Cooperative Studies Program #563 - Prazosin and Combat Trauma PTSD

Study Overview
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Brief Summary
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Background: Posttraumatic stress disorder (PTSD) is a debilitating and disabling mental disorder that afflicts at least 25% of Veterans who have suffered life-threatening war zone trauma. Trauma-related nightmares and sleep disturbance are among the most treatment-resistant PTSD symptoms in Veterans. Increased responsiveness to central nervous system (CNS) norepinephrine (NE) contributes to the pathophysiology of overall PTSD and treatment-resistant nighttime symptoms. Placebo-controlled pilot studies demonstrate that the generically available CNS-active alpha-1 adrenoreceptor antagonist prazosin substantially reduces PTSD trauma nightmares and sleep disturbance and improves global clinical status (sense of well being and ability to function) in Veterans. Objective: The primary objective is to demonstrate in a large multi-site placebo-controlled trial in Veterans with war zone trauma-induced PTSD that prazosin is efficacious for PTSD trauma nightmares, sleep disturbance, and global clinical status. A secondary objective is to demonstrate prazosin effectiveness for these outcome measures during clinically meaningful long-term (26 week) maintenance treatment of PTSD. The investigators will also address prazosin efficacy and long-term effectiveness for improving total PTSD symptoms, comorbid depression, quality of life, and physical functioning. Methods: This 26 week randomized double-blind placebo-controlled study is designed to demonstrate both short term efficacy and long term effectiveness of prazosin for PTSD. The research design encompasses a shorter-term, more tightly controlled efficacy component and a longer-term, more .real world. effectiveness component. Three hundred twenty-six Veterans with war zone -related PTSD and persistent trauma nightmares will be randomized 1:1 to prazosin or placebo. Study drug will be increased using a flexible dose titration schedule based on clinical response and adverse effects to an optimum maintenance dose (1-20 mg/day). During the first 10 weeks of the study, participants will be randomized to prazosin or placebo. Previous psychotropic medications and/or psychotherapy will be maintained constant. Short term efficacy will be determined during the first 10 weeks. During the remaining 16 weeks of the 26 week trial, subjects will continue to receive stable-dose double-blind prazosin or placebo, but will have the option to receive additional psychotropic medications and/or psychotherapeutic interventions, as needed, per the judgment of the study Clinician Prescriber. It is hypothesized that prazosin will remain more clinically effective than placebo at the end of the 26-week trial, demonstrating that prazosin adds benefit over-and-above other treatments that are naturalistically administered by providers in a .real world. clinical setting. Prazosin will be judged efficacious at 10 weeks if superior to placebo on all three primary outcome measures assessing trauma nightmares, sleep disturbance, and global clinical status: the Recurrent Distressing Dreams item of the Clinician Administered PTSD Scale (CAPS), the Pittsburgh Sleep Quality Index (PSQI), and the Clinical Global Impression of Change (CGIC). Secondary outcome measures will assess prazosin effects on total PTSD symptoms, depression, physical functioning, and quality of life. Adverse effects and cardiovascular measures, including supine and standing blood pressure (BP) and heart rate (HR) will be assessed.

Official Title
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CSP #563 - Prazosin and Combat Trauma PTSD (PACT)

Conditions
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PTSD, Sleep Disorders

