VSL: Veteran Stress and Learning Study

• Sponsor: VA Office of Research and Development (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00674570
• Collaborator: (none)
• Enrollment: 111
• Location: 1
• Arms: 3
• Actual Duration (Months): 77.2
• Patients Per Site Per Month: 1.4

Study Details

Study Description

Brief Summary

This is a research study examining the use of two medications, Hydrocortisone and D-Cycloserine, compared to an inactive substance (placebo), on their ability to reduce fear responses and memory of fear in Veterans with symptoms of Posttraumatic Stress Disorder (PTSD). These responses will be tested using a fear learning and memory task administered by computer.

Condition or Disease	Intervention/Treatment	Phase
Stress Disorders, Posttraumatic	Drug: Hydrocortisone; Drug: D-Cycloserine; Drug: Placebo	Phase 4

Study Design

• Study Type: Interventional
• Actual Enrollment: 111 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Basic Science
• Official Title: Effects of Hydrocortisone and D-Cycloserine on Fear Extinction in Veterans With Posttraumatic Stress Disorder
• Actual Study Start Date: Jan 13, 2009
• Actual Primary Completion Date: Jun 22, 2015
• Actual Study Completion Date: Jun 22, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1: Hydrocortisone Hydrocortisone	Drug: Hydrocortisone; 25 mg/oral one hour prior to extinction task
Experimental: Arm 2: D-Cycloserine D-Cycloserine	Drug: D-Cycloserine; 50 mg/oral one hour prior to extinction task
Placebo Comparator: Arm 3: Placebo Placebo	Drug: Placebo; One hour prior to extinction task

Outcome Measures

Primary Outcome Measures

1. Proportion of Maximum Skin Conductance Response (SCR) in Microsiemens (µS) [15 minute measurement intervals on Study Days 7, 9, and 16]

   Psychophysiology measurements occurred on day 7 for fear conditioning, day 9 for fear extinction, and day 11 for extinction retention. The primary outcome measures are presented for the first and last conditioned stimulus (CS) trials during fear conditioning and extinction and for the first 2 trials during retention. Conditioned Responses (CR): An SCR score was obtained for each CS by subtracting the mean skin conductance level (SCL) in microsiemens (µS) for the 2-s interval immediately preceding CS onset from the max SC level in µS during the 8-s CS presentation. Unconditioned Response (UCR): An SCR score for the UCR was obtained by subtracting the mean SCL in µS within 6-8 s following CS offset from the max increase in SC level during the .5-6.5 time interval following the CS offset, corresponding to the onset of the .5s US. SC responses were range corrected using each participant's maximum response to the UCS or CS during acquisition trials of the fear conditioning phase.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• Veterans and civilians with an age range of 18 to 65 years

• Participants must be physically healthy volunteers

Exclusion Criteria:

• Individuals who fall outside the age range

• Individuals with medical conditions that would interfere with participation

• Other criteria

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	San Francisco VA Medical Center, San Francisco, CA	San Francisco	California	United States	94121

Sponsors and Collaborators

• VA Office of Research and Development

Investigators

• Principal Investigator: Sabra S Inslicht, PhD, San Francisco VA Medical Center, San Francisco, CA

Study Documents (Full-Text)

None provided.

More Information

Publications

• Alexandra Kredlow M, Pineles SL, Inslicht SS, Marin MF, Milad MR, Otto MW, Orr SP. Assessment of skin conductance in African American and Non-African American participants in studies of conditioned fear. Psychophysiology. 2017 Nov;54(11):1741-1754. doi: 10.1111/psyp.12909. Epub 2017 Jul 4.
• Inslicht SS, Metzler TJ, Garcia NM, Pineles SL, Milad MR, Orr SP, Marmar CR, Neylan TC. Sex differences in fear conditioning in posttraumatic stress disorder. J Psychiatr Res. 2013 Jan;47(1):64-71. doi: 10.1016/j.jpsychires.2012.08.027. Epub 2012 Oct 26.

