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

Primary Purpose

Acute Stress Reaction

Status
Completed
Phase
Phase 2
Locations
Germany
Study Type
Interventional
Intervention
Neurexan®
Placebo
Sponsored by
Biologische Heilmittel Heel GmbH
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Stress Reaction

Eligibility Criteria

31 Years - 59 Years (Adult)MaleAccepts Healthy Volunteers

Inclusion Criteria:

  1. Male
  2. Age between ≥31 to ≤59 years
  3. Fluent in German language
  4. Nonsmoker
  5. Able to understand the explanations and instructions given by the study physician
  6. Willing to adhere to the prohibitions and restrictions specified in this protocol
  7. Healthy on the basis of clinical laboratory tests, physical examination, medical history, vital signs performed at Screening Visit
  8. Magnetic Resonance Imaging (MRI) compatible
  9. Participants must have signed a written informed consent document prior to any study procedure indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study
  10. Trier Inventory for Chronic Stress (TICS) Score ≥ 9 and ≤ 36
  11. Perceived Stress Scale (PSS) > 9

Exclusion Criteria:

  1. Current or past history of psychotic features or a diagnosis of any psychiatric disorder as defined in the Diagnostic and Statistical Manual of Mental Disorder 4th edition (DSM-IV) Axis I (recurrent major depression, panic disorder, social phobia, obsessive-compulsory disorder; alcohol dependency; schizophrenia and mania)
  2. History of depressive episodes during the last 3 months prior to Screening Visit
  3. Use of any psychotropic medication or suffering from severe psychiatric illness during the last 3 months prior to Screening Visit
  4. Intake of prescription drugs for sleeping disorders or nervousness within one month prior to Screening Visit
  5. Intake of over the counter (OTC) medication for the treatment of sleeping disorders or nervousness within the last (one) week prior to Screening Visit
  6. High chronic stress as verified with the TICS-SSCS (> 36)
  7. Low chronic stress as verified with the TICS-SSCS (< 9) and PSS ≤ 9
  8. Participants with Blood Pressure (BP) ≥ 160/100 on day 0 and at randomization
  9. Participants with treated hypertension
  10. Known allergies and/or hypersensitivity to ingredients of Neurexan® (Passiflora incarnata, Avena sativa, Coffea arabica, Zincum isovalerianicum, lactose monohydrate, magnesium stearate) or Placebo (Lactose monohydrate, magnesium stearate)
  11. Known Lactose intolerance
  12. Use of any psychological stress-management intervention within the last 4 weeks prior to Screening Visit
  13. History of substance, drug, including nicotine, or alcohol abuse within the preceding 3 months prior to Screening Visit
  14. Alcohol, drug, nicotine intake within the last 24 hours before day 0 and at randomization - confirmed by positive screening tests
  15. Body Mass Index (BMI) > 30 kg/m2
  16. Works regularly nights shifts
  17. Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic or hematologic disease as defined by clinical screening interview
  18. Any somatic disease or other condition the Investigator or their duly assigned representatives believes could affect the ability of the individual to complete the study or the interpretation of the study results
  19. Participants with medical illness that may have influenced brain morphology and/or physiology (e.g. uncontrolled hypertension, diabetes)
  20. Participants with a history of one or more seizures without a clear and resolved aetiology
  21. Participants with claustrophobia
  22. Participants with tinnitus
  23. Clinically significant acute illness within 7 days prior to randomization
  24. Presence of metallic (ferromagnetic) implants (heart pacemaker, aneurysm clips), tattoos or piercings
  25. Have received an experimental drug or used an experimental medical device (participation in any other clinical trial) within the last 30 days before study inclusion
  26. Participants whose ability to speak for themselves lacks or can be doubted

Sites / Locations

  • Clinical Affective Neuroimaging Laboratory (CANLAB)

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Neurexan®

Placebo

Arm Description

0.6 mg / tablet, 3 tablets, 40-60 minutes before the second MRI Intervention: Drug: Neurexan®

