluded prior to randomization.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Neurexan®</title>
          <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
        </group>
        <group group_id="P2">
          <title>Placebo</title>
          <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="34"/>
                <participants group_id="P2" count="32"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="34"/>
                <participants group_id="P2" count="30"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="2"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Adverse Event</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="1"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. Two premature terminators could not be evaluated for primary efficacy, so 34 participants in the Neurexan group and 30 participants in the Placebo group formed the Full Analysis Set for analysis of efficacy.</population>
      <group_list>
        <group group_id="B1">
          <title>Neurexan®</title>
          <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to&#xD;
-30 minutes&#xD;
Neurexan®</description>
        </group>
        <group group_id="B2">
          <title>Placebo</title>
          <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="34"/>
            <count group_id="B2" value="32"/>
            <count group_id="B3" value="66"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="41.1" spread="7.0"/>
                    <measurement group_id="B2" value="40.7" spread="8.2"/>
                    <measurement group_id="B3" value="40.9" spread="7.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="32"/>
                    <measurement group_id="B3" value="66"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="32"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <description>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. Two premature terminators could not be evaluated for primary efficacy, so 34 participants in the Neurexan group and 30 participants in the Placebo group formed the Full Analysis Set for analysis of efficacy.</description>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Germany</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="32"/>
                    <measurement group_id="B3" value="66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Acute Stress Measured by Tension</title>
        <description>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&#xD;
= &quot;not at all&quot; to 100 = &quot;highly&quot;. The measurements started with first intake of Neurexan or Placebo 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.</description>
        <time_frame>-210 minutes to +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Acute Stress Measured by Tension</title>
          <description>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&#xD;
= &quot;not at all&quot; to 100 = &quot;highly&quot;. The measurements started with first intake of Neurexan or Placebo 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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
          <units>mm*min</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3335.7" lower_limit="345" upper_limit="16411"/>
                    <measurement group_id="O2" value="3360.3" lower_limit="0" upper_limit="21115"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null-hypotheses of no treatment differences were tested by the two-sided t-tests from the respective ANCOVAs.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.7726</p_value>
            <p_value_desc>Threshold less than or equal to 0.05. The final analysis demonstrated reasonable doubt of the implicit normality assumption of the two sets of AUC data, thus medians presented for efficacy analysis. Need for further investigation (ex-post analyses).</p_value_desc>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Acute Stress Measured by Nervousness</title>
        <description>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&#xD;
= &quot;not at all&quot; to 100 = &quot;highly&quot;. The measurements started with first intake of Neurexan or Placebo 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.</description>
        <time_frame>-210 minutes to +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Acute Stress Measured by Nervousness</title>
          <description>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&#xD;
= &quot;not at all&quot; to 100 = &quot;highly&quot;. The measurements started with first intake of Neurexan or Placebo 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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
          <units>mm*min</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="3147.4" lower_limit="247" upper_limit="17050"/>
                    <measurement group_id="O2" value="3022.5" lower_limit="0" upper_limit="21409"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <groups_desc>The null-hypotheses of no treatment differences were tested by the two-sided t-tests from the respective ANCOV As.</groups_desc>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.5702</p_value>
            <p_value_desc>Threshold less than or equal to 0.05. The final analysis demonstrated reasonable doubt of the implicit normality assumption of the two sets of AUC data, thus medians presented for efficacy analysis. Need for further investigation (ex-post analyses).</p_value_desc>
            <method>ANCOVA</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Saliva Alpha Amylase</title>
        <description>The stress biomarkers plasma and saliva cortisol, alpha amylase, 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.</description>
        <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Saliva Alpha Amylase</title>
          <description>The stress biomarkers plasma and saliva cortisol, alpha amylase, 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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
