Acute Stress Reaction
Conditions
Keywords
acute stress reaction, stress, stress perception, physiological stress response, Neurexan
Brief summary
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
Detailed description
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®.
Interventions
DRUGNeurexan®
0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes
OTHERPlacebo
6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes
Sponsors
Biologische Heilmittel Heel GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
31 Years to 59 Years
Healthy volunteers
Yes
Inclusion criteria
1. Provide written informed consent 2. Healthy male or female 3. age between 31 to 59 years 4. Fluent in German language. 5. Ability to understand the explanations and instructions given by the study physician
Exclusion criteria
1. allergies to ingredients of Neurexan® (Passiflora incarnata, Avena sativa, Coffea arabica, Zincum isovalerianicum, lactose monohydrate, magnesium stearate) or Placebo 2. lactose intolerance 3. use of any psychological stress-management intervention within the last 4 weeks 4. sick leave for any reason 5. participation in any other clinical study 3 months prior to Screening Visit 6. current or recent (3 months prior to Screening Visit) history of substance abuse or drug dependence including nicotine and alcohol (as verified in the respective IDCL list) 7. smokers 8. alcohol intake within last 24 hours (before Baseline Visit V3) 9. shift workers or work regularly during night time 10. use of any psychotropic medication or suffering from severe psychiatric illness needing acute intervention 11. BMI \> 30 kg/m2 12. currently pregnant (verified by urine pregnancy test) or lactating 13. participation in a previous TSST study 14. high chronic stress as verified with the TICS-SSCS (a score of ≥ 23 on the screening scale for chronic stress meets the criterion of being chronically stressed) 15. major mental disorder as verified with the IDCL (depressive episode, panic disorder, social phobia, obsessive-compulsory disorder; alcohol dependency; schizophrenia and mania.) 16. employee of the Sponsor, one of the investigators or the CRO 17. use of any concomitant medication except contraceptives 18. any somatic disease or other condition the Investigator or their duly assigned representatives believes may affect the ability of the individual to complete the study or the interpretation of the study results 19. Individuals whose ability to speak for themselves lacks or can be doubted
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Acute Stress Measured by Tension | -210 minutes to +100 minutes | 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. |
| Acute Stress Measured by Nervousness | -210 minutes to +100 minutes | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Changes in Saliva Cortisol | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 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. |
| Changes in Saliva Alpha Amylase | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 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. |
| Changes in Plasma Adrenocorticotropic Hormone (ACTH) | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 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. |
| Changes in Plasma Cortisol | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 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. |
| Changes in Plasma Catecholamines (Epinephrine) | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 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. |
| Changes in Plasma Catecholamines (Norepinephrine) | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 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. |
| Changes in Natural Killer (NK) Cells (Subgroup) | -60 minutes, +15 minutes, +45 minutes, +100 minutes | 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. |
| Changes in Blood Pressure | -15 minutes, 0 minutes, +15 minutes, +45 minutes | 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. |
| Changes in Heart Rate | -15 minutes, 0 minutes, +15 minutes, +45 minutes | 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. |
| State Anxiety and Stress Perception Measured by STAI-X1 | -90 minutes, +15 minutes, +100 minutes | 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. |
| Psychological Questionnaire (Modified Somatic SCL90) | -210 minutes, +100 minutes | 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. |
Countries
Germany
Participant flow
Recruitment details
Recruitment was carried out in 2 outpatient clinics in Germany (Marburg and Essen).
Pre-assignment details
All 66 healthy participants were enrolled and none of them was excluded prior to randomization.
Participants by arm
| Arm | Count |
|---|---|
| Neurexan® 0.6 mg / tablet, 6 tablets, 1 tablet every 30 minutes from -180 minutes to
-30 minutes
Neurexan® | 34 |
| Placebo 6 tablets, 1 tablet every 30 minutes from -180 minutes to -30 minutes
Placebo | 32 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 1 |
Baseline characteristics
| Characteristic | Neurexan® | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 34 Participants | 32 Participants | 66 Participants |
| Age, Continuous | 41.1 Years STANDARD_DEVIATION 7 | 40.7 Years STANDARD_DEVIATION 8.2 | 40.9 Years STANDARD_DEVIATION 7.6 |
| Region of Enrollment Germany | 34 participants | 32 participants | 66 participants |
| Sex: Female, Male Female | 18 Participants | 16 Participants | 34 Participants |
| Sex: Female, Male Male | 16 Participants | 16 Participants | 32 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 4 / 34 | 3 / 32 |
| serious Total, serious adverse events | 0 / 34 | 0 / 32 |
Outcome results
Primary
Acute Stress Measured by Nervousness
Tension and nervousness were self-assessed by the participants on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) before and after a stress test. The VAS is used to determine the subjective impression of tension and nervousness on a 10 cm bipolar visual scale ranging from 0 = not at all to 100 = highly. The measurements started with first intake of Neurexan or 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.