3 tablets, 40-60 minutes before the second MRI

Outcomes

Primary Outcome Measures

Reduced amygdala responsiveness measured by negative face to form contrasts in the Hariri task (Hariri et. al., 2000; Hariri et. al., 2003) after verum versus placebo condition
Primary Outcome 1: Effect of drug, driven by significantly smaller amygdala activations in the contrast (negative faces vs forms) in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates.
Reduced functional connectivity density (FCD) in amygdala after verum versus placebo condition during rest.
Primary Outcome 2: Interaction of time and drug, driven by significantly greater reductions of amygdala functional connectivity density (FCD) in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates.
Reduced whole brain functional connectivity of amygdala after verum versus placebo condition during rest.
Primary Outcome 3: Interaction of time and drug, driven by significantly greater changes (smaller and greater, two sided effects because of inclusion of top down and bottom up processes in different regions) of amygdala seeded connectivities in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the whole brain.
Reduced local resting state activity of amygdala after verum versus placebo condition.
Primary Outcome 4: Interaction of time and drug, driven by significantly greater reductions of amygdala ALFF in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates.
Increased effective connectivity from frontal cortex to amygdala during Hariri experiment after verum versus placebo condition.
Primary Outcome 5: Influence of drug on directed connectivity in an effective connectivity model (DCM) from ventral prefrontal cortex (vPFC) towards amygdala, driven by positive effects of verum on directed negative effective (top down) connectivity from vPFC to amygdala. Significance for the modulating effect of drug on effective connectivity is accepted for a p level of 0.05, for a winning model selected based on Bayesian information criterion (BIC) across all subjects and scans (verum and placebo) (Sladky et al 2013).
Reduced stress network activation during stress (MIST) in verum relative to placebo.
Primary Outcome 6: Effect of drug, driven by significantly smaller activations in anterior cingulate cortex, medio-orbitofrontal cortex, hippocampus, amygdala, and hypothalamus in the contrast (hard vs easy) in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates.

Secondary Outcome Measures

Normalized EEG frontal frequency changes associated with normalized HRV in verum relative to placebo conditions.
High morning cortisol and alpha-amylase level predicts increased subjective stress response (VAS, STAI-XI), effect which is reversed in verum but not in placebo condition.
Individual cortisol and alpha-amylase level at 8 timepoints during the MRI visits, VAS (tensions and nervousness) at 7 timepoints, and STAI-X1 at 6 timepoints will be computed as the area under the curve. The relation between change in cortisol, VAS (tension and nervousness) and personality traits (TCI), coping to stress (ABI, FKK), self-esteem (Rosenberg Self-Esteem), and childhood traumatic experiences (CTQ) will be investigated by the use of non-parametric correlations analysis. Changes in subject reported outcome instruments and stress response by morning cortisol and alpha amylase will be evaluated within the framework of formal crossover analyses. Due to unknown distributions, the analysis will be of nonparametric nature.
Reduced subjects stress perception as assessed with STAI-XI, VAS after MIST task in verum relative to placebo condition.
The analysis is already described under point "Outcome 8" and "Outcome 10" of secondary outcome measures.
Personality traits assessed with TCI predicted stress response.
It will be investigated how personality traits (TCI), anxiety level (STAI), depressive symptoms (BDI-II), self-esteem, subject's coping strategies as well as cognitive processes predict stress response and the relation with Neurexan® efficiency. Regression analyses will be conducted on resting state functional connectivity in placebo and verum conditions. These exploratory analyses are hypothesis generating in order to confine follow up investigations.