          <units>IU/mL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>- 60 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="112.9" lower_limit="19.7" upper_limit="353.7"/>
                    <measurement group_id="O2" value="133.3" lower_limit="23.7" upper_limit="421.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="201.9" lower_limit="78.4" upper_limit="729.7"/>
                    <measurement group_id="O2" value="216.0" lower_limit="49.3" upper_limit="670.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="140.8" lower_limit="25.6" upper_limit="420.4"/>
                    <measurement group_id="O2" value="142.1" lower_limit="37.1" upper_limit="484.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+100 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="149.9" lower_limit="29.2" upper_limit="465.1"/>
                    <measurement group_id="O2" value="140.6" lower_limit="35.1" upper_limit="417.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Saliva Cortisol</title>
        <description>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.</description>
        <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Saliva Cortisol</title>
          <description>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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
          <units>nmol/mL</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>- 60 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="7.1" lower_limit="3.0" upper_limit="17.4"/>
                    <measurement group_id="O2" value="7.1" lower_limit="2.7" upper_limit="32.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="19.4" lower_limit="7.2" upper_limit="120.8"/>
                    <measurement group_id="O2" value="20.0" lower_limit="6.1" upper_limit="86.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="15.3" lower_limit="7.0" upper_limit="80.7"/>
                    <measurement group_id="O2" value="21.2" lower_limit="3.9" upper_limit="81.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+100 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6.4" lower_limit="3.7" upper_limit="20.9"/>
                    <measurement group_id="O2" value="8.9" lower_limit="3.6" upper_limit="21.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Plasma Adrenocorticotropic Hormone (ACTH)</title>
        <description>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.</description>
        <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. For evaluation of plasma ACTH, 31 Neurexan and 29 Placebo participants were evaluated due to insufficient sample.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Plasma Adrenocorticotropic Hormone (ACTH)</title>
          <description>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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. For evaluation of plasma ACTH, 31 Neurexan and 29 Placebo participants were evaluated due to insufficient sample.</population>
          <units>ng/L</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>- 60 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="22.5" lower_limit="9.2" upper_limit="330.4"/>
                    <measurement group_id="O2" value="19.1" lower_limit="5.5" upper_limit="493.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="37.7" lower_limit="13.9" upper_limit="124.2"/>
                    <measurement group_id="O2" value="37.0" lower_limit="13.6" upper_limit="209.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="20.3" lower_limit="7.5" upper_limit="42.3"/>
                    <measurement group_id="O2" value="20.7" lower_limit="7.5" upper_limit="79.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+100 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="11.3" lower_limit="3.2" upper_limit="24.4"/>
                    <measurement group_id="O2" value="10.7" lower_limit="5.4" upper_limit="24.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Plasma Cortisol</title>
        <description>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.</description>
        <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. For evaluation of plasma Cortisol, 31 Neurexan and 29 Placebo participants were evaluated due to insufficient sample.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Plasma Cortisol</title>
          <description>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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. For evaluation of plasma Cortisol, 31 Neurexan and 29 Placebo participants were evaluated due to insufficient sample.</population>
          <units>nmol/L</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="31"/>
                <count group_id="O2" value="29"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>- 60 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="331.6" lower_limit="97.6" upper_limit="614.8"/>
                    <measurement group_id="O2" value="325.5" lower_limit="54.2" upper_limit="1006.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="441.1" lower_limit="281.4" upper_limit="987.1"/>
                    <measurement group_id="O2" value="569.8" lower_limit="174.1" upper_limit="1048.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="403.1" lower_limit="223.7" upper_limit="1260"/>
                    <measurement group_id="O2" value="535.4" lower_limit="142.5" upper_limit="841.2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+100 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="228.4" lower_limit="94.6" upper_limit="671.8"/>
                    <measurement group_id="O2" value="273.3" lower_limit="108.5" upper_limit="658.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Plasma Catecholamines (Epinephrine)</title>
        <description>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.</description>
        <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. For evaluation of plasma Epinephrine, 30 Neurexan and 26 Placebo participants were evaluated due to insufficient sample.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Plasma Catecholamines (Epinephrine)</title>