Time frame: -210 minutes to +100 minutes
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neurexan® | Acute Stress Measured by Nervousness | 3147.4 mm*min |
| Placebo | Acute Stress Measured by Nervousness | 3022.5 mm*min |
Comparison: The null-hypotheses of no treatment differences were tested by the two-sided t-tests from the respective ANCOV As.p-value: 0.5702ANCOVA
Primary
Acute Stress Measured by Tension
Tension and nervousness were self-assessed by the participants on a 0 to 100 millimeter (mm) Visual Analogue Scale (VAS) before and after a stress test. The VAS is used to determine the subjective impression of tension and nervousness on a 10 cm bipolar visual scale ranging from 0 = not at all to 100 = highly. The measurements started with first intake of Neurexan or 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.
Time frame: -210 minutes to +100 minutes
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.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Neurexan® | Acute Stress Measured by Tension | 3335.7 mm*min |
| Placebo | Acute Stress Measured by Tension | 3360.3 mm*min |
Comparison: The null-hypotheses of no treatment differences were tested by the two-sided t-tests from the respective ANCOVAs.p-value: 0.7726ANCOVA
Secondary
Changes in Blood Pressure
Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording. The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test.
Time frame: -15 minutes, 0 minutes, +15 minutes, +45 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Changes in Blood Pressure | Systolic -15 min | 122.0 mmHg |
| Neurexan® | Changes in Blood Pressure | Systolic 0 min | 132.0 mmHg |
| Neurexan® | Changes in Blood Pressure | Systolic +15 min | 125.0 mmHg |
| Neurexan® | Changes in Blood Pressure | Systolic +45 min | 121.5 mmHg |
| Neurexan® | Changes in Blood Pressure | Diastolic - 15 min | 79.5 mmHg |
| Neurexan® | Changes in Blood Pressure | Diastolic 0 min | 81.0 mmHg |
| Neurexan® | Changes in Blood Pressure | Diastolic +15 min | 83.5 mmHg |
| Neurexan® | Changes in Blood Pressure | Diastolic +45 min | 81.0 mmHg |
| Placebo | Changes in Blood Pressure | Diastolic +45 min | 83.0 mmHg |
| Placebo | Changes in Blood Pressure | Systolic -15 min | 123.5 mmHg |
| Placebo | Changes in Blood Pressure | Diastolic - 15 min | 81.5 mmHg |
| Placebo | Changes in Blood Pressure | Systolic 0 min | 142.0 mmHg |
| Placebo | Changes in Blood Pressure | Diastolic +15 min | 89.0 mmHg |
| Placebo | Changes in Blood Pressure | Systolic +15 min | 133.5 mmHg |
| Placebo | Changes in Blood Pressure | Diastolic 0 min | 91.0 mmHg |
| Placebo | Changes in Blood Pressure | Systolic +45 min | 125.0 mmHg |
Secondary
Changes in Heart Rate
Blood pressure and heart rate were measured before and after a stress test by continuous cardiovascular recording. The measurements started 30 minutes before stress test and were repeated until 45 minutes after the end of the stress test.
Time frame: -15 minutes, 0 minutes, +15 minutes, +45 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Changes in Heart Rate | -15 min | 70.0 beats per minute |
| Neurexan® | Changes in Heart Rate | 0 min | 88.0 beats per minute |
| Neurexan® | Changes in Heart Rate | +15 min | 69.5 beats per minute |
| Neurexan® | Changes in Heart Rate | +45 min | 71.0 beats per minute |
| Placebo | Changes in Heart Rate | +45 min | 71.0 beats per minute |
| Placebo | Changes in Heart Rate | -15 min | 69.0 beats per minute |
| Placebo | Changes in Heart Rate | +15 min | 71.0 beats per minute |
| Placebo | Changes in Heart Rate | 0 min | 89.5 beats per minute |
Secondary
Changes in Natural Killer (NK) Cells (Subgroup)
The Natural Killer Cells as immune cells and stress biomarkers were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test.
