Clinical Trial Results:
Early-life stress, the endocannabinoid system, and fear memory extinction
Summary
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EudraCT number |
2017-004823-66 |
Trial protocol |
NL |
Global end of trial date |
08 Jul 2021
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Results information
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Results version number |
v1(current) |
This version publication date |
16 Jul 2022
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First version publication date |
16 Jul 2022
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Other versions |
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 |
NL62274.091.17
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
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WHO universal trial number (UTN) |
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Sponsors
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Sponsor organisation name |
Radboud university medical center
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Sponsor organisation address |
P.O. Box 9101, Nijmegen, Netherlands, 6500 HB
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Public contact |
Dept Psychiatry Radboudumc, Radboudumc, +31 243613490, robbert-jan.verkes@radboudumc.nl
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Scientific contact |
Dept Psychiatry Radboudumc, Radboudumc, +31 243613490, robbert-jan.verkes@radboudumc.nl
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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 |
08 Jul 2021
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
08 Jul 2021
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Global end of trial reached? |
Yes
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Global end of trial date |
08 Jul 2021
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
Primary objective: Our key objective is to determine if glucocorticoid administration and/or THC administration facilitates fear memory extinction retention in an experimental model of exposure therapy in healthy individuals with early life stress.
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Protection of trial subjects |
After every screening session and at each end of the experimental session, we will conclude with a structured interview in which we will ask participants if they experience emotional disturbances triggered by the questions (e.g., regarding early-life trauma), at that moment or later, we can redirect them for additional help if needed. When participants are excluded from participation, we will carefully explain to them the reason for exclusion.
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Background therapy |
n.a. | ||
Evidence for comparator |
n.a. | ||
Actual start date of recruitment |
03 Oct 2019
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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 |
Netherlands: 54
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Worldwide total number of subjects |
54
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EEA total number of subjects |
54
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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) |
54
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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 |
The recruitment started on 03-10-2019 to 08-07-2021 and was in The Netherlands. | ||||||||||||
Pre-assignment
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Screening details |
Healthy adults aged between 18-45 yrs old, gender-mixed, no illness, and current treatment. Participant were selected based presence or absence of a history of childhood trauma. | ||||||||||||
Period 1
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Period 1 title |
Data collection (overall period)
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Is this the baseline period? |
Yes | ||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||
Roles blinded |
Subject, Investigator | ||||||||||||
Blinding implementation details |
Both participants and researchers are blinded from the information of randomization .
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Childhood trauma group | ||||||||||||
Arm description |
The participants were assigned to the traumatized group. | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Hydrocortisone
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Investigational medicinal product code |
RVG 50730
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Other name |
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
20mg hydrocortisone dissolved in juice.
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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 |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
20mg undistinguishable placebo (cellulose) dispersed in juice.
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Arm title
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Control group | ||||||||||||
Arm description |
The participants assigned to control group | ||||||||||||
Arm type |
Experimental | ||||||||||||
Investigational medicinal product name |
Hydrocortisone
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Investigational medicinal product code |
RVG 50730
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Other name |
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Pharmaceutical forms |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
20mg hydrocortisone dispersed in the juice allowing affordable blinding of the study participants from treatment.
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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 |
Oral liquid
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Routes of administration |
Oral use
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Dosage and administration details |
20mg undistinguishable placebo dispersed in the juice allowing affordable blinding of the study participants from treatment.
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Baseline characteristics reporting groups
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Reporting group title |
Data collection
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||
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Subject analysis sets
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Subject analysis set title |
Drug effect on fear extinction retention
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
The raw physiological data were converted and analyzed with an in-house tool in matlab. A repeated measures ANOVA was applied as a statistical model to check if the effect of hydrocortisone on fear extinction retention was equal or not in the traumatized group compared to control group.
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Subject analysis set title |
Drug effect on neural activity to autobiographical memory
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Subject analysis set type |
Full analysis | ||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
To determine the effect of hydrocortisone on neural activity during emotional memory recall in the traumatized vs. control groups. The (functional) MRI data was preprocessed and analyzed in matlab 2021.
