Prazosin vs Paroxetine in Combat Stress-Related Post-Traumatic Stress Disorder (PTSD) Nightmares & Sleep Disturbance

• Sponsor: Seattle Institute for Biomedical and Clinical Research (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00202449
• Collaborator: United States Department of Defense (U.S. Fed), VA Puget Sound Health Care System (U.S. Fed)
• Enrollment: 59
• Locations: 2
• Arms: 3
• Duration (Months): 43
• Patients Per Site: 29.5
• Patients Per Site Per Month: 0.7

Study Details

Study Description

Brief Summary

The purposes of this study are:

• to evaluate the efficacy and tolerability of the drug prazosin compared to placebo for combat stress-related nightmares, sleep disturbance and overall function in recently combat-exposed returnees from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF).

• to evaluate the effects of the selective serotonin reuptake inhibitor (SSRI) paroxetine on behavioral symptoms and overall function in this population.

Condition or Disease	Intervention/Treatment	Phase
Stress Disorders, Post-Traumatic; Sleep Disorders	Drug: prazosin; Drug: paroxetine; Drug: Placebo	N/A

Detailed Description

Trauma-related nightmares and sleep disruption that follow combat exposure are distressing and frequently treatment resistant symptoms that impair quality of life and overall function. These symptoms closely resemble core nighttime symptoms of posttraumatic stress disorder (PTSD), and are increasingly recognized in returnees from Operation Iraqi Freedom (OIF) and Operation Enduring Freedom (OEF). Prazosin, a generically available brain active alpha-1 adrenergic receptor antagonist, markedly reduced or eliminated combat trauma-related nightmares and sleep disruption in 23 of 25 combat-exposed returnees from OIF at Madigan Army Medical Center (MAMC). The use of prazosin in OIF returnees was based on clinical efficacy of prazosin for trauma-related nightmares, sleep disturbance, and overall function in Vietnam combat veterans with chronic PTSD. The only drugs FDA approved for PTSD are the selective serotonin reuptake inhibitors (SSRIs) sertraline and paroxetine. However, SSRI effectiveness in combat trauma PTSD, especially for nighttime symptoms, remains questionable.

This is a placebo-controlled clinical trial of prazosin vs. the SSRI paroxetine for combat trauma-related nightmares, sleep disturbance, and overall posttraumatic stress disorder (PTSD) clinical severity in OIF/OEF returnees. Both neurobiologic considerations and our preliminary clinical treatment data provide support for the proposed trial. Preclinical and clinical studies suggest a role for increased central nervous system (CNS) adrenergic outflow and/or responsiveness in PTSD pathophysiology. Possible mechanisms include alpha-1 adrenergic receptor-mediated effects on sleep physiology, corticotropin releasing hormone secretion, and disruption of cognitive processing.

Here we propose a double-blind, placebo-controlled parallel group 12 week clinical trial of prazosin vs. paroxetine to test the following hypotheses:

Hypothesis 1. Prazosin will be more effective than paroxetine or placebo for reducing frequency and intensity of combat trauma-related nightmares (as measured by the "distressing dreams" item of the Clinician Administered PTSD Scale [CAPS]).

Hypothesis 2. Prazosin will be more effective than paroxetine or placebo for improving sleep quality (as measured by the Pittsburgh Sleep Quality Index [PSQI]).

Hypothesis 3. Prazosin will be more effective than paroxetine or placebo for improving overall clinical status (as measured by the Clinical Global Impression of Change [CGIC]).

Hypothesis 4. Prazosin will be better tolerated than paroxetine as measured by days retained in the study and frequency of adverse events.

Primary outcome measures will assess trauma-related nightmares, sleep disturbance and change in global clinical status: these will include the CAPS [59] Recurrent Distressing Dreams item, the PSQI (60) and the CGIC (58) score. Secondary outcome measures will include total CAPS score, the CAPS subscale scores (Reexperiencing/ Intrusions, Avoidance/Numbing, and Hyperarousal), the Nightmare Frequency Questionnaire (NFQ), Insomnia Severity Index, and measures of depressive signs and symptoms, quality of life, and number of study days completed.