Time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Changes in Natural Killer (NK) Cells (Subgroup) | - 60 min | 13.5 percentage of lymphocytes |
| Neurexan® | Changes in Natural Killer (NK) Cells (Subgroup) | +15 min | 21.00 percentage of lymphocytes |
| Neurexan® | Changes in Natural Killer (NK) Cells (Subgroup) | +45 min | 10.30 percentage of lymphocytes |
| Neurexan® | Changes in Natural Killer (NK) Cells (Subgroup) | +100 min | 13.10 percentage of lymphocytes |
| Placebo | Changes in Natural Killer (NK) Cells (Subgroup) | +100 min | 8.65 percentage of lymphocytes |
| Placebo | Changes in Natural Killer (NK) Cells (Subgroup) | - 60 min | 11.65 percentage of lymphocytes |
| Placebo | Changes in Natural Killer (NK) Cells (Subgroup) | +45 min | 9.10 percentage of lymphocytes |
| Placebo | Changes in Natural Killer (NK) Cells (Subgroup) | +15 min | 20.40 percentage of lymphocytes |
Secondary
Changes in Plasma Adrenocorticotropic Hormone (ACTH)
The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test.
Time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Changes in Plasma Adrenocorticotropic Hormone (ACTH) | - 60 min | 22.5 ng/L |
| Neurexan® | Changes in Plasma Adrenocorticotropic Hormone (ACTH) | +15 min | 37.7 ng/L |
| Neurexan® | Changes in Plasma Adrenocorticotropic Hormone (ACTH) | +45 min | 20.3 ng/L |
| Neurexan® | Changes in Plasma Adrenocorticotropic Hormone (ACTH) | +100 min | 11.3 ng/L |
| Placebo | Changes in Plasma Adrenocorticotropic Hormone (ACTH) | +100 min | 10.7 ng/L |
| Placebo | Changes in Plasma Adrenocorticotropic Hormone (ACTH) | - 60 min | 19.1 ng/L |
| Placebo | Changes in Plasma Adrenocorticotropic Hormone (ACTH) | +45 min | 20.7 ng/L |
| Placebo | Changes in Plasma Adrenocorticotropic Hormone (ACTH) | +15 min | 37.0 ng/L |
Secondary
Changes in Plasma Catecholamines (Epinephrine)
The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test.
Time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Changes in Plasma Catecholamines (Epinephrine) | - 60 min | 42.6 ng/L |
| Neurexan® | Changes in Plasma Catecholamines (Epinephrine) | +15 min | 32.9 ng/L |
| Neurexan® | Changes in Plasma Catecholamines (Epinephrine) | +45 min | 41.4 ng/L |
| Neurexan® | Changes in Plasma Catecholamines (Epinephrine) | +100 min | 31.9 ng/L |
| Placebo | Changes in Plasma Catecholamines (Epinephrine) | +100 min | 41.1 ng/L |
| Placebo | Changes in Plasma Catecholamines (Epinephrine) | - 60 min | 35.6 ng/L |
| Placebo | Changes in Plasma Catecholamines (Epinephrine) | +45 min | 26.4 ng/L |
| Placebo | Changes in Plasma Catecholamines (Epinephrine) | +15 min | 47.4 ng/L |
Secondary
Changes in Plasma Catecholamines (Norepinephrine)
The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test.
Time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Changes in Plasma Catecholamines (Norepinephrine) | - 60 min | 463.0 ng/L |
| Neurexan® | Changes in Plasma Catecholamines (Norepinephrine) | +15 min | 584.0 ng/L |
| Neurexan® | Changes in Plasma Catecholamines (Norepinephrine) | +45 min | 481.0 ng/L |
| Neurexan® | Changes in Plasma Catecholamines (Norepinephrine) | +100 min | 451.5 ng/L |
| Placebo | Changes in Plasma Catecholamines (Norepinephrine) | +100 min | 482.5 ng/L |
| Placebo | Changes in Plasma Catecholamines (Norepinephrine) | - 60 min | 457.0 ng/L |
| Placebo | Changes in Plasma Catecholamines (Norepinephrine) | +45 min | 476.0 ng/L |
| Placebo | Changes in Plasma Catecholamines (Norepinephrine) | +15 min | 591.5 ng/L |
Secondary
Changes in Plasma Cortisol
The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test.
Time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Changes in Plasma Cortisol | - 60 min | 331.6 nmol/L |
| Neurexan® | Changes in Plasma Cortisol | +15 min | 441.1 nmol/L |
| Neurexan® | Changes in Plasma Cortisol | +45 min | 403.1 nmol/L |
| Neurexan® | Changes in Plasma Cortisol | +100 min | 228.4 nmol/L |
| Placebo | Changes in Plasma Cortisol | +100 min | 273.3 nmol/L |
| Placebo | Changes in Plasma Cortisol | - 60 min | 325.5 nmol/L |
| Placebo | Changes in Plasma Cortisol | +45 min | 535.4 nmol/L |
| Placebo | Changes in Plasma Cortisol | +15 min | 569.8 nmol/L |
Secondary
Changes in Saliva Alpha Amylase
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.