          <description>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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. For evaluation of plasma Epinephrine, 30 Neurexan and 26 Placebo participants were evaluated due to insufficient sample.</population>
          <units>ng/L</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>- 60 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42.6" lower_limit="10.0" upper_limit="98.0"/>
                    <measurement group_id="O2" value="35.6" lower_limit="8.1" upper_limit="146.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="32.9" lower_limit="10.0" upper_limit="116.0"/>
                    <measurement group_id="O2" value="47.4" lower_limit="10.0" upper_limit="126.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="41.4" lower_limit="10.0" upper_limit="152.0"/>
                    <measurement group_id="O2" value="26.4" lower_limit="10.0" upper_limit="101.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+100 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.9" lower_limit="0.0" upper_limit="91.3"/>
                    <measurement group_id="O2" value="41.1" lower_limit="11.3" upper_limit="89.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Plasma Catecholamines (Norepinephrine)</title>
        <description>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.</description>
        <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. For evaluation of plasma Norepinephrine, 30 Neurexan and 26 Placebo participants were evaluated due to insufficient sample.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Plasma Catecholamines (Norepinephrine)</title>
          <description>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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. For evaluation of plasma Norepinephrine, 30 Neurexan and 26 Placebo participants were evaluated due to insufficient sample.</population>
          <units>ng/L</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="30"/>
                <count group_id="O2" value="26"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>- 60 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="463.0" lower_limit="99" upper_limit="990"/>
                    <measurement group_id="O2" value="457.0" lower_limit="253" upper_limit="1329"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="584.0" lower_limit="150" upper_limit="1352"/>
                    <measurement group_id="O2" value="591.5" lower_limit="316" upper_limit="1856"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="481.0" lower_limit="231" upper_limit="1530"/>
                    <measurement group_id="O2" value="476.0" lower_limit="168" upper_limit="1189"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+100 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="451.5" lower_limit="215" upper_limit="1318"/>
                    <measurement group_id="O2" value="482.5" lower_limit="230" upper_limit="815"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Natural Killer (NK) Cells (Subgroup)</title>
        <description>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.</description>
        <time_frame>-60 minutes, +15 minutes, +45 minutes, +100 minutes</time_frame>
        <population>The test was only conducted in the Essen site where 15 participants randomized to Neurexan and 16 participants randomized to Placebo could be evaluated for NK cells.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Natural Killer (NK) Cells (Subgroup)</title>
          <description>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.</description>
          <population>The test was only conducted in the Essen site where 15 participants randomized to Neurexan and 16 participants randomized to Placebo could be evaluated for NK cells.</population>
          <units>percentage of lymphocytes</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="15"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>- 60 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.5" lower_limit="5.5" upper_limit="23.2"/>
                    <measurement group_id="O2" value="11.65" lower_limit="6.3" upper_limit="21.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="21.00" lower_limit="9.1" upper_limit="36.2"/>
                    <measurement group_id="O2" value="20.40" lower_limit="8.0" upper_limit="37.3"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="10.30" lower_limit="3.3" upper_limit="20.4"/>
                    <measurement group_id="O2" value="9.10" lower_limit="5.4" upper_limit="18.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+100 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="13.10" lower_limit="4.3" upper_limit="20.9"/>
                    <measurement group_id="O2" value="8.65" lower_limit="5.5" upper_limit="21.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Blood Pressure</title>
        <description>Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording.&#xD;
The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test.</description>
        <time_frame>-15 minutes, 0 minutes, +15 minutes, +45 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Blood Pressure</title>
          <description>Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording.&#xD;
The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
          <units>mmHg</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Systolic -15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="122.0" lower_limit="96" upper_limit="153"/>
                    <measurement group_id="O2" value="123.5" lower_limit="102" upper_limit="147"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Systolic 0 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="132.0" lower_limit="106" upper_limit="201"/>
                    <measurement group_id="O2" value="142.0" lower_limit="110" upper_limit="168"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Systolic +15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="125.0" lower_limit="99" upper_limit="164"/>