Full Information

First Posted
October 28, 2015
Last Updated
January 27, 2016
Sponsor
Biologische Heilmittel Heel GmbH
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1. Study Identification

Unique Protocol Identification Number
NCT02602275
Brief Title
Neuronal Correlates of Neurexan® Action in Mildly to Moderately Stressed Probands
Acronym
NEURIM
Official Title
Neuronal Correlates of Neurexan® Action in Mildly to Moderately Stressed Probands - A Randomized, Placebo-controlled, Double-blind, Cross-over Trial of Mode of Action and Response Prediction by Functional Magnetic Resonance Imaging MRI
Study Type
Interventional

2. Study Status

Record Verification Date
January 2016
Overall Recruitment Status
Completed
Study Start Date
August 2015 (undefined)
Primary Completion Date
December 2015 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Biologische Heilmittel Heel GmbH

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to explore the effect of Neurexan® on the brain response when participants undergo an emotional stressful condition in verum compared to placebo.
Detailed Description
A randomized placebo-controlled, double-blind, two-period crossover study with an explorative design. 40 healthy males aged 31-59 years will be included in the study. Participant allocation to either Neurexan® or Placebo at study start is randomized with a ratio of 1:1, i.e. 20 Neurexan® first to 20 Placebo first individuals. Participants receive totally three tablets of either Neurexan® or Placebo per treatment period orally.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Stress Reaction

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Crossover Assignment
Masking
ParticipantCare ProviderInvestigator
Allocation
Randomized
Enrollment
53 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Neurexan®
Arm Type
Experimental
Arm Description
0.6 mg / tablet, 3 tablets, 40-60 minutes before the second MRI Intervention: Drug: Neurexan®
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
3 tablets, 40-60 minutes before the second MRI
Intervention Type
Drug
Intervention Name(s)
Neurexan®
Intervention Description
There are two experimental conditions; in one condition participants receive Neurexan® and the second condition they receive Placebo for oral administration (three tablets) in a cross over design. In the experimantal arm participants will receive verum on DAY1/PERIOD 1 and will receive placebo on DAY2/PERIOD 2.
Intervention Type
Other
Intervention Name(s)
Placebo
Intervention Description
There are two experimental conditions; in one condition participants receive Neurexan® and the second condition they receive Placebo for oral administration (three tablets) in a cross over design. In the comparator arm participants will receive placebo on DAY1/PERIOD 1 and will receive verum on DAY2/PERIOD 2.
Primary Outcome Measure Information:
Title
Reduced amygdala responsiveness measured by negative face to form contrasts in the Hariri task (Hariri et. al., 2000; Hariri et. al., 2003) after verum versus placebo condition
Description
Primary Outcome 1: Effect of drug, driven by significantly smaller amygdala activations in the contrast (negative faces vs forms) in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates.
Time Frame
Day 1 and Day 2
Title
Reduced functional connectivity density (FCD) in amygdala after verum versus placebo condition during rest.
Description
Primary Outcome 2: Interaction of time and drug, driven by significantly greater reductions of amygdala functional connectivity density (FCD) in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates.
Time Frame
Day 1 and Day 2
Title
Reduced whole brain functional connectivity of amygdala after verum versus placebo condition during rest.
Description
Primary Outcome 3: Interaction of time and drug, driven by significantly greater changes (smaller and greater, two sided effects because of inclusion of top down and bottom up processes in different regions) of amygdala seeded connectivities in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the whole brain.
Time Frame
Day 1 and Day 2
Title
Reduced local resting state activity of amygdala after verum versus placebo condition.
Description
Primary Outcome 4: Interaction of time and drug, driven by significantly greater reductions of amygdala ALFF in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates.
Time Frame
Day 1 and Day 2
Title
Increased effective connectivity from frontal cortex to amygdala during Hariri experiment after verum versus placebo condition.
Description
Primary Outcome 5: Influence of drug on directed connectivity in an effective connectivity model (DCM) from ventral prefrontal cortex (vPFC) towards amygdala, driven by positive effects of verum on directed negative effective (top down) connectivity from vPFC to amygdala. Significance for the modulating effect of drug on effective connectivity is accepted for a p level of 0.05, for a winning model selected based on Bayesian information criterion (BIC) across all subjects and scans (verum and placebo) (Sladky et al 2013).
Time Frame
Day 1 and Day 2
Title
Reduced stress network activation during stress (MIST) in verum relative to placebo.
Description
Primary Outcome 6: Effect of drug, driven by significantly smaller activations in anterior cingulate cortex, medio-orbitofrontal cortex, hippocampus, amygdala, and hypothalamus in the contrast (hard vs easy) in verum compared to placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates.
Time Frame
Day 1 and Day 2
Secondary Outcome Measure Information:
Title
Normalized EEG frontal frequency changes associated with normalized HRV in verum relative to placebo conditions.
Time Frame
Day 1 and Day 2
Title
High morning cortisol and alpha-amylase level predicts increased subjective stress response (VAS, STAI-XI), effect which is reversed in verum but not in placebo condition.
Description
Individual cortisol and alpha-amylase level at 8 timepoints during the MRI visits, VAS (tensions and nervousness) at 7 timepoints, and STAI-X1 at 6 timepoints will be computed as the area under the curve. The relation between change in cortisol, VAS (tension and nervousness) and personality traits (TCI), coping to stress (ABI, FKK), self-esteem (Rosenberg Self-Esteem), and childhood traumatic experiences (CTQ) will be investigated by the use of non-parametric correlations analysis. Changes in subject reported outcome instruments and stress response by morning cortisol and alpha amylase will be evaluated within the framework of formal crossover analyses. Due to unknown distributions, the analysis will be of nonparametric nature.
Time Frame
Day 1 and Day 2
Title
Reduced subjects stress perception as assessed with STAI-XI, VAS after MIST task in verum relative to placebo condition.
Description
The analysis is already described under point "Outcome 8" and "Outcome 10" of secondary outcome measures.
Time Frame
Day 1 and Day 2
Title
Personality traits assessed with TCI predicted stress response.
Description
It will be investigated how personality traits (TCI), anxiety level (STAI), depressive symptoms (BDI-II), self-esteem, subject's coping strategies as well as cognitive processes predict stress response and the relation with Neurexan® efficiency. Regression analyses will be conducted on resting state functional connectivity in placebo and verum conditions. These exploratory analyses are hypothesis generating in order to confine follow up investigations.
Time Frame
Screening Visit