Study Design

• Study Type: Interventional
• Actual Enrollment: 59 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: A Placebo-Controlled Trial of Prazosin vs. Paroxetine in Combat Stress-Related PTSD Nightmares and Sleep Disturbance
• Study Start Date: Jul 1, 2004
• Actual Primary Completion Date: Feb 1, 2008
• Actual Study Completion Date: Feb 1, 2008

Arms and Interventions

Arm	Intervention/Treatment
Experimental: 1 Prazosin	Drug: prazosin; taken by mouth, twice daily, titrated up to efficacy or a maximum of 5 mg at 10a and 25 mg at bedtime for duration of study; Other Names: Minipress
Active Comparator: 2 Paroxetine	Drug: paroxetine; 20 mg taken at 10a for duration of the study; Other Names: Paxil, Paxil CR
Placebo Comparator: 3 Placebo	Drug: Placebo; Placebo

Outcome Measures

Primary Outcome Measures

1. Change in Combat Trauma-related Nightmares From the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams Item at Week 12 [Baseline and Week 12]

   Item B-2 "recurrent distressing dreams of the event" is a single item from the Clinician Administered PTSD Scale. The rating consists of two parts: Frequency and Intensity. Symptom frequency rated 0 to 4. Symptom intensity rated 0 to 4. Frequency plus Intensity ratings equal the total score. A higher score is worse; a lower score is better. This outcome measure evaluates the change in score from Baseline to Week 12. Minimum = 0 Maximum = 8

2. Change in Sleep From the Pittsburgh Sleep Quality Index From Baseline to Week 12 [Baseline to Week 12]

   Pittsburgh Sleep Quality Index is a self-report questionnaire assessing sleep quality and disturbances over a 1-month time interval. A global score is obtained by summing the seven component subscales (total score range: 0-21). A score of 5 or less indicates good sleep quality. A score of more than 5 indicates poor sleep quality. Change is measured from Baseline to Week 12.

3. Change in Global Trauma-related Symptom Severity and Functioning From the Clinical Global Impression of Change From Baseline to Week 12 [Baseline to Week 12]

   The Clinical Global Impression of Change is a 7-point scale that rates global change compared to baseline (1=markedly improved, 2=moderately improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=moderately worse, 7=markedly worse). The CGIC is used to determine the impact of treatment effects on meaningful and distinct change in overall sense of well-being and functioning. This outcome measure evaluates change from baseline to Week 12.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 50 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Hazardous duty in Iraq or Afghanistan with the US Armed Forces during Operations Iraqi Freedom and Operation Enduring Freedom

• Exposure to at least a moderate level of combat (>5 on Revised Combat Exposure Scale)

• Good general medical health

• Stable dose of non-excluded medications for at least 4 weeks prior to randomization

• 5 on CAPS recurrent distressing dreams item

• 5 on CAPS difficulty falling or staying asleep item

Exclusion Criteria:

• Acute or significant chronic medical illness, preexisting hypotension or orthostatic hypotension, pancreatitis, gout, Ménière's disease, benign positional vertigo, narcolepsy, or any other unstable medical condition.

• Women of childbearing potential with either positive pregnancy test or refusal to use effective birth control method will be excluded.

• Lifetime schizophrenia, schizoaffective disorder, bipolar disorder, psychotic disorder or any Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) cognitive disorder, current delirium, substance dependence disorder within 3 months of the study, severe psychiatric instability or severe situational life crises, including evidence of being actively suicidal or homicidal, or any behavior which poses an immediate danger to patient or others.

• Allergy or previous adverse reaction to prazosin or other alpha-1 antagonist or paroxetine or any other SSRI, no concurrent use of another alpha-1 antagonist agent, no concurrent use of an antidepressant (other than trazodone prescribed for sleep).

