Trial Outcomes & Findings for Neuronal Correlates of Neurexan® Action in Mildly to Moderately Stressed Probands (NCT NCT02602275)
NCT ID: NCT02602275
Last Updated: 2025-06-24
Results Overview
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.
COMPLETED
PHASE2
53 participants
1 hour after taking a single dose of Neurexan or placebo
2025-06-24
Participant Flow
Out of 53 screened subjects, 40 met all eligibility criteria and were randomized.
Participant milestones
| Measure |
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.
|
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.
|
|---|---|---|
|
Day 1
STARTED
|
20
|
20
|
|
Day 1
Received Intervention
|
20
|
19
|
|
Day 1
COMPLETED
|
20
|
19
|
|
Day 1
NOT COMPLETED
|
0
|
1
|
|
Washout (7-35 Days)
STARTED
|
20
|
19
|
|
Washout (7-35 Days)
COMPLETED
|
20
|
19
|
|
Washout (7-35 Days)
NOT COMPLETED
|
0
|
0
|
|
Day 2
STARTED
|
20
|
19
|
|
Day 2
COMPLETED
|
20
|
19
|
|
Day 2
NOT COMPLETED
|
0
|
0
|
Reasons for withdrawal
| Measure |
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.
|
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.
|
|---|---|---|
|
Day 1
Physician Decision
|
0
|
1
|
Baseline Characteristics
Neuronal Correlates of Neurexan® Action in Mildly to Moderately Stressed Probands
Baseline characteristics by cohort
| Measure |
Neurexan First, Then Placebo
n=20 Participants
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.
|
Placebo First, Then Neurexan
n=19 Participants
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.
|
Total
n=39 Participants
Total of all reporting groups
|
|---|---|---|---|
|
Age, Continuous
Age
|
43.2 years
STANDARD_DEVIATION 10.0 • n=5 Participants
|
43.7 years
STANDARD_DEVIATION 9.6 • n=7 Participants
|
43.7 years
STANDARD_DEVIATION 9.8 • n=5 Participants
|
|
Sex: Female, Male
Female
|
0 Participants
n=5 Participants
|
0 Participants
n=7 Participants
|
0 Participants
n=5 Participants
|
|
Sex: Female, Male
Male
|
20 Participants
n=5 Participants
|
19 Participants
n=7 Participants
|
39 Participants
n=5 Participants
|
|
Region of Enrollment
Germany
|
20 Participants
n=5 Participants
|
19 Participants
n=7 Participants
|
39 Participants
n=5 Participants
|
PRIMARY outcome
Timeframe: 1 hour after taking a single dose of Neurexan or placeboThe 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.
Outcome measures
| Measure |
Neurexan
n=39 Participants
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.
|
Placebo
n=39 Participants
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.
|
|---|---|---|
|
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
|
0.196 Beta value
Standard Deviation 0.045
|
0.361 Beta value
Standard Deviation 0.040
|
PRIMARY outcome
Timeframe: 1 hour after taking a single dose of Neurexan or placeboPopulation: Of the 39 participants, 3 were excluded due to excessive micromovement artifacts, and 1 was excluded due to data corruption.
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).
Outcome measures
| Measure |
Neurexan
n=35 Participants
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.
|
Placebo
n=35 Participants
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.
|
|---|---|---|
|
Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Global Functional Connectivity Density of the Amygdala at Rest
|
0.0139 normalized FCD strength
Standard Deviation 0.1338
|
-0.0073 normalized FCD strength
Standard Deviation 0.0855
|
PRIMARY outcome
Timeframe: 1 hour after taking a single dose of Neurexan or placeboPopulation: Of the 39 participants, 3 were excluded due to excessive micromovement artifacts, and 1 was excluded due to data corruption.
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.
Outcome measures
| Measure |
Neurexan
n=35 Participants
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.
|
Placebo
n=35 Participants
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.
|
|---|---|---|
|
Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Change in Whole-Brain Functional Connectivity of the Amygdala at Rest
|
-0.0127 Binary connectivity coefficient
Standard Deviation 0.0328
|
0.0239 Binary connectivity coefficient
Standard Deviation 0.0346
|
PRIMARY outcome
Timeframe: 1 hour after taking a single dose of Neurexan or placeboThe 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.
Outcome measures
| Measure |
Neurexan
n=21 Participants
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.
|
Placebo
n=21 Participants
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.
|
|---|---|---|
|
Functional Magnetic Resonance Imaging (fMRI) Resting-State Data: Baseline Activity of the Amygdala at Rest as Measured by Amplitude of Low-Frequency Fluctuations (ALFF)
|
-0.0120 fractional ALFF
Standard Deviation 0.02534
|
0.0007 fractional ALFF
Standard Deviation 0.03590
|
PRIMARY outcome
Timeframe: 1.5 hours after taking a single dose of Neurexan or placeboPopulation: Of the 39 participants, 3 were excluded due to excessive micromovement artifacts.
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.
Outcome measures
| Measure |
Neurexan
n=36 Participants
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.
|
Placebo
n=36 Participants
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.
|
|---|---|---|
|
Functional Magnetic Resonance Imaging (fMRI) Task Data: Stress Network Activation in Response to Psychosocial Stress Induction.
|
0.02 Beta Estimate
Standard Deviation 0.14
|
0.41 Beta Estimate
Standard Deviation 0.14
|
Adverse Events
Neurexan
Placebo
Serious adverse events
Adverse event data not reported
Other adverse events
Adverse event data not reported
Additional Information
Head of Clinical Research
Biologische Heilmittel Heel GmbH
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place