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| ID | Type | Description | Link |
|---|---|---|---|
| 2015-001802-32 | EudraCT Number |
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The purpose of this study is to explore the effect of Neurexan® on the brain response when participants undergo an emotional stressful condition in verum compared to placebo.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Neurexan first, then Placebo | Experimental | Participants received a single dose of three Neurexan tablets on trial Day 1. Following a washout period of 7 to 35 days, they received a single dose of three placebo tablets on trial Day 2. |
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| Placebo first, then Neurexan | Experimental | Participants received a single dose of three Placebo tablets on trial Day 1. Following a washout period of 7 to 35 days, they received a single dose of three Neurexan tablets on trial Day 2. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Neurexan | Drug | 0.6 mg / tablet |
|
| Measure | Description | Time Frame |
|---|---|---|
| Functional Magnetic Resonance Imaging (fMRI) Task Data: BOLD Activation Changes Within Amygdala During Negative Faces in the Hariri Face Matching Task Between Placebo and Neurexan Treatment | The neuronal drug effect was assessed by measuring changes in amygdala activity between placebo and Neurexan using fMRI 1 hour after treatment. The left amygdala was prespecified as region of interest for emotional processing and social stress. Amygdala activation in response to negative emotional faces versus neutral forms in the Hariri task was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation explained by a variable, here negatives faces or forms. Beta values serve as index of neural activity, the higher the beta value, the higher the activity. A paired t-test analysis of extracted beta values for the left amygdala was performed comparing placebo and Neurexan treatment. Amygdala hypersensitivity to negative stimuli is associated with anxiety disorders and increased stress sensitivity, while a reduction in amygdala activation may indicate a calming or modulating effect of the intervention. | 1 hour after taking a single dose of Neurexan or placebo |
| Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Global Functional Connectivity Density of the Amygdala at Rest | Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Highly connected functional hubs were identified by global functional connectivity density (gFCD) analysis. The number of voxels with a positive rsFC larger than the predefined threshold of r > 0.6 at a whole brain level was evaluated. gFCD was calculated for each voxel as the total number of significant correlations between this voxel and all voxels in gray matter. The gFCD value in each voxel was divided by the global mean value to improve normality. The larger the number of significant correlations, the greater the gFCD strength. Changes in gFCD strength of the amygdala from pre-dose to 1-hour post-dose were compared between the Neurexan and Placebo conditions using a within-subject repeated-measures ANOVA with main effects of time (pre- vs. post-dose) and drug (placebo vs. Nx4) and their interaction (time x drug). | 1 hour after taking a single dose of Neurexan or placebo |
| Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Whole-Brain Functional Connectivity of the Amygdala at Rest |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Martin Walter, PD Dr Med. | Clinical Affective Neuroimaging Laboratory, Univ. Magdeburg, Germany | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Clinical Affective Neuroimaging Laboratory (CANLAB) | Magdeburg | Germany |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 32123197 | Result | Herrmann L, Vicheva P, Kasties V, Danyeli LV, Szycik GR, Denzel D, Fan Y, Meer JV, Vester JC, Eskoetter H, Schultz M, Walter M. fMRI Revealed Reduced Amygdala Activation after Nx4 in Mildly to Moderately Stressed Healthy Volunteers in a Randomized, Placebo-Controlled, Cross-Over Trial. Sci Rep. 2020 Mar 2;10(1):3802. doi: 10.1038/s41598-020-60392-w. | |
| 34729551 |
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Out of 53 screened subjects, 40 met all eligibility criteria and were randomized.