Time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Changes in Saliva Alpha Amylase | - 60 min | 112.9 IU/mL |
| Neurexan® | Changes in Saliva Alpha Amylase | +15 min | 201.9 IU/mL |
| Neurexan® | Changes in Saliva Alpha Amylase | +45 min | 140.8 IU/mL |
| Neurexan® | Changes in Saliva Alpha Amylase | +100 min | 149.9 IU/mL |
| Placebo | Changes in Saliva Alpha Amylase | +100 min | 140.6 IU/mL |
| Placebo | Changes in Saliva Alpha Amylase | - 60 min | 133.3 IU/mL |
| Placebo | Changes in Saliva Alpha Amylase | +45 min | 142.1 IU/mL |
| Placebo | Changes in Saliva Alpha Amylase | +15 min | 216.0 IU/mL |
Secondary
Changes in Saliva Cortisol
The stress biomarkers plasma and saliva cortisol and alpha amylase and Adrenocorticotropic Hormone and catecholamines (norepinephrine and epinephrine) were measured before and after a stress test. The measurements started 60 minutes before stress test and were repeated until 100 minutes after the end of the stress test.
Time frame: -60 minutes, +15 minutes, +45 minutes, +100 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Changes in Saliva Cortisol | - 60 min | 7.1 nmol/mL |
| Neurexan® | Changes in Saliva Cortisol | +45 min | 15.3 nmol/mL |
| Neurexan® | Changes in Saliva Cortisol | +100 min | 6.4 nmol/mL |
| Neurexan® | Changes in Saliva Cortisol | +15 min | 19.4 nmol/mL |
| Placebo | Changes in Saliva Cortisol | +100 min | 8.9 nmol/mL |
| Placebo | Changes in Saliva Cortisol | - 60 min | 7.1 nmol/mL |
| Placebo | Changes in Saliva Cortisol | +15 min | 20.0 nmol/mL |
| Placebo | Changes in Saliva Cortisol | +45 min | 21.2 nmol/mL |
Secondary
Psychological Questionnaire (Modified Somatic SCL90)
The SCL90 has 90 items with dimensions like depression, somatization, obsessive-compulsive disorder, social insecurity, anxiety, phobic anxiety, aggression/hostility, paranoid ideation, psychoticism and each item in a subscale ranged from 0 to 4. The lower range values are favorable outcomes and higher are worse outcomes. The modified somatic SCL90 uses the SCL90 somatization items, but instead of a 7 day timeframe asks for now. The corresponding items from SCL90 were: 1, 4, 12, 27, 40, 42, 48, 49, 52, 53, 56, 58 and the introductory question: How much do you currently suffer from (Wie sehr leiden Sie momentan unter:). The median of the average Modified Somatic SCL90 score is reported. The average score was calculated at each time point as the sum score divided by the number of non-missing individual question results for subjects with no more than 2 missing responses. The lower values in the range represent favorable outcomes while the higher values represent worse outcomes.
Time frame: -210 minutes, +100 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | Psychological Questionnaire (Modified Somatic SCL90) | - 210 min | 0.000 units on a scale |
| Neurexan® | Psychological Questionnaire (Modified Somatic SCL90) | +100 min | 0.000 units on a scale |
| Placebo | Psychological Questionnaire (Modified Somatic SCL90) | - 210 min | 0.000 units on a scale |
| Placebo | Psychological Questionnaire (Modified Somatic SCL90) | +100 min | 0.000 units on a scale |
Secondary
State Anxiety and Stress Perception Measured by STAI-X1
State anxiety and stress perception were measured by State-Trait Anxiety Inventory X1 before and after a stress test. The measurements took place 90 minutes before 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.
Time frame: -90 minutes, +15 minutes, +100 minutes
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.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Neurexan® | State Anxiety and Stress Perception Measured by STAI-X1 | - 90 min | 31.0 units on a scale |
| Neurexan® | State Anxiety and Stress Perception Measured by STAI-X1 | +15 min | 54.5 units on a scale |
| Neurexan® | State Anxiety and Stress Perception Measured by STAI-X1 | +100 min | 33.0 units on a scale |
| Placebo | State Anxiety and Stress Perception Measured by STAI-X1 | - 90 min | 29.5 units on a scale |
| Placebo | State Anxiety and Stress Perception Measured by STAI-X1 | +15 min | 51.5 units on a scale |
| Placebo | State Anxiety and Stress Perception Measured by STAI-X1 | +100 min | 31.5 units on a scale |