                    <measurement group_id="O2" value="133.5" lower_limit="105" upper_limit="153"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Systolic +45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="121.5" lower_limit="96" upper_limit="163"/>
                    <measurement group_id="O2" value="125.0" lower_limit="101" upper_limit="182"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Diastolic - 15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="79.5" lower_limit="58" upper_limit="109"/>
                    <measurement group_id="O2" value="81.5" lower_limit="61" upper_limit="98"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Diastolic 0 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="81.0" lower_limit="66" upper_limit="117"/>
                    <measurement group_id="O2" value="91.0" lower_limit="63" upper_limit="107"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Diastolic +15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="83.5" lower_limit="65" upper_limit="115"/>
                    <measurement group_id="O2" value="89.0" lower_limit="63" upper_limit="109"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Diastolic +45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="81.0" lower_limit="34" upper_limit="113"/>
                    <measurement group_id="O2" value="83.0" lower_limit="63" upper_limit="113"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Heart Rate</title>
        <description>Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording.&#xD;
The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test.</description>
        <time_frame>-15 minutes, 0 minutes, +15 minutes, +45 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Heart Rate</title>
          <description>Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording.&#xD;
The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
          <units>beats per minute</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>-15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="70.0" lower_limit="55" upper_limit="96"/>
                    <measurement group_id="O2" value="69.0" lower_limit="52" upper_limit="94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>0 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="88.0" lower_limit="65" upper_limit="115"/>
                    <measurement group_id="O2" value="89.5" lower_limit="65" upper_limit="131"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="69.5" lower_limit="56" upper_limit="94"/>
                    <measurement group_id="O2" value="71.0" lower_limit="53" upper_limit="119"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+45 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="71.0" lower_limit="59" upper_limit="106"/>
                    <measurement group_id="O2" value="71.0" lower_limit="55" upper_limit="91"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>State Anxiety and Stress Perception Measured by STAI-X1</title>
        <description>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 the stress test and were repeated at 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 =&quot;not at all&quot; to 4 =&quot;very true&quot;. 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.</description>
        <time_frame>-90 minutes, +15 minutes, +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>State Anxiety and Stress Perception Measured by STAI-X1</title>
          <description>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 the stress test and were repeated at 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 =&quot;not at all&quot; to 4 =&quot;very true&quot;. 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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>- 90 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.0" lower_limit="21" upper_limit="45"/>
                    <measurement group_id="O2" value="29.5" lower_limit="22" upper_limit="50"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+15 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="54.5" lower_limit="24" upper_limit="74"/>
                    <measurement group_id="O2" value="51.5" lower_limit="23" upper_limit="68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+100 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="33.0" lower_limit="20" upper_limit="69"/>
                    <measurement group_id="O2" value="31.5" lower_limit="22" upper_limit="48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Psychological Questionnaire (Modified Somatic SCL90)</title>
        <description>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 &quot;now&quot;. The corresponding items from SCL90 were: 1, 4, 12, 27, 40, 42, 48, 49, 52, 53, 56, 58 and the introductory question: &quot;How much do you currently suffer from&quot; (&quot;Wie sehr leiden Sie momentan unter:&quot;). 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.</description>
        <time_frame>-210 minutes, +100 minutes</time_frame>
        <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
        <group_list>
          <group group_id="O1">
            <title>Neurexan®</title>
            <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Psychological Questionnaire (Modified Somatic SCL90)</title>
          <description>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 &quot;now&quot;. The corresponding items from SCL90 were: 1, 4, 12, 27, 40, 42, 48, 49, 52, 53, 56, 58 and the introductory question: &quot;How much do you currently suffer from&quot; (&quot;Wie sehr leiden Sie momentan unter:&quot;). 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.</description>
          <population>34 participants were randomized to Neurexan and 32 participants to Placebo and all randomized participants were included in the Safety Set. 34 Neurexan and 30 Placebo participants that could be evaluated for primary efficacy formed the Full Analysis Set for analysis of efficacy.</population>