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| ID | Title | Description |
|---|---|---|
| FG000 | Neurexan First, Then Placebo | Participants received a single dose of three Neurexan tablets on experimental Day 1. Following a washout period of 7 to 35 days, they received a single dose of three placebo tablets on experimental Day 2. |
| FG001 | Placebo First, Then Neurexan | Participants received a single dose of three placebo tablets on experimental Day 1. Following a washout period of 7 to 35 days, they received a single dose of three Neurexan tablets on experimental Day 2. |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Day 1 |
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| Washout (7-35 Days) |
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| Day 2 |
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One subject from the placebo-first sequence was withdrawn on Day 1 before receiving the investigational medication (no dose was administered). No baseline data were collected for this subject, leaving 19 subjects in this sequence.
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| ID | Title | Description |
|---|---|---|
| BG000 | Neurexan First, Then Placebo | Participants received a single dose of three Neurexan tablets on trial Day 1. Following a washout period of 7 to 35 days, they received a single dose of three placebo tablets on trial Day 2. |
| BG001 | Placebo First, Then Neurexan |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Functional Magnetic Resonance Imaging (fMRI) Task Data: BOLD Activation Changes Within Amygdala During Negative Faces in the Hariri Face Matching Task Between Placebo and Neurexan Treatment | The neuronal drug effect was assessed by measuring changes in amygdala activity between placebo and Neurexan using fMRI 1 hour after treatment. The left amygdala was prespecified as region of interest for emotional processing and social stress. Amygdala activation in response to negative emotional faces versus neutral forms in the Hariri task was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation explained by a variable, here negatives faces or forms. Beta values serve as index of neural activity, the higher the beta value, the higher the activity. A paired t-test analysis of extracted beta values for the left amygdala was performed comparing placebo and Neurexan treatment. Amygdala hypersensitivity to negative stimuli is associated with anxiety disorders and increased stress sensitivity, while a reduction in amygdala activation may indicate a calming or modulating effect of the intervention. | Posted | Mean | Standard Deviation | Beta value | 1 hour after taking a single dose of Neurexan or placebo |
1 day for each intervention
Continuous recording of all adverse events on treatment days after randomization and receipt of at least one dose of the intervention.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Neurexan | Participants received a single dose of three Neurexan tablets (0.6 mg / tablet) on either Day 1 or Day 2 of the trial. The Neurexan "arm" refers to the Neurexan condition in the crossover trial. On the other trial day, the same participants received Placebo. |
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Limited to male participants with mild to moderate chronic stress.
| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Head of Clinical Research | Biologische Heilmittel Heel GmbH | +49 7221 501 | 0 | info@heel.com |
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| ID | Term |
|---|---|
| D040701 | Stress Disorders, Traumatic, Acute |
| ID | Term |
|---|---|
| D040921 | Stress Disorders, Traumatic |
| D000068099 | Trauma and Stressor Related Disorders |
| D001523 | Mental Disorders |
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| ID | Term |
|---|---|
| C483503 | neurexan |
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| Placebo | Drug | Neurexan-matched Placebo tablet |
|
Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Left centromedial amygdala (CeMA) was defined as the seed based on probabilistic cytoarchitectonic maps. The time course of the average BOLD signal within the seed was correlated with the signals in each voxel in the whole brain. The Pearson correlation coefficients were transformed to Z values (Fisher's Z), resulting in a map representing voxel-wise strength of rsFC to the seed region. Changes in left CeMA rsFC from pre-dose to post-dose, evaluated as binary connectivity coefficients, were compared between the Neurexan and Placebo conditions. |
| 1 hour after taking a single dose of Neurexan or placebo |
| Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Baseline Activity of the Amygdala at Rest as Measured by Amplitude of Low-Frequency Fluctuations (ALFF) | The time series in each voxel of the rs-fMRI data were converted to the frequency domain using a Fast Fourier Transform (FFT), and the power spectrum was obtained. The square root of the power spectrum was computed and then averaged across each predefined frequency band. This averaged square root was taken as amplitude of low frequency fluctuation (ALFF). A ratio of the power spectrum of low-frequency range to that of the entire frequency range, i.e. the fractional ALFF (fALFF), was computed. High fALFF in the amygdala may reflect hyperactivity and could serve as a marker for heightened stress sensitivity. To examine the effect of drug on rs-metrics (RS1) while taking baseline rs-metrics before drug administration (RS0) as control variable, mean fALFF values of the amygdala were compared between placebo and Neurexan. | 1 hour after taking a single dose of Neurexan or placebo |
| Functional Magnetic Resonance Imaging (fMRI) Task Data: Stress Network Activation in Response to Psychosocial Stress Induction. | The neuronal drug effect was assessed by measuring activity changes within a predefined stress network, comprising the anterior cingulate cortex, medial orbitofrontal cortex, hippocampus, amygdala, and hypothalamus, between placebo and Neurexan using fMRI. Stress network activation in response to psychosocial stress induced by the ScanSTRESS paradigm was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation that is explained by a variable, in this case mental rotation or simple matching of figures. Beta-estimates serve as an index of neural activity, the higher the beta value, the higher the activity. The paradigm contrast (stress-control) for each participant was taken to a second level analysis of all voxels comprised by an ACC mask. A voxelwise paired t-test, controlled for multiple comparison, compared placebo and verum conditions. The endpoint was assessed approximately 1.5 hours post-dose after a single dose of Neurexan or placebo. | 1.5 hours after taking a single dose of Neurexan or placebo |
| Chand T, Alizadeh S, Jamalabadi H, Herrmann L, Krylova M, Surova G, van der Meer J, Wagner G, Engert V, Walter M. EEG revealed improved vigilance regulation after stress exposure under Nx4 - A randomized, placebo-controlled, double-blind, cross-over trial. IBRO Neurosci Rep. 2021 Sep 25;11:175-182. doi: 10.1016/j.ibneur.2021.09.002. eCollection 2021 Dec. |
| 34912250 | Result | 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. |
| 35438535 | Result | 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. |
| 36434512 | Result | Nanni-Zepeda M, Alizadeh S, Chand T, Kasties V, Fan Y, van der Meer J, Herrmann L, Vester JC, Schulz M, Naschold B, Walter M. Trait anxiety is related to Nx4's efficacy on stress-induced changes in amygdala-centered resting state functional connectivity: a placebo-controlled cross-over trial in mildly to moderately stressed healthy volunteers. BMC Neurosci. 2022 Nov 24;23(1):68. doi: 10.1186/s12868-022-00754-4. |
| 35213077 | Result | 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. |
| 32971266 | Derived | 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. |
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Participants received a single dose of three placebo tablets on trial Day 1. Following a washout period of 7 to 35 days, they received a single dose of three Neurexan tablets on trial Day 2. |
| BG002 | Total | Total of all reporting groups |
| years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Region of Enrollment | Count of Participants | Participants |
|
| ID |
|---|
| Title |
|---|
| Description |
|---|
| OG000 | Neurexan | Participants received a single dose of three tablets Neurexan on one of two trial days (Day 1 or Day 2). The Neurexan "arm" describes the Neurexan condition of crossover trial. On the other day, the same participants received Placebo. |
| OG001 | Placebo | Participants received a single dose of three tablets Placebo on one of two trial days (Day 1 or Day 2). The Placebo "arm" describes the Placebo condition of crossover trial. On the other day, the same participants received Neurexan. |
|
|
|