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End points reporting groups
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Reporting group title |
Childhood trauma group
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Reporting group description |
The participants were assigned to the traumatized group. | ||
Reporting group title |
Control group
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Reporting group description |
The participants assigned to control group | ||
Subject analysis set title |
Drug effect on fear extinction retention
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
The raw physiological data were converted and analyzed with an in-house tool in matlab. A repeated measures ANOVA was applied as a statistical model to check if the effect of hydrocortisone on fear extinction retention was equal or not in the traumatized group compared to control group.
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Subject analysis set title |
Drug effect on neural activity to autobiographical memory
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
To determine the effect of hydrocortisone on neural activity during emotional memory recall in the traumatized vs. control groups. The (functional) MRI data was preprocessed and analyzed in matlab 2021.
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End point title |
Autonomic nervous system indices of the fear response and its recovery after extinction. | ||||||||||||||||
End point description |
Our primary endpoint is retention of safety learning in an experimental model of exposure therapy. This measure is operationalized as the magnitude of spontaneous recovery of differential autonomic nervous system reactivity (primarily indexed by skin conductance responses) to fear-conditioned stimuli (vs. control stimuli) one day after extinction (i.e., safety learning).
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End point type |
Primary
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End point timeframe |
Primary endpoint is measured 24 hrs after administration of the drug to assess drug effects on retention of safety learning.
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Notes [1] - data for two participants was lost due to technical failure |
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Statistical analysis title |
Between-group comparison of drug effect | ||||||||||||||||
Statistical analysis description |
Preliminary analysis of the difference in effect of hydrocortisone on retention of extinction memory in the childhood trauma versus control group
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Comparison groups |
Childhood trauma group v Control group
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Number of subjects included in analysis |
52
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Analysis specification |
Pre-specified
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Analysis type |
other [2] | ||||||||||||||||
P-value |
= 0.2 | ||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||
Parameter type |
Mean difference (net) | ||||||||||||||||
Point estimate |
0.28
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Confidence interval |
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level |
95% | ||||||||||||||||
sides |
2-sided
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lower limit |
-0.15 | ||||||||||||||||
upper limit |
0.72 | ||||||||||||||||
Variability estimate |
Standard error of the mean
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Dispersion value |
0.22
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Notes [2] - Test of an experimental effect. |
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Adverse events information
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Timeframe for reporting adverse events |
From 03-10-2019 to 08-07-2021, there were adverse events involving four participants.
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Adverse event reporting additional description |
Four adverse events were reported by participants. All procedures were terminated upon adverse events. Investigators followed standard procedures such as calming down and monitoring the participant, and following up the next day.
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Assessment type |
Non-systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
25.0
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Reporting groups
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Reporting group title |
Childhood trauma group
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Reporting group description |
These are healthy volunteer participants selected for history of childhood trauma. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Non-trauma control group
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Reporting group description |
These are healthy volunteer participants selected for absence of a history of childhoof trauma. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Frequency threshold for reporting non-serious adverse events: 5% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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Were there any global substantial amendments to the protocol? Yes | |||||||
Date |
Amendment |
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24 Jul 2019 |
Due to a substantial delay in the production of one of the study medications used in our study (THC tablets, produced by Echo Pharmaceuticals), we have decided to split our three-armed study design (placebo, hydrocortisone, THC) into two two-armed substudies (hydrocortisone versus placebo, THC versus placebo). This will allow us to start data acquisition for the hydrocortisone versus placebo substudy while waiting for the release of the THC tablets. |
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08 Jul 2021 |
The study was ended in May 2022 due to continuing delays in the production of one of the study medications used in our study (THC tablets, produced by Echo Pharmaceuticals). Therefore, only one of the two substudies (hydrocortisone versus placebo) has been completed, while the second substudy (THC versus placebo) cannot be conducted anymore. |
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Interruptions (globally) |
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Were there any global interruptions to the trial? Yes | |||||||
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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. | |||||||
Due to the delay of THC providing, we split up the 2*3 study into two 2*2 substudies, namely there was no direct comparison between the effect of Hydrocortisone and THC on fear recall retention and relevant central neural activity. |