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
31 Years
Maximum Age & Unit of Time
59 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Male Age between ≥31 to ≤59 years Fluent in German language Nonsmoker Able to understand the explanations and instructions given by the study physician Willing to adhere to the prohibitions and restrictions specified in this protocol Healthy on the basis of clinical laboratory tests, physical examination, medical history, vital signs performed at Screening Visit Magnetic Resonance Imaging (MRI) compatible Participants must have signed a written informed consent document prior to any study procedure indicating that they understand the purpose of and procedures required for the study and are willing to participate in the study Trier Inventory for Chronic Stress (TICS) Score ≥ 9 and ≤ 36 Perceived Stress Scale (PSS) > 9 Exclusion Criteria: Current or past history of psychotic features or a diagnosis of any psychiatric disorder as defined in the Diagnostic and Statistical Manual of Mental Disorder 4th edition (DSM-IV) Axis I (recurrent major depression, panic disorder, social phobia, obsessive-compulsory disorder; alcohol dependency; schizophrenia and mania) History of depressive episodes during the last 3 months prior to Screening Visit Use of any psychotropic medication or suffering from severe psychiatric illness during the last 3 months prior to Screening Visit Intake of prescription drugs for sleeping disorders or nervousness within one month prior to Screening Visit Intake of over the counter (OTC) medication for the treatment of sleeping disorders or nervousness within the last (one) week prior to Screening Visit High chronic stress as verified with the TICS-SSCS (> 36) Low chronic stress as verified with the TICS-SSCS (< 9) and PSS ≤ 9 Participants with Blood Pressure (BP) ≥ 160/100 on day 0 and at randomization Participants with treated hypertension Known allergies and/or hypersensitivity to ingredients of Neurexan® (Passiflora incarnata, Avena sativa, Coffea arabica, Zincum isovalerianicum, lactose monohydrate, magnesium stearate) or Placebo (Lactose monohydrate, magnesium stearate) Known Lactose intolerance Use of any psychological stress-management intervention within the last 4 weeks prior to Screening Visit History of substance, drug, including nicotine, or alcohol abuse within the preceding 3 months prior to Screening Visit Alcohol, drug, nicotine intake within the last 24 hours before day 0 and at randomization - confirmed by positive screening tests Body Mass Index (BMI) > 30 kg/m2 Works regularly nights shifts Serious, unstable illnesses including hepatic, renal, gastroenterologic, respiratory, cardiovascular, endocrinologic, neurologic, immunologic or hematologic disease as defined by clinical screening interview Any somatic disease or other condition the Investigator or their duly assigned representatives believes could affect the ability of the individual to complete the study or the interpretation of the study results Participants with medical illness that may have influenced brain morphology and/or physiology (e.g. uncontrolled hypertension, diabetes) Participants with a history of one or more seizures without a clear and resolved aetiology Participants with claustrophobia Participants with tinnitus Clinically significant acute illness within 7 days prior to randomization Presence of metallic (ferromagnetic) implants (heart pacemaker, aneurysm clips), tattoos or piercings Have received an experimental drug or used an experimental medical device (participation in any other clinical trial) within the last 30 days before study inclusion Participants whose ability to speak for themselves lacks or can be doubted
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Martin Walter, PD Dr Med.
Organizational Affiliation
Clinical Affective Neuroimaging Laboratory, Univ. Magdeburg, Germany
Official's Role
Principal Investigator
Facility Information:
Facility Name
Clinical Affective Neuroimaging Laboratory (CANLAB)
City
Magdeburg
Country
Germany

