Cooperative Studies Program #563 - Prazosin and Combat Trauma PTSD
Condition: PTSD; Sleep Disorders
MeSH terms: Sleep Wake Disorders
Intervention: prazosin; placebo
Intervention description: 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.; "sugar" pill
Intervention MeSH terms: Prazosin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: Double (Participant, Investigator)
Enrollment: 304.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: Accepts Healthy Volunteers
Keywords: Combat Trauma; Post traumatic stress disorder; PTSD; Sleep Disturbance; Trauma-Related Nightmares

Summary:

      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.
    

Eligibility 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 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.