CSP #563 - Prazosin and Combat Trauma PTSD (PACT)
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. We 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.
|Study Design:||Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Investigator)
Primary Purpose: Treatment
|Official Title:||CSP #563 - Prazosin and Combat Trauma PTSD (PACT)|
- Change in Frequency and/or Severity of Combat Trauma-related Nightmares [ Time Frame: All primary outcome measures were administered at 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. ] [ Designated as safety issue: No ]Possible range for CAPS total score 0-136, CAPS re-experiencing 0-40, CAPS Avoidance and Numbing 0-56, CAPS Hyperarousal 0-40, CAPS Significant Distress 0-12, Recurrent Distressing Dreams 0-8. Higher score indicates more severe PTSD symptoms.
- Change in Pittsburgh Sleep Quality Index [ Time Frame: All primary outcome measures were administered at 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. ] [ Designated as safety issue: No ]Possible range for PSQI global score 0-21, and possible range for each component 0-3. Higher PSQI score indicates worse quality of sleep.
- Clinical Global Impression of Change [ Time Frame: All primary outcome measures were administered at 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. ] [ Designated as safety issue: No ]Possible range for 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.
- Change in PTSD Symptom Severity, Change in Depressive Symptoms, Change in Quality of Life, Change in Health-related Quality of Life, and Change in Alcohol Use. [ Time Frame: The total CAPS will be administered at screen, baseline, and at 6, 10, 18, and 26 weeks (or early termination). All other secondary outcome measures will be administered at 6, 10, 14, 18, 22 and 26 weeks (or early termination). ] [ Designated as safety issue: No ]
|Study Start Date:||January 2010|
|Study Completion Date:||May 2013|
|Primary Completion Date:||February 2013 (Final data collection date for primary outcome measure)|
Active Comparator: Arm 1
Subjects randomized to this arm will be on prazosin.
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.
Placebo Comparator: Arm 2
Subjects randomized to this arm will be on placebo.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00532493
|United States, California|
|VA Medical Center, Loma Linda|
|Loma Linda, California, United States, 92357|
|VA Medical Center, Long Beach|
|Long Beach, California, United States, 90822|
|VA Palo Alto Health Care System|
|Palo Alto, California, United States, 94304-1290|
|United States, Florida|
|VA Medical Center, Miami|
|Miami, Florida, United States, 33125|
|United States, Georgia|
|Atlanta VA Medical and Rehab Center, Decatur|
|Decatur, Georgia, United States, 30033|
|United States, Missouri|
|VA Medical Center, Kansas City MO|
|Kansas City, Missouri, United States, 64128|
|United States, New Mexico|
|New Mexico VA Health Care System, Albuquerque|
|Albuquerque, New Mexico, United States, 87108-5153|
|United States, New York|
|New York Harbor HCS|
|New York, New York, United States, 10010|
|United States, North Carolina|
|VA Medical Center, Durham|
|Durham, North Carolina, United States, 27705|
|Salisbury, North Carolina, United States, 28144|
|United States, Rhode Island|
|VA Medical Center, Providence|
|Providence, Rhode Island, United States, 02908|
|United States, South Carolina|
|WJB Dorn Veterans Hospital, Columbia|
|Columbia, South Carolina, United States, 29209|
|United States, Utah|
|VA Salt Lake City Health Care System, Salt Lake City|
|Salt Lake City, Utah, United States, 84148|
|United States, Washington|
|VA Puget Sound Health Care System Seattle Division, Seattle, WA|
|Seattle, Washington, United States, 98108|
|United States, Wisconsin|
|Wlliam S. Middleton Memorial Veterans Hospital, Madison|
|Madison, Wisconsin, United States, 53705|
|Study Chair:||Murray Raskind, MD||VA Puget Sound Health Care System Seattle Division, Seattle, WA|