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Walter Reed Army Medical Center	Washington	District of Columbia	United States	20307
2	Madigan Army Medical Center	Fort Lewis	Washington	United States	98431

Sponsors and Collaborators

• Seattle Institute for Biomedical and Clinical Research
• United States Department of Defense
• VA Puget Sound Health Care System

Investigators

• Principal Investigator: Murray Raskind, MD, Director, Mental Health Services and Director, Mental Illness Research, Education, and Clinical Center VA Puget Sound Health Care System

Study Documents (Full-Text)

None provided.

More Information

Publications

• Peskind ER, Bonner LT, Hoff DJ, Raskind MA. Prazosin reduces trauma-related nightmares in older men with chronic posttraumatic stress disorder. J Geriatr Psychiatry Neurol. 2003 Sep;16(3):165-71.
• Raskind MA, Dobie DJ, Kanter ED, Petrie EC, Thompson CE, Peskind ER. The alpha1-adrenergic antagonist prazosin ameliorates combat trauma nightmares in veterans with posttraumatic stress disorder: a report of 4 cases. J Clin Psychiatry. 2000 Feb;61(2):129-33.
• Raskind MA, Peskind ER, Kanter ED, Petrie EC, Radant A, Thompson CE, Dobie DJ, Hoff D, Rein RJ, Straits-Tröster K, Thomas RG, McFall MM. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry. 2003 Feb;160(2):371-3.
• Raskind MA, Thompson C, Petrie EC, Dobie DJ, Rein RJ, Hoff DJ, McFall ME, Peskind ER. Prazosin reduces nightmares in combat veterans with posttraumatic stress disorder. J Clin Psychiatry. 2002 Jul;63(7):565-8.

• Responsible Party: Seattle Institute for Biomedical and Clinical Research
• ClinicalTrials.gov Identifier: NCT00202449
• Other Study ID Numbers: Raskind 0046; DoD #PR054292; UW HS #04-1469-V 02
• First Posted: Sep 20, 2005
• Last Update Posted: Jul 10, 2018
• Last Verified: Jun 1, 2018

• Keywords provided by Seattle Institute for Biomedical and Clinical Research: Prazosin; Paroxetine; Stress Disorders, Post-Traumatic; Sleep Disorders
• Additional relevant MeSH terms: Sleep Wake Disorders; Parasomnias; Dyssomnias; Disease; Stress Disorders, Traumatic; Stress Disorders, Post-Traumatic; Prazosin; Paroxetine

Study Results

Participant Flow

Arm/Group Title	Prazosin	Paroxetine	Placebo
Arm/Group Description	Prazosin is a brain active alpha-1 adrenal receptor antagonist. Dose initiated at an initial dose of 1 mg qhs and titrated up to a maximum dose of 30 mg/day according to weight, age and presence or absence of daytime symptoms.	Paroxetine is a Selective Serotonin Reuptake Inhibitor. Dose started and maintained at 20 mg q10A.	Placebo is an inert substance used as a standard comparator in clinical pharmacologic trials.
Period Title: Overall Study
STARTED	18	20	21
COMPLETED	7	9	9
NOT COMPLETED	11	11	12

Baseline Characteristics

Arm/Group Title	Prazosin	Paroxetine	Placebo	Total
Arm/Group Description	Prazosin is a brain active alpha-1 adrenal receptor antagonist. Dose initiated at an initial dose of 1 mg qhs and titrated up to a maximum dose of 30 mg/day according to weight, age and presence or absence of daytime symptoms.	Paroxetine is a Selective Serotonin Reuptake Inhibitor. Dose started and maintained at 20 mg q10A.	Placebo is an inert substance used as a standard comparator in clinical pharmacologic trials.	Total of all reporting groups
Overall Participants	18	20	21	59
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	18 100%	20 100%	21 100%	59 100%
>=65 years	0 0%	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	29 (7)	28 (5)	32 (9)	30 (7)
Sex: Female, Male (Count of Participants)
Female	1 5.6%	1 5%	1 4.8%	3 5.1%
Male	17 94.4%	19 95%	20 95.2%	56 94.9%
Region of Enrollment (participants) [Number]
United States	18 100%	20 100%	21 100%	59 100%

