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

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
Department of Veterans Affairs
ClinicalTrials.gov Identifier:
NCT00532493
First received: September 18, 2007
Last updated: May 19, 2014
Last verified: May 2014
  Purpose

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.


Condition Intervention Phase
PTSD
Sleep Disorders
Drug: prazosin
Other: placebo
Phase 3

Study Type: Interventional
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)

Resource links provided by NLM:


Further study details as provided by Department of Veterans Affairs:

Primary Outcome Measures:
  • 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.


Secondary Outcome Measures:
  • 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 ]

Enrollment: 304
Study Start Date: January 2010
Study Completion Date: May 2013
Primary Completion Date: February 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Arm 1
Subjects randomized to this arm will be on prazosin.
Drug: 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.
Other: placebo
"sugar" pill

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
Criteria

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 DD-214, Combat Action Ribbon (Marines), Combat Infantry Badge (Army), or other clear evidence of war zone trauma exposure.
  • Eligible for VA health care.
  • 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 > 20mmHg 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., CPAP, 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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00532493

Locations
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 VAMC
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
Sponsors and Collaborators
Investigators
Study Chair: Murray Raskind, MD VA Puget Sound Health Care System Seattle Division, Seattle, WA
  More Information

No publications provided

Responsible Party: Department of Veterans Affairs
ClinicalTrials.gov Identifier: NCT00532493     History of Changes
Other Study ID Numbers: 563
Study First Received: September 18, 2007
Results First Received: April 2, 2014
Last Updated: May 19, 2014
Health Authority: United States: Federal Government
United States: Food and Drug Administration

Keywords provided by Department of Veterans Affairs:
Combat Trauma
Post traumatic stress disorder
PTSD
Sleep Disturbance
Trauma-Related Nightmares

Additional relevant MeSH terms:
Sleep Disorders
Parasomnias
Stress Disorders, Post-Traumatic
Nervous System Diseases
Neurologic Manifestations
Signs and Symptoms
Mental Disorders
Stress Disorders, Traumatic
Anxiety Disorders
Prazosin
Antihypertensive Agents
Cardiovascular Agents
Therapeutic Uses
Pharmacologic Actions
Adrenergic alpha-1 Receptor Antagonists
Adrenergic alpha-Antagonists
Adrenergic Antagonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on July 10, 2014