NOSSTIP: Neurobiology of Sleep and Sleep Treatment Response in Returning Veterans

• Sponsor: University of Pittsburgh (Other)
• Overall Status: Completed
• CT.gov ID: NCT01637584
• Collaborator: (none)
• Enrollment: 40
• Location: 1
• Arms: 2
• Duration (Months): 31
• Patients Per Site Per Month: 1.3

Study Details

Study Description

Brief Summary

The overarching objectives of this study are: 1) To investigate the neurobiology of posttraumatic stress disorder (PTSD) during Rapid Eye Movement (REM) and Non-Rapid Eye Movement (NREM) sleep relative to wakefulness; 2) To identify the neurobiological underpinnings of sleep treatment response to prazosin or placebo during wakefulness, REM sleep, and NREM sleep in Operation Iraqi Freedom/Operation Enduring Freedom (OIF/OEF) ( veterans with PTSD; and 3) To explore pre-treatment brain activity patterns during wakefulness, REM sleep, and NREM sleep that predict sleep treatment response. We will also explore the stability of the Positron Emission Tomography (PET) signal by comparing pre- and post-placebo changes in brain glucose metabolism in non-responders. For non-PTSD veterans, the stability of the PET signal will be evaluated in a subsample of 6 veterans without PTSD who will repeat the PET imaging procedures 8 weeks after the initial PET series.

The overarching hypothesis is that PTSD is characterized by neurobiological alterations in the amygdala, medial prefrontal cortex (mPFC), and brain centers involved in the regulation of NREM and REM sleep, and that these neurobiological changes are normalized with effective sleep treatment.

Condition or Disease	Intervention/Treatment	Phase
Non PTSD; PTSD	Drug: Prazosin; Drug: Placebo	N/A

Detailed Description

PTSD affects both daytime functioning and sleep. Complaints of poor sleep, objective disruption of sleep, and heightened sympathovagal tone during sleep occurring early after trauma exposure increase the risk of developing PTSD up to one year later. (1-4). Insomnia is one the most common reasons for referral to mental health services in active duty personnel (5). In military personnel returning from Iraq and Afghanistan, more than 70 percent of those with PTSD report sleep problems and fatigue, whereas more than 25% percent of those without PTSD endorse these symptoms (6). Other disruptive nocturnal behaviors and sleep disorders including sleep terrors, nocturnal anxiety attacks, simple and complex motor behaviors and vocalizations, acting out dreams, sleep apnea, and periodic leg movement disorders are also frequently reported by PTSD patients (7-12). In PTSD, sleep disturbances independently contribute to poor clinical outcomes such as increased severity of daytime PTSD symptoms (8), depression (13), suicidality (13), general psychiatric distress (14), poorer quality of life and functioning (14), poorer perceived physical health (14), and increased substance use (15;16).

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Neurobiology of Sleep and Sleep Treatment Response in Returning Veterans
• Study Start Date: Apr 1, 2010
• Actual Primary Completion Date: Nov 1, 2012
• Actual Study Completion Date: Nov 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Prazosin Active medication arm. Prazosin is an FDA approved medication, originally designed as an anti-hypertension medication. Side effects of the medication in some include sleepiness and once asleep, sustained sleep.	Drug: Prazosin; The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.
Placebo Comparator: Placebo A placebo is a sugar pill, which will be used to compare with the results of the active medication	Drug: Placebo; The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.

Outcome Measures

Primary Outcome Measures

1. Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose [Baseline and post-intervention at 8-10 weeks]

   The reported Z value reflect the magnitude of the state difference (Wake vs. Non-REM or Wake vs. REM) within the prazosin group pre-to-post treatment, and after using a mask to adjust for the spurious effects of the passage of time.