          <units>units on a scale</units>
          <param>Median</param>
          <dispersion>Full Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="34"/>
                <count group_id="O2" value="30"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>- 210 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.000" lower_limit="0.00" upper_limit="0.83"/>
                    <measurement group_id="O2" value="0.000" lower_limit="0.00" upper_limit="0.42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>+100 min</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.000" lower_limit="0.00" upper_limit="0.75"/>
                    <measurement group_id="O2" value="0.000" lower_limit="0.00" upper_limit="0.33"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Randomization until individual study end</time_frame>
      <desc>All adverse events that occurred after the participant has received at least one dose of the product under investigation were to be collected and reported</desc>
      <group_list>
        <group group_id="E1">
          <title>Neurexan®</title>
          <description>0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Neurexan®</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes&#xD;
Placebo</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>MedDRA (15.1)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="4" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="3" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Nausea</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Feeling Cold</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Fatigue</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Investigations</title>
            <event_list>
              <event>
                <sub_title>Blood Pressure Decrease</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Nervous system disorders</title>
            <event_list>
              <event>
                <sub_title>Tremor</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Procedural dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Headache</sub_title>
                <counts group_id="E1" subjects_affected="2" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="32"/>
              </event>
              <event>
                <sub_title>Dizziness</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Skin and subcutaneous tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Hyperhidrosis</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="34"/>
                <counts group_id="E2" subjects_affected="1" subjects_at_risk="32"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>Investigator agreements are in place restricting the PI from independently publishing the study results. Currently working with both PIs on several publications of the NEUPRO studies.</restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Christine Frank, PhD</name_or_title>
      <organization>Biologische Heilmittel Heel GmbH</organization>
      <phone>+49 7221 501 3188</phone>
      <email>christine.frank@heel.com</email>
    </point_of_contact>
  </clinical_results>
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01703819
org study id: C1201
secondary id: 2012-002358-22
nct id: NCT01703819
lead sponsor: 
has dmc: No
The purpose of this study is to evaluate the efficacy of acutely dosed Neurexan using an
      experimental stress test called the Trier Social Stress Test
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®.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Acute Stress Measured by Tension
time frame: -210 minutes to +100 minutes
description: 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 Placebo 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.
measure: Acute Stress Measured by Nervousness
time frame: -210 minutes to +100 minutes
description: 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 Placebo 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.
measure: Changes in Saliva Alpha Amylase
time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
description: The stress biomarkers plasma and saliva cortisol, alpha amylase, 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.
measure: Changes in Saliva Cortisol
time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
description: 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.
measure: Changes in Plasma Adrenocorticotropic Hormone (ACTH)
time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
description: 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.
measure: Changes in Plasma Cortisol
time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
description: 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.
measure: Changes in Plasma Catecholamines (Epinephrine)
time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
description: 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.
measure: Changes in Plasma Catecholamines (Norepinephrine)
time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
description: 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.
measure: Changes in Natural Killer (NK) Cells (Subgroup)
time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
description: 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.
measure: Changes in Blood Pressure
time frame: -15 minutes, 0 minutes, +15 minutes, +45 minutes
description: 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.
measure: Changes in Heart Rate
time frame: -15 minutes, 0 minutes, +15 minutes, +45 minutes
description: 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.
measure: State Anxiety and Stress Perception Measured by STAI-X1
time frame: -90 minutes, +15 minutes, +100 minutes
description: 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 the stress test and were repeated at 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.
measure: Psychological Questionnaire (Modified Somatic SCL90)
time frame: -210 minutes, +100 minutes
description: 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.