Outcome Measures

1. Primary Outcome

Title	Change in Combat Trauma-related Nightmares From the Clinician Administered PTSD Scale (CAPS) Recurrent Distressing Dreams Item at Week 12
Description	Item B-2 "recurrent distressing dreams of the event" is a single item from the Clinician Administered PTSD Scale. The rating consists of two parts: Frequency and Intensity. Symptom frequency rated 0 to 4. Symptom intensity rated 0 to 4. Frequency plus Intensity ratings equal the total score. A higher score is worse; a lower score is better. This outcome measure evaluates the change in score from Baseline to Week 12. Minimum = 0 Maximum = 8
Time Frame	Baseline and Week 12

Outcome Measure Data

Analysis Population Description

Number of subjects analyzed equals the number of subjects who were able to complete this assessment at week 12 (e.g., completed the study).

Arm/Group Title	Prazosin	Paroxetine	Placebo
Arm/Group Description	Prazosin is a brain active alpha-1 adrenal receptor antagonist. Dose initiated at an initial dose of 1 mg qhs and titrated up to a maximum dose of 30 mg/day according to weight, age and presence or absence of daytime symptoms.	Paroxetine is a Selective Serotonin Reuptake Inhibitor. Dose started and maintained at 20 mg q10A.	Placebo is an inert substance used as a standard comparator in clinical pharmacologic trials.
Measure Participants	9	7	9
Mean (Standard Deviation) [scale points]	-1.29 (1.11)	-3.11 (2.52)	-2.67 (3.0)

2. Primary Outcome

Title	Change in Sleep From the Pittsburgh Sleep Quality Index From Baseline to Week 12
Description	Pittsburgh Sleep Quality Index is a self-report questionnaire assessing sleep quality and disturbances over a 1-month time interval. A global score is obtained by summing the seven component subscales (total score range: 0-21). A score of 5 or less indicates good sleep quality. A score of more than 5 indicates poor sleep quality. Change is measured from Baseline to Week 12.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Number of subjects analyzed equals the number of subjects who were able to complete this assessment at Week 12 (e.g., completed the study).

Arm/Group Title	Prazosin	Paroxetine	Placebo
Arm/Group Description	Prazosin is a brain active alpha-1 adrenal receptor antagonist. Dose initiated at an initial dose of 1 mg qhs and titrated up to a maximum dose of 30 mg/day according to weight, age and presence or absence of daytime symptoms.	Paroxetine is a Selective Serotonin Reuptake Inhibitor. Dose started and maintained at 20 mg q10A.	Placebo is an inert substance used as a standard comparator in clinical pharmacologic trials.
Measure Participants	6	9	9
Mean (Standard Deviation) [scale points]	-2.33 (2.94)	-6.44 (3.91)	-3.33 (5.45)

3. Primary Outcome

Title	Change in Global Trauma-related Symptom Severity and Functioning From the Clinical Global Impression of Change From Baseline to Week 12
Description	The Clinical Global Impression of Change is a 7-point scale that rates global change compared to baseline (1=markedly improved, 2=moderately improved, 3=minimally improved, 4=no change, 5=minimally worse, 6=moderately worse, 7=markedly worse). The CGIC is used to determine the impact of treatment effects on meaningful and distinct change in overall sense of well-being and functioning. This outcome measure evaluates change from baseline to Week 12.
Time Frame	Baseline to Week 12

Outcome Measure Data

Analysis Population Description

Number of subjects analyzed equals the number of subjects who were able to complete this assessment at week 12 (e.g., completed the study).