Secondary Outcome Measures

1. Pittsburgh Sleep Quality Index (PSQI): [Baseline and post-treatment at 8-10 weeks]

   Self-report sleep quality measure. Scores range from 0 to 21, with higher scores reflecting poorer sleep quality.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria:

• OIF/OEF veteran

• Between the ages of 18 and 50 years old

• Not taking medications known to affect sleep or wake function for 2 weeks

Additional selection criteria for PTSD subjects are:

• Trauma occurred three months or more before study entry

• Meeting diagnostic criteria for current PTSD according to the Clinician Administered PTSD Scale (CAPS)

• Participants will remain in ongoing counseling services

Additional selection criterion for non-PTSD healthy subjects:

• Not meet DSM-IV diagnostic criteria for current PTSD

• Have a total score < 13 on the Beck Depression Inventory

• Participants who are active-duty military personnel will be required to obtain permission from their commander to participate in this study.

Exclusion Criteria:

• Current diagnosis of untreated, severe depression as determined by the Structured Clinical Interview for Diagnostic and Statistical Manual- IV Edition (DSM-IV), non-patient version

• Beck Depression Inventory > 30

• History of psychotic or bipolar disorder

• Current history (within 3 months) of substance or alcohol abuse

• Significant or unstable acute or chronic medical conditions

• Other current sleep disorders

• Presence of implanted devices or metal in body such as cardiac pacemaker, aneurysm clip, ear implant, shrapnel, neurostimulators or other metal devices

• Fear of closed spaces

• Previous radiation exposure (past year) that exceeds recommended safety limits

• Pregnancy or breast feeding

• Resting blood pressure < 90/60 at the screening physical examination

• Heart rate > 100 beats/minutes

• Current use of a beta-blocker

• Use of an alpha-1 antagonist agent in the previous 3 weeks

• Refusal to follow the safety measures in the case of use of a phosphodiesterase 5 inhibitor (Cialis, Viagra, Levitra)

• Unexpected, untreated, or serious EKG findings

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Western Psychiatric Institute and Clinic	Pittsburgh	Pennsylvania	United States	15213

Sponsors and Collaborators

• University of Pittsburgh

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Anne Germain, Associate Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT01637584
• Other Study ID Numbers: PRO08050307
• First Posted: Jul 11, 2012
• Last Update Posted: May 23, 2017
• Last Verified: Mar 1, 2017

• Additional relevant MeSH terms: Prazosin

Study Results

Participant Flow

Arm/Group Title	Prazosin	Placebo
Arm/Group Description	Active medication arm. Prazosin is an FDA approved medication, originally designed as an anti-hypertension medication. Side effects of the medication in some include sleepiness and once asleep, sustained sleep. Prazosin: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.	A placebo is a sugar pill, which will be used to compare with the results of the active medication Placebo: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.
Period Title: Overall Study
STARTED	20	20
COMPLETED	19	17
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	Prazosin	Placebo	Total
Arm/Group Description	Active medication arm. Prazosin is an FDA approved medication, originally designed as an anti-hypertension medication. Side effects of the medication in some include sleepiness and once asleep, sustained sleep. Prazosin: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.	A placebo is a sugar pill, which will be used to compare with the results of the active medication Placebo: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.	Total of all reporting groups
Overall Participants	20	20	40
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29.7 (6.55)	27.2 (6.25)	27.7 (5.14)
Sex: Female, Male (Count of Participants)
Female	3 15%	4 20%	7 17.5%
Male	17 85%	16 80%	33 82.5%

Outcome Measures

1. Primary Outcome

Title	Whole Brain Relative Regional Cerebral Metabolic Rate of Glucose
Description	The reported Z value reflect the magnitude of the state difference (Wake vs. Non-REM or Wake vs. REM) within the prazosin group pre-to-post treatment, and after using a mask to adjust for the spurious effects of the passage of time.
Time Frame	Baseline and post-intervention at 8-10 weeks

Outcome Measure Data

Analysis Population Description

9 of the 20 participants who were randomized to prazosin and 13 of the participants randomized to placebo provided scans pre- and post-treatment that were of sufficiency quality to be included in the final analyses.