Intervention / Treatment
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* Drug: prazosin
* Other: placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age >18 years. Exposure to one or more life-threatening war zone trauma events per the Combat Exposure Scale [78] and documented by Department of Defense (DD) Form 214, Combat Action Ribbon (Marines), Combat Infantry Badge (Army), or other clear evidence of war zone trauma exposure. Eligible for VA health care. Diagnostic and Statistical Manual of Mental Disorders (DSM)-IV diagnosis of PTSD derived from the CAPS. CAPS total score >50. CAPS Recurrent Distressing Dreams item score >5 (of maximum score of 8). Capable of giving informed consent. Stable dose of non-exclusionary (see below) medications for at least 4 weeks prior to randomization. Psychotherapeutic treatment stable for at least 4 weeks prior to randomization. Good general medical health (see Medical Exclusion Criteria below). Female participants must agree to use a reliable form of birth control during the study. Exclusion Criteria: Medical: Acute or unstable chronic medical illness, including unstable angina, recent myocardial infarction (within 6 months), congestive heart failure, preexisting hypotension (systolic <110) or orthostatic hypotension (systolic drop > 20 millimeters of mercury after two minutes standing or any drop accompanied by dizziness); chronic renal or hepatic failure, pancreatitis, Meniere's disease, benign positional vertigo; narcolepsy. Untreated sleep apnea, diagnosed by a sleep study, is exclusionary. Treated sleep apnea (e.g., Continuous Positive Airway Pressure, surgery) will not be exclusionary. Allergy or previous adverse reaction to prazosin or other alpha-1 antagonist. Wounds requiring surgery, embedded shrapnel, and recent surgical amputation do not comprise an exclusion if the individual is otherwise medically eligible. Women of childbearing potential with positive pregnancy test or refusal to use effective birth control method, or who are breastfeeding will be excluded. Psychiatric/Behavioral: Meets DSM-IV criteria for current schizophrenia, schizoaffective disorder, psychotic disorder not otherwise specified (NOS), delirium, or any DSM-IV cognitive disorder. Exclusion for psychotic disorder is not to be confused with combat trauma-induced reexperiencing symptoms (transient dissociative states or flashbacks), which will not be exclusionary. Substance dependence disorder within 3 months or any current substance dependence (stable methadone maintenance will not be exclusionary). Current cocaine or stimulant abuse. 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. Nonsuicidal depression comorbid with PTSD will not be exclusionary (see below). Medications/Therapies: Current use of prazosin or other alpha-1 antagonist. Previous adequate trial of prazosin for PTSD. Subjects on trazodone will undergo a 2-week washout period before baseline assessment. (Combining prazosin and trazodone may increase risk of priapism). Sildenafil (Viagra), tadalafil (Cialis), and vardenafil (Levitra) will be not be permitted during the study dose titration period because of increased risk of hypotension in combination with alpha-1 blockers. Following achieving stable dose of study drug, sildenafil, tadalafil, and vardenafil will be permitted at 1/2 the usual starting dose. Stimulants or alternative medications with stimulant properties (e.g., ephedra). Recent exposure therapy and/or Eye Movement Desensitization and Reprogramming (EMDR). These therapies must have been completed > 4 weeks before randomization. Other psychotropic medications and/or maintenance psychotherapy at a stable dose for at least 4 weeks will not be exclusionary.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Prazosin Group<br>Subjects randomized to this arm will be on prazosin. | Drug: prazosin<br>* Subjects will be titrated up to the optimum tolerated dose based on the Dosing Algorithm. Males and females will be titrated differently with females titrated slower and to a lower maximum daily dose. The first dose will be taken while the participant is in bed for the night to avoid orthostatic syncope, an uncommon but recognized first dose effect of prazosin or any alpha-1 antagonist if started at a high dose. As a further precaution, male subjects will be advised to sit on the toilet for urination at night during the first week of dose titration. The first dose effect is avoidable by starting treatment with a low dose (1 mg at bedtime) and then titrating the dose upward gradually.<br>|
| Placebo Comparator: Placebo Group<br>Subjects randomized to this arm will be on placebo. | Other: placebo<br>* sugar pill<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| CAPS Recurrent Distressing Dreams Item | Change from baseline in frequency and/or severity of combat trauma-related nightmares will be assessed by the CAPS Recurrent Distressing Dreams item. Possible range for Recurrent Distressing Dreams is 0-8. Higher score indicates more severe PTSD symptoms. | This primary outcome measure was administered at baseline and week 10. The change of the 10-week from baseline was reported. | 
| Pittsburgh Sleep Quality Index (PSQI) | Change from baseline in possible range for PSQI global score 0-21. Higher PSQI score indicates worse quality of sleep. | This primary outcome measure was administered at baseline and week 10. The change of the 10-week from baseline was reported. | 
| Clinical Global Impression of Change (CGIC) | Change from baseline in possible range for Clinical Global Impression of Change 1-7. As compared to baseline global condition, 1 is marked improvement, 2 is moderate improvement, 3 is minimal improvement, 4 is no change, 5 is minimal worsening, 6 is moderate worsening, and 7 is marked worsening. | This primary outcome measure was administered at baseline and week 10. The change of the 10-week from baseline was reported. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pittsburgh Sleep Quality Index | Change from baseline in possible range for PSQI global score 0-21. Higher PSQI score indicates worse quality of sleep. | This secondary outcome measure was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks (or early termination). | 
| CAPS Recurrent Distressing Dreams Item | Change from baseline in frequency and/or severity of combat trauma-related nightmares will be assessed by the CAPS Recurrent Distressing Dreams item. Possible range for Recurrent Distressing Dreams is 0-8. Higher score indicates more severe PTSD symptoms. | This secondary outcome measure was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks (or early termination) to assess temporal course of changes in symptoms in response to prazosin or placebo. | 
| Clinical Global Impression of Change | Change from baseline in possible range for Clinical Global Impression of Change (CGIC) 1-7. As compared to baseline global condition, 1 is marked improvement, 2 is moderate improvement, 3 is minimal improvement, 4 is no change, 5 is minimal worsening, 6 is moderate worsening, and 7 is marked worsening. | This secondary outcome measure was administered at 6, 10, 14, 18, 22 and 26 weeks (or early termination). | 
| Total CAPS Score | Change from baseline in possible range for CAPS total score is 0-136. Higher score indicates more severe PTSD symptoms. | The total CAPS was administered at baseline, 6, 10, 18, and 26 weeks (or early termination). | 
| PTSD Checklist-Military Version (PCL-M) Score | Change from baseline in possible range for PCL-M score 17-85. Higher PCL score indicates greater propensity for chronic and delayed PTSD. | This secondary outcome was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks to assess change in PTSD symptom severity. | 
| Patient Health Questionnaire-9 (PHQ9) | Change from baseline in possible range for PHQ9 score is 0-27. Higher PHQ9 score indicates more severe depression. | This secondary outcome measure was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks (or early termination). | 
| SF-12 Physical Standardized Score (SF-12 PCS) | Change from baseline in possible range for SF-12 PCS is 6-72. Higher SF-12 score indicates better level of health. | This secondary outcome measure was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks (or early termination). | 
| SF-12 Mental Standardized Score (SF-12 MCS) | Change from baseline in possible range for SF-12 MCS is 5-76. Higher SF-12 score indicates better level of health. | This secondary outcome measure was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks (or early termination). | 
| Quality of Life Inventory (QOLI) | Change from baseline in possible range for QOLI is -6 to 6. Higher QOLI indicates better satisfaction with life. | This secondary outcome measure was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks (or early termination). | 
| Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) | Change from baseline in possible range for Audit-C score is 0-12. Higher score indicates heavier use of alcohol. A score of >=4 for male and a score of >=3 for female meets the criteria for alcohol use disorders. | This secondary outcome measure was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks (or early termination). | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Combat Trauma, Post traumatic stress disorder, PTSD, Sleep Disturbance, Trauma-Related Nightmares