Arm/Group Title	Prazosin	Paroxetine	Placebo
Arm/Group Description	Prazosin is a brain active alpha-1 adrenal receptor antagonist. Dose initiated at an initial dose of 1 mg qhs and titrated up to a maximum dose of 30 mg/day according to weight, age and presence or absence of daytime symptoms.	Paroxetine is a Selective Serotonin Reuptake Inhibitor. Dose started and maintained at 20 mg q10A.	Placebo is an inert substance used as a standard comparator in clinical pharmacologic trials.
Measure Participants	7	9	9
Mean (Standard Deviation) [scale points]	3.14 (1.86)	2.11 (1.05)	2.33 (1.22)

Adverse Events

Time Frame	12 weeks
Adverse Event Reporting Description	Adverse events were collected over the course of 12 weeks.
Arm/Group Title	Prazosin		Paroxetine		Placebo
Arm/Group Description	Prazosin is a brain active alpha-1 adrenal receptor antagonist. Dose initiated at an initial dose of 1 mg qhs and titrated up to a maximum dose of 30 mg/day according to weight, age and presence or absence of daytime symptoms.		Paroxetine is a Selective Serotonin Reuptake Inhibitor. Dose started and maintained at 20 mg q10A.		Placebo is an inert substance used as a standard comparator in clinical pharmacologic trials.
All Cause Mortality
	Prazosin		Paroxetine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Prazosin		Paroxetine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/18 (0%)		0/20 (0%)		0/21 (0%)
Other (Not Including Serious) Adverse Events
	Prazosin		Paroxetine		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/18 (16.7%)		3/20 (15%)		1/21 (4.8%)
Cardiac disorders
heart palpitations	0/18 (0%)	0	0/20 (0%)	0	1/21 (4.8%)	1
Ear and labyrinth disorders
dizziness	0/18 (0%)	0	0/20 (0%)	0	1/21 (4.8%)	1
Eye disorders
PAK bilateral eye surgery	0/18 (0%)	0	1/20 (5%)	1	0/21 (0%)	0
conjunctivitis	1/18 (5.6%)	1	0/20 (0%)	0	0/21 (0%)	0
change in vision	1/18 (5.6%)	1	0/20 (0%)	0	0/21 (0%)	0
Gastrointestinal disorders
stomach pain	0/18 (0%)	0	0/20 (0%)	0	1/21 (4.8%)	3
diarrhea	2/18 (11.1%)	4	0/20 (0%)	0	0/21 (0%)	0
surgery for dyskinesia of esophagus and diverticulum of esophagus, acquired.	1/18 (5.6%)	1	0/20 (0%)	0	0/21 (0%)	0
vomiting	1/18 (5.6%)	1	0/20 (0%)	0	0/21 (0%)	0
General disorders
dry mouth	0/18 (0%)	0	0/20 (0%)	0	1/21 (4.8%)	1
central chest discomfort	1/18 (5.6%)	1	0/20 (0%)	0	0/21 (0%)	0
Musculoskeletal and connective tissue disorders
shoulder pain	0/18 (0%)	0	1/20 (5%)	1	0/21 (0%)	0
Nervous system disorders
numbness in face and hands	0/18 (0%)	0	0/20 (0%)	0	1/21 (4.8%)	1
Psychiatric disorders
anxiety with palpitations	0/18 (0%)	0	0/20 (0%)	0	1/21 (4.8%)	1
panic attack	1/18 (5.6%)	2	0/20 (0%)	0	0/21 (0%)	0
difficulty concentrating	0/18 (0%)	0	0/20 (0%)	0	1/21 (4.8%)	1
Renal and urinary disorders
nocturnal urinary incontinence	1/18 (5.6%)	1	0/20 (0%)	0	0/21 (0%)	0
reaction to study drug (paroxetine)	0/18 (0%)	0	1/20 (5%)	1	0/21 (0%)	0
abnormal ejaculation	0/18 (0%)	0	1/20 (5%)	1	0/21 (0%)	0
Respiratory, thoracic and mediastinal disorders
nasal congestion	0/18 (0%)	0	0/20 (0%)	0	1/21 (4.8%)	1
Skin and subcutaneous tissue disorders
allertic reaction to tramadol - hives/itching	0/18 (0%)	0	0/20 (0%)	0	1/21 (4.8%)	1

Limitations/Caveats

High rate of early termination leading to small number of patients analyzed.

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.