Arm/Group Title	Prazosin -Placebo
Arm/Group Description	Difference in relative brain glucose metabolism between states and pre-to-post treatment for participants randomized to prazosin after adjusting for non-significant changes in the placebo group.
Measure Participants	22
Pre-to-Post Treatment (Wakefulness > NREM)	3.78
Pre-to-Post Treatment (Wakefulness < NREM)	3.76
Pre-to-Post Treatment (Wakefulness > REM)	3.52
Pre-to-Post Treatment (Wakefulness < REM)	3.36
Within-state time-dependent decrease in rCMRglc	4.12
Within-state time-dependent increase in rCMRglc	3.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Prazosin -Placebo
	Comments	Wakefulness > Non-Rapid Eye Movement (NREM): Mean K-cluster voxels (Ke)=15,586: x,y,z= -36, -74, 0. Left Brodmann's Area (BA) 3, 6, 7, 10, 17, 19, 20,21,23, 38
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.001
	Comments	Threshold for significance: <.05
	Method	Full Factorial ANOVAs and Paired T-tests
	Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Prazosin -Placebo
	Comments	Wakefulness < NREM: Ke=7,013: x,y,z= 26, 22, -40. Right BA 4, 10-14, 21, 25, 32, 38, 45;
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.039
	Comments	Threshold for significance: <.05
	Method	Full Factorial ANOVAs and Paired T-tests
	Comments

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Prazosin -Placebo
	Comments	Wakefulness > (Rapid Eye Movement (REM): No cluster size, coordinates, or brain regions to report
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.701
	Comments	Threshold for significance: <.05
	Method	Full Factorial ANOVAs and Paired T-tests
	Comments

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Prazosin -Placebo
	Comments	Wakefulness < REM: No cluster size, coordinates, or brain regions to report
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	1.00
	Comments	Threshold for significance: <.05
	Method	Full Factorial ANOVAs and Paired T-tests
	Comments

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Prazosin -Placebo
	Comments	Within-state decrease in rCMRglc: Ke=6,150: x,y,z= -30, -30, 2. Left BA 40, insula, hippocampus, caudate, and putamen;
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.03
	Comments	Threshold for significance: <.05
	Method	Full Factorial ANOVAs and Paired T-tests
	Comments

Statistical Analysis 6

Statistical Analysis Overview	Comparison Group Selection	Prazosin -Placebo
	Comments	Within-state increase in rCMRglc: Ke=7,049: x,y,z= 66, -18, 26. Right BA 1, 3, 15, 21, 22, 23, 41, 42
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments	Threshold for significance: <.05
	Method	Full Factorial ANOVAs and Paired T-tests
	Comments

2. Secondary Outcome

Title	Pittsburgh Sleep Quality Index (PSQI):
Description	Self-report sleep quality measure. Scores range from 0 to 21, with higher scores reflecting poorer sleep quality.
Time Frame	Baseline and post-treatment at 8-10 weeks

Outcome Measure Data

Analysis Population Description

9 of the 20 participants who were randomized to prazosin and 13 of the participants randomized to prazosin provided scans pre- and post-treatment that were of sufficiency quality to be included in the final analyses.

Arm/Group Title	Prazosin	Placebo
Arm/Group Description	Active medication arm. Prazosin is an FDA approved medication, originally designed as an anti-hypertension medication. Side effects of the medication in some include sleepiness and once asleep, sustained sleep. Prazosin: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.	A placebo is a sugar pill, which will be used to compare with the results of the active medication Placebo: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.
Measure Participants	9	13
PSQI: Baseline	9.25 (2.64)	8.08 (2.72)
PSQI: Post	6.71 (4.31)	6.54 (2.57)

Adverse Events

Arm/Group Title	Prazosin		Placebo
Arm/Group Description	Active medication arm. Prazosin is an FDA approved medication, originally designed as an anti-hypertension medication. Side effects of the medication in some include sleepiness and once asleep, sustained sleep. Prazosin: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.		A placebo is a sugar pill, which will be used to compare with the results of the active medication Placebo: The medication will be administered in the same manner, regardless of active or placebo, as the study physician and investigators, as well as the participants, will be blind to the type of medication they are taking.
All Cause Mortality
	Prazosin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Prazosin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Prazosin		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/20 (0%)		0/20 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.