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT00674570
• Other Study ID Numbers: CDA-2-037-07F; H841-31915-01A
• First Posted: May 8, 2008
• Last Update Posted: May 30, 2019
• Last Verified: May 1, 2019

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: Yes
• Keywords provided by VA Office of Research and Development: Stress Disorders, Posttraumatic; Hydrocortisone; Cycloserine; Extinction, Psychological; PTSD; San Francisco
• Additional relevant MeSH terms: Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Cycloserine; Hydrocortisone

Study Results

Participant Flow

Pre-assignment Detail	Participation involved 4 study visits, with randomization to intervention arm and drug administration occurring on visit 3. The discrepancy between 111 participants who were initially enrolled and 106 at randomization resulted from 5 participants who dropped out between screening and visit 3, when they were to have been assigned into a group.

Arm/Group Title	Arm 1: Hydrocortisone	Arm 2: D-Cycloserine	Arm 3: Placebo
Arm/Group Description	Hydrocortisone Hydrocortisone: 25 mg/oral one hour prior to extinction task	D-Cycloserine D-Cycloserine: 50 mg/oral one hour prior to extinction task	Placebo Placebo: One hour prior to extinction task
Period Title: Overall Study
STARTED	37	34	35
COMPLETED	37	32	35
NOT COMPLETED	0	2	0

Baseline Characteristics

Arm/Group Title	Arm 1: Hydrocortisone	Arm 2: D-Cycloserine	Arm 3: Placebo	Total
Arm/Group Description	Hydrocortisone Hydrocortisone: 25 mg/oral one hour prior to extinction task	D-Cycloserine D-Cycloserine: 50 mg/oral one hour prior to extinction task	Placebo Placebo: One hour prior to extinction task	Total of all reporting groups
Overall Participants	37	34	35	106
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	36.0 (12.8)	41.1 (13.7)	40.0 (11.8)	38.6 (12.6)
Sex: Female, Male (Count of Participants)
Female	23 62.2%	21 61.8%	18 51.4%	62 58.5%
Male	14 37.8%	13 38.2%	17 48.6%	44 41.5%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	7 18.9%	4 11.8%	7 20%	18 17%
Not Hispanic or Latino	30 81.1%	30 88.2%	28 80%	88 83%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	3 8.1%	4 11.8%	1 2.9%	8 7.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	5 13.5%	6 17.6%	7 20%	18 17%
White	22 59.5%	21 61.8%	25 71.4%	68 64.2%
More than one race	7 18.9%	3 8.8%	2 5.7%	12 11.3%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (Count of Participants)
United States	37 100%	34 100%	35 100%	106 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Maximum Skin Conductance Response (SCR) in Microsiemens (µS)
Description	Psychophysiology measurements occurred on day 7 for fear conditioning, day 9 for fear extinction, and day 11 for extinction retention. The primary outcome measures are presented for the first and last conditioned stimulus (CS) trials during fear conditioning and extinction and for the first 2 trials during retention. Conditioned Responses (CR): An SCR score was obtained for each CS by subtracting the mean skin conductance level (SCL) in microsiemens (µS) for the 2-s interval immediately preceding CS onset from the max SC level in µS during the 8-s CS presentation. Unconditioned Response (UCR): An SCR score for the UCR was obtained by subtracting the mean SCL in µS within 6-8 s following CS offset from the max increase in SC level during the .5-6.5 time interval following the CS offset, corresponding to the onset of the .5s US. SC responses were range corrected using each participant's maximum response to the UCS or CS during acquisition trials of the fear conditioning phase.
Time Frame	15 minute measurement intervals on Study Days 7, 9, and 16

