Clinical Trial Results:
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
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Summary
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EudraCT number |
2015-001802-32 |
Trial protocol |
DE |
Global end of trial date |
03 Dec 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
02 Sep 2022
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First version publication date |
02 Sep 2022
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Other versions |
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Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
C1501
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT02602275 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Biologische Heilmittel Heel GmbH
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Sponsor organisation address |
Dr.-Reckeweg-Straße 2-4, Baden-Baden, Germany, 76532
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Public contact |
Biologische Heilmittel Heel GmbH, Biologische Heilmittel Heel GmbH, +49 72215010, info@heel.com
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Scientific contact |
Biologische Heilmittel Heel GmbH, Biologische Heilmittel Heel GmbH, +49 72215010, info@heel.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
03 Dec 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
03 Dec 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
03 Dec 2015
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
The main objective of this clinical trial was to explore via functional MRI (fMRI) the effects of Neurexan® on the neuronal response in different brain regions while participants were either at rest or underwent different tasks in Verum compared to Placebo. The different tasks assessed by fMRI were an emotional task (Hariri) and a stress task (ScanStress) as the main interest was evaluating Neurexan’s effect on the brain stress response.
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Protection of trial subjects |
The trial was conducted in compliance with the protocol, the ethical principles of the Declaration of Helsinki, the International Conference on Harmonisation (ICH) Good Clinical Practice (GCP), and all applicable national laws and regulations.
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Background therapy |
- | ||
Evidence for comparator |
- | ||
Actual start date of recruitment |
01 Aug 2015
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
Germany: 40
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Worldwide total number of subjects |
40
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EEA total number of subjects |
40
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
40
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
This was a single centre trial at the Clinical Affective Neuroimaging Laboratory (CANLAB), Magdeburg, Germany. Screening was restricted to the area of the site. | |||||||||
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Pre-assignment
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Screening details |
Screening was restricted to healthy males, aged 31 to 59 years, with mild to moderate chronic stress. Screening was stopped after inclusion of the anticipated 40 participants. One subject was withdrawn due to a ‘cerebral finding’ on Day 1 before the treatment with the investigational medication was started (no dose applied). | |||||||||
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Period 1
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Period 1 title |
overall trial
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Is this the baseline period? |
No | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator | |||||||||
Blinding implementation details |
This was a double-blind, randomised trial and all involved personnel on site, at the sponsor and the CRO were blinded during the trial. No emergency unblinding was necessary during the trial.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Neurexan | |||||||||
Arm description |
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 the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan - on the other day, the same participants received Placebo. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Neurexan
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Investigational medicinal product code |
Nx4
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Sublingual use
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Dosage and administration details |
Single sublingual administration of 3 tablets Neurexan
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Arm title
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Placebo | |||||||||
Arm description |
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 the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan - on the other day, the same participants received Neurexan. | |||||||||
Arm type |
Placebo | |||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Sublingual use
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Dosage and administration details |
Single sublingual administration of 3 tablets Placebo
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Period 2
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Period 2 title |
Baseline
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Is this the baseline period? |
Yes [1] | |||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | |||||||||
Roles blinded |
Subject, Investigator | |||||||||
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Neurexan - Placebo | |||||||||
Arm description |
Participants received a single dose of three tablets Neurexan on Day 1 and Placebo on Day 2 of the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Neurexan
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Investigational medicinal product code |
Nx4
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Sublingual use
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Dosage and administration details |
Single sublingual administration of 3 tablets Neurexan
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Arm title
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Placebo - Neurexan | |||||||||
Arm description |
Participants received a single dose of three tablets Placebo on Day 1 and Neurexan on Day 2 of the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan. | |||||||||
Arm type |
Experimental | |||||||||
Investigational medicinal product name |
Neurexan
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Investigational medicinal product code |
Nx4
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Sublingual use
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Dosage and administration details |
Single sublingual administration of 3 tablets Neurexan
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Investigational medicinal product name |
Neurexan
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Investigational medicinal product code |
Nx4
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Other name |
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Pharmaceutical forms |
Tablet
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Routes of administration |
Sublingual use
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Dosage and administration details |
Single sublingual administration of 3 tablets Neurexan
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| Notes [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period. Justification: This was a crossover trial and the trial results were reported per condition (Verum vs Placebo) in an "overall trial" period as suggested in "Option 3" FAQ83, EudraCT & EU CTR Frequently asked questions. A second period (baseline) is given for reporting the baseline characteristics of the two sequences, Placebo first and Verum first. |
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| Notes [2] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Out of 40 randomised subjects, 39 subjects were included into the safety, ITT and PP evaluation. One subject was withdrawn from trial before trial medication was started (no dose applied) and the subject was excluded from all analysis populations. |
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Baseline characteristics reporting groups
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Reporting group title |
Neurexan - Placebo
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Reporting group description |
Participants received a single dose of three tablets Neurexan on Day 1 and Placebo on Day 2 of the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Placebo - Neurexan
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Reporting group description |
Participants received a single dose of three tablets Placebo on Day 1 and Neurexan on Day 2 of the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Neurexan
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Reporting group description |
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 the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan - on the other day, the same participants received Placebo. | ||
Reporting group title |
Placebo
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Reporting group description |
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 the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan - on the other day, the same participants received Neurexan. | ||
Reporting group title |
Neurexan - Placebo
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Reporting group description |
Participants received a single dose of three tablets Neurexan on Day 1 and Placebo on Day 2 of the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan. | ||
Reporting group title |
Placebo - Neurexan
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Reporting group description |
Participants received a single dose of three tablets Placebo on Day 1 and Neurexan on Day 2 of the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan. | ||
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End point title |
Reduced amygdala responsiveness measured by negative face to form contrasts in the Hariri task after Verum versus Placebo condition | ||||||||||||
End point description |
Effect of drug, driven by significantly smaller amygdala activations Blood Oxygenation Level Dependent (BOLD) response in the contrast (negative faces vs forms) in Neurexan 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.