| Primary | Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Global Functional Connectivity Density of the Amygdala at Rest | Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Highly connected functional hubs were identified by global functional connectivity density (gFCD) analysis. The number of voxels with a positive rsFC larger than the predefined threshold of r > 0.6 at a whole brain level was evaluated. gFCD was calculated for each voxel as the total number of significant correlations between this voxel and all voxels in gray matter. The gFCD value in each voxel was divided by the global mean value to improve normality. The larger the number of significant correlations, the greater the gFCD strength. Changes in gFCD strength of the amygdala from pre-dose to 1-hour post-dose were compared between the Neurexan and Placebo conditions using a within-subject repeated-measures ANOVA with main effects of time (pre- vs. post-dose) and drug (placebo vs. Nx4) and their interaction (time x drug). | Of the 39 participants, 3 were excluded due to excessive micromovement artifacts, and 1 was excluded due to data corruption. | Posted | Mean | Standard Deviation | normalized FCD strength | 1 hour after taking a single dose of Neurexan or placebo |
|
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|
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| Primary | Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Whole-Brain Functional Connectivity of the Amygdala at Rest | Resting-state fMRI scans were performed before dosing and approximately 1 hour after a single dose of Neurexan or Placebo. Left centromedial amygdala (CeMA) was defined as the seed based on probabilistic cytoarchitectonic maps. The time course of the average BOLD signal within the seed was correlated with the signals in each voxel in the whole brain. The Pearson correlation coefficients were transformed to Z values (Fisher's Z), resulting in a map representing voxel-wise strength of rsFC to the seed region. Changes in left CeMA rsFC from pre-dose to post-dose, evaluated as binary connectivity coefficients, were compared between the Neurexan and Placebo conditions. | Of the 39 participants, 3 were excluded due to excessive micromovement artifacts, and 1 was excluded due to data corruption. | Posted | Mean | Standard Deviation | Binary connectivity coefficient | 1 hour after taking a single dose of Neurexan or placebo |
|
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|
|
| Primary | Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Baseline Activity of the Amygdala at Rest as Measured by Amplitude of Low-Frequency Fluctuations (ALFF) | The time series in each voxel of the rs-fMRI data were converted to the frequency domain using a Fast Fourier Transform (FFT), and the power spectrum was obtained. The square root of the power spectrum was computed and then averaged across each predefined frequency band. This averaged square root was taken as amplitude of low frequency fluctuation (ALFF). A ratio of the power spectrum of low-frequency range to that of the entire frequency range, i.e. the fractional ALFF (fALFF), was computed. High fALFF in the amygdala may reflect hyperactivity and could serve as a marker for heightened stress sensitivity. To examine the effect of drug on rs-metrics (RS1) while taking baseline rs-metrics before drug administration (RS0) as control variable, mean fALFF values of the amygdala were compared between placebo and Neurexan. | Posted | Mean | Standard Deviation | fractional ALFF | 1 hour after taking a single dose of Neurexan or placebo |
|
|
|
|
| Primary | Functional Magnetic Resonance Imaging (fMRI) Task Data: Stress Network Activation in Response to Psychosocial Stress Induction. | The neuronal drug effect was assessed by measuring activity changes within a predefined stress network, comprising the anterior cingulate cortex, medial orbitofrontal cortex, hippocampus, amygdala, and hypothalamus, between placebo and Neurexan using fMRI. Stress network activation in response to psychosocial stress induced by the ScanSTRESS paradigm was assessed. Beta values (i.e. parameter estimates) indicate the proportion of activation that is explained by a variable, in this case mental rotation or simple matching of figures. Beta-estimates serve as an index of neural activity, the higher the beta value, the higher the activity. The paradigm contrast (stress-control) for each participant was taken to a second level analysis of all voxels comprised by an ACC mask. A voxelwise paired t-test, controlled for multiple comparison, compared placebo and verum conditions. The endpoint was assessed approximately 1.5 hours post-dose after a single dose of Neurexan or placebo. | Of the 39 participants, 3 were excluded due to excessive micromovement artifacts. | Posted | Mean | Standard Deviation | Beta Estimate | 1.5 hours after taking a single dose of Neurexan or placebo |
|
|
|
|
| 0 |
| 39 |
| 0 |
| 39 |
| 0 |
| 39 |
| EG001 | Placebo | Participants received a single dose of three Placebo tablets on either Day 1 or Day 2 of the trial. The Placebo "arm" refers to the Placebo condition in the crossover trial. On the other trial day, the same participants received Neurexan. | 0 | 39 | 0 | 39 | 0 | 39 |
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