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Arm 1: Hydrocortisone	Arm 2: D-Cycloserine	Arm 3: Placebo
Arm/Group Description	Hydrocortisone Hydrocortisone: 25 mg/oral one hour prior to extinction task	D-Cycloserine D-Cycloserine: 50 mg/oral one hour prior to extinction task	Placebo Placebo: One hour prior to extinction task
Measure Participants	37	32	35
Fear Conditioning: Beginning	.0325522 (.0351212)	.0245775 (.0367306)	-.0181339 (.0328529)
Fear Conditioning: End	.1233174 (.0351212)	.1024914 (.0367306)	.1276977 (.0328529)
Fear Extinction: Beginning	.0298132 (.0313355)	.0674658 (.0327715)	.1104578 (.0313355)
Fear Extinction: End	.0013351 (.0313355)	-.026853 (.0327715)	.0854075 (.0313355)
Extinction Retention	-.0101856 (.0388043)	-.0248148 (.0405825)	.0985292 (.0393708)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm 2: D-Cycloserine, Arm 3: Placebo
	Comments	Fear Conditioning Beginning (first trial)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=.66
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-.02
	Confidence Interval	(2-Sided) 95%; -.15 to .10
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .06
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Hydrocortisone, Arm 3: Placebo
	Comments	Fear Conditioning Beginning (first trial)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=.41
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	-.05
	Confidence Interval	(2-Sided) 95%; -.17 to .07
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .06
	Estimation Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Arm 2: D-Cycloserine, Arm 3: Placebo
	Comments	Fear Conditioning End (last trial)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=.43
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	.05
	Confidence Interval	(2-Sided) 95%; -.07 to .18
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .06
	Estimation Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Hydrocortisone, Arm 3: Placebo
	Comments	Fear Conditioning End (last trial)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=.47
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Median Difference (Net)
	Estimated Value	.04
	Confidence Interval	(2-Sided) 95%; -.07 to .17
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .06
	Estimation Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Hydrocortisone, Arm 3: Placebo
	Comments	Fear Extinction Beginning (first trial)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=.065
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	.09
	Confidence Interval	(2-Sided) 95%; -.01 to .20
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .05
	Estimation Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Arm 2: D-Cycloserine, Arm 3: Placebo
	Comments	Fear Extinction Beginning (first trial)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=.34
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	.05
	Confidence Interval	(2-Sided) 95%; -.05 to .15
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .05
	Estimation Comments

Statistical Analysis 7

Statistical Analysis Overview	Comparison Group Selection	Arm 2: D-Cycloserine, Arm 3: Placebo
	Comments	Extinction End (last trial)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	=.003
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	.16
	Confidence Interval	(2-Sided) 95%; .06 to .26
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .05
	Estimation Comments

Statistical Analysis 8

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Hydrocortisone, Arm 3: Placebo
	Comments	Extinction End (last trial)
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.02
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	.12
	Confidence Interval	(2-Sided) 95%; .02 to .22
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .05
	Estimation Comments

Statistical Analysis 9

Statistical Analysis Overview	Comparison Group Selection	Arm 2: D-Cycloserine, Arm 3: Placebo
	Comments	Extinction Retention (first 2 trials) First trials were selected as a test of extinction retention, since repeated presentations of the CS without a UCS were expected to result in additional fear extinction.
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	=.006
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	.18
	Confidence Interval	(2-Sided) 95%; .05 to .30
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .06
	Estimation Comments

Statistical Analysis 10

Statistical Analysis Overview	Comparison Group Selection	Arm 1: Hydrocortisone, Arm 3: Placebo
	Comments	Extinction retention
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	=.01
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Net)
	Estimated Value	.16
	Confidence Interval	(2-Sided) 95%; .04 to .28
	Parameter Dispersion	Type: Standard Error of the Mean; Value: .06
	Estimation Comments

Adverse Events

Time Frame	Approximately, one month for each participant during their enrollment in the study.
Arm/Group Title	Arm 1: Hydrocortisone		Arm 2: D-Cycloserine		Arm 3: Placebo
Arm/Group Description	Hydrocortisone Hydrocortisone: 25 mg/oral one hour prior to extinction task		D-Cycloserine D-Cycloserine: 50 mg/oral one hour prior to extinction task		Placebo Placebo: One hour prior to extinction task
All Cause Mortality
	Arm 1: Hydrocortisone		Arm 2: D-Cycloserine		Arm 3: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/32 (0%)		0/35 (0%)
Serious Adverse Events
	Arm 1: Hydrocortisone		Arm 2: D-Cycloserine		Arm 3: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/32 (0%)		0/35 (0%)
Other (Not Including Serious) Adverse Events
	Arm 1: Hydrocortisone		Arm 2: D-Cycloserine		Arm 3: Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/37 (0%)		0/32 (0%)		0/35 (0%)

Limitations/Caveats

Technical difficulties rendered corrugator electromyogram data unusable for analysis. We selected skin conductance as a primary measure of sympathetic activity rather than heart rate, which has both sympathetic and parasympathetic influences.

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.