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End point type |
Primary
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End point timeframe |
Endpoint assessed about 1 hour post dose after a single dose of Neurexan or Placebo
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Statistical analysis title |
Paired T-Test | ||||||||||||
Statistical analysis description |
Paired t-test analysis for the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan.
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Comparison groups |
Neurexan v Placebo
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Number of subjects included in analysis |
78
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.05 | ||||||||||||
Method |
Paired t-test | ||||||||||||
Confidence interval |
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End point title |
Reduced functional connectivity density in amygdala after Verum versus Placebo condition during rest | ||||||||||||
End point description |
Interaction of time and drug, driven by significantly greater reductions of amygdala functional connectivity density (FCD) in Verum compared to Placebo conditions. Significance level was 0.05, corrected for multiple comparisons in the search volume which is anatomically defined by the AAL (Automated Anatomical Labelling Atlas) coordinates.
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End point type |
Primary
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End point timeframe |
Endpoint assessed about 1 hour post dose after a single dose of Neurexan or Placebo
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| Notes [1] - 3 excluded due to high micro-movement artefacts and 1 excluded due to data corruption. [2] - 3 excluded due to high micro-movement artefacts and 1 excluded due to data corruption. |
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Statistical analysis title |
Paired T-Test | ||||||||||||
Statistical analysis description |
Paired t-test analysis for the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan.
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Comparison groups |
Neurexan v Placebo
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Number of subjects included in analysis |
70
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
> 0.05 | ||||||||||||
Method |
Paired t-test | ||||||||||||
Confidence interval |
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End point title |
Reduced whole brain functional connectivity of amygdala after Verum versus Placebo condition during rest | ||||||||||||
End point description |
Interaction of time and drug, driven by significantly greater changes of amygdala seeded connectivities in Verum compared to Placebo conditions. Significance level is 0.05, corrected for multiple comparisons in the whole brain.
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End point type |
Primary
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End point timeframe |
Endpoint assessed about 1 hour post dose after a single dose of Neurexan or Placebo
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| Notes [3] - 3 subjects excluded due to high micro-movement artefacts and 1 excluded due to data corruption [4] - 3 subjects excluded due to high micro-movement artefacts and 1 excluded due to data corruption |
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Statistical analysis title |
Paired T-Test | ||||||||||||
Statistical analysis description |
Paired t-test analysis for the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan.
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Comparison groups |
Neurexan v Placebo
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Number of subjects included in analysis |
70
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.001 [5] | ||||||||||||
Method |
Paired t-test | ||||||||||||
Confidence interval |
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| Notes [5] - Since we controlled for multiplicity due to multiple primary hypotheses by means of the principle of a priori ordered hypotheses and a preceding endpoint was not met, the outcome of this analysis was regarded as purely exploratory. |
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End point title |
Reduced local resting state activity of amygdala after Verum versus Placebo condition | ||||||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
Endpoint assessed about 1 hour post dose after a single dose of Neurexan or Placebo
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Statistical analysis title |
Paired T-Test | ||||||||||||
Statistical analysis description |
Paired t-test analysis for the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan.
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Comparison groups |
Placebo v Neurexan
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Number of subjects included in analysis |
42
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
> 0.05 [6] | ||||||||||||
Method |
Paired t-test | ||||||||||||
Confidence interval |
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| Notes [6] - Since we controlled for multiplicity due to multiple primary hypotheses by means of the principle of a priori ordered hypotheses and a preceding endpoint was not met, the outcome of this analysis was regarded as purely exploratory. |
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End point title |
Reduced stress network activation during stress in Verum versus Placebo condition | ||||||||||||
End point description |
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.
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End point type |
Primary
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End point timeframe |
Endpoint assessed about 1.5 hours post dose after a single dose of Neurexan or Placebo
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| Notes [7] - 3 excluded due to high micro-movement artefacts [8] - 3 excluded due to high micro-movement artefacts |
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Statistical analysis title |
Paired T-Test | ||||||||||||
Statistical analysis description |
Paired t-test analysis for the two-period, two-treatment crossover trial with 1:1 randomisation of the two treatment sequences Neurexan-Placebo and Placebo-Neurexan.
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Comparison groups |
Placebo v Neurexan
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Number of subjects included in analysis |
72
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
< 0.05 [9] | ||||||||||||
Method |
Paired t-test | ||||||||||||
Confidence interval |
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| Notes [9] - Since we controlled for multiplicity due to multiple primary hypotheses by means of the principle of a priori ordered hypotheses and a preceding endpoint was not met, the outcome of this analysis was regarded as purely exploratory. |
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Adverse events information [1]
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Timeframe for reporting adverse events |
Continuous recording of all adverse events on treatment days after randomisation and receipt of at least one dose of the IMP. Serious procedure-related adverse events were reported starting from the enrolment.
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Assessment type |
Systematic | |||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||
Dictionary version |
18.1
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Reporting groups
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Reporting group title |
Neurexan
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Reporting group description |
- | |||||||||||||||
Reporting group title |
Placebo
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Reporting group description |
- | |||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | ||||||||||||||||
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| Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: No non-serious adverse events occurred during the trial. |
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? No | |||
Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| Limited to male participants with mild to moderate chronic stress. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/32123197 http://www.ncbi.nlm.nih.gov/pubmed/35438535 http://www.ncbi.nlm.nih.gov/pubmed/34912250 http://www.ncbi.nlm.nih.gov/pubmed/35213077 http://www.ncbi.nlm.nih.gov/pubmed/34729551 |
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