arm group label: Neurexan®
arm group type: Experimental
description: 0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes
arm group label: Placebo
arm group type: Placebo Comparator
description: 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes
intervention type: Drug
intervention name: Neurexan®
description: 0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes
arm group label: Neurexan®
intervention type: Other
intervention name: Placebo
description: 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes
arm group label: Placebo
other name: Lactose monohydrate, magnesium stearate.
criteria: 
gender: All
minimum age: 31 Years
maximum age: 59 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Manfred Schedlowski, PhD
role: Principal Investigator
affiliation: Institut für Medizinische Psychologie und Verhaltensimmunbiologie Universitätsklinikum Essen
facility: 
facility: 
country: Germany
citation: McEwen BS. Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev. 2007 Jul;87(3):873-904. doi: 10.1152/physrev.00041.2006.
PMID: 17615391
citation: Elsenbruch S, Lucas A, Holtmann G, Haag S, Gerken G, Riemenschneider N, Langhorst J, Kavelaars A, Heijnen CJ, Schedlowski M. Public speaking stress-induced neuroendocrine responses and circulating immune cell redistribution in irritable bowel syndrome. Am J Gastroenterol. 2006 Oct;101(10):2300-7. doi: 10.1111/j.1572-0241.2006.00837.x. Epub 2006 Sep 4.
PMID: 16952284
citation: Kirschbaum C, Pirke KM, Hellhammer DH. The 'Trier Social Stress Test'--a tool for investigating psychobiological stress responses in a laboratory setting. Neuropsychobiology. 1993;28(1-2):76-81. doi: 10.1159/000119004.
PMID: 8255414
citation: Hellhammer J, Schubert M. The physiological response to Trier Social Stress Test relates to subjective measures of stress during but not before or after the test. Psychoneuroendocrinology. 2012 Jan;37(1):119-24. doi: 10.1016/j.psyneuen.2011.05.012.
PMID: 21689890
citation: Schult J, Hero T, Hellhammer J. Effects of powdered fertilized eggs on the stress response. Clin Nutr. 2010 Apr;29(2):255-60. doi: 10.1016/j.clnu.2009.09.004. Epub 2009 Oct 17.
PMID: 19837490
citation: Mason JW. A review of psychoendocrine research on the pituitary-adrenal cortical system. Psychosom Med. 1968 Sep-Oct;30(5):Suppl:576-607. No abstract available.
PMID: 4303377
citation: Weiss JM. Somatic effects of predictable and unpredictable shock. Psychosom Med. 1970 Jul-Aug;32(4):397-408. doi: 10.1097/00006842-197007000-00008. No abstract available.
PMID: 5535207
citation: Pawlak CR, Jacobs R, Mikeska E, Ochsmann S, Lombardi MS, Kavelaars A, Heijnen CJ, Schmidt RE, Schedlowski M. Patients with systemic lupus erythematosus differ from healthy controls in their immunological response to acute psychological stress. Brain Behav Immun. 1999 Dec;13(4):287-302. doi: 10.1006/brbi.1999.0553.
PMID: 10600217
citation: Schedlowski M, Hosch W, Oberbeck R, Benschop RJ, Jacobs R, Raab HR, Schmidt RE. Catecholamines modulate human NK cell circulation and function via spleen-independent beta 2-adrenergic mechanisms. J Immunol. 1996 Jan 1;156(1):93-9.
PMID: 8598500
citation: Schmid-Ott G, Jacobs R, Jager B, Klages S, Wolf J, Werfel T, Kapp A, Schurmeyer T, Lamprecht F, Schmidt RE, Schedlowski M. Stress-induced endocrine and immunological changes in psoriasis patients and healthy controls. A preliminary study. Psychother Psychosom. 1998;67(1):37-42. doi: 10.1159/000012257.
PMID: 9491439
responsible party type: Sponsor
mesh term: Fractures, Stress
mesh term: Stress Disorders, Traumatic, Acute
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 