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
35438535
Citation
Chand T, Alizadeh S, Li M, Fan Y, Jamalabadi H, Danyeli L, Nanni-Zepeda M, Herrmann L, Van der Meer J, Vester JC, Schultz M, Naschold B, Walter M. Nx4 Modulated Resting-State Functional Connectivity Between Amygdala and Prefrontal Cortex in a Placebo-Controlled, Crossover Trial. Brain Connect. 2022 Nov;12(9):812-822. doi: 10.1089/brain.2021.0189. Epub 2022 Jun 10.
Results Reference
derived
PubMed Identifier
35213077
Citation
Herrmann L, Kasties V, Boden C, Li M, Fan Y, Van der Meer J, Vester JC, Seilheimer B, Schultz M, Alizadeh S, Walter M. Nx4 attenuated stress-induced activity of the anterior cingulate cortex-A post-hoc analysis of a randomized placebo-controlled crossover trial. Hum Psychopharmacol. 2022 Sep;37(5):e2837. doi: 10.1002/hup.2837. Epub 2022 Feb 25.
Results Reference
derived
PubMed Identifier
34912250
Citation
Mayer K, Krylova M, Alizadeh S, Jamalabadi H, van der Meer J, Vester JC, Naschold B, Schultz M, Walter M. Nx4 Reduced Susceptibility to Distraction in an Attention Modulation Task. Front Psychiatry. 2021 Nov 29;12:746215. doi: 10.3389/fpsyt.2021.746215. eCollection 2021.
Results Reference
derived
PubMed Identifier
32971266
Citation
Krylova M, Alizadeh S, Izyurov I, Teckentrup V, Chang C, van der Meer J, Erb M, Kroemer N, Koenig T, Walter M, Jamalabadi H. Evidence for modulation of EEG microstate sequence by vigilance level. Neuroimage. 2021 Jan 1;224:117393. doi: 10.1016/j.neuroimage.2020.117393. Epub 2020 Sep 21.
Results Reference
derived

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

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