Cooperative Studies Program #563 - Prazosin and Combat Trauma PTSD

NCT00532493 | Completed Phase 3 Results DMC FDA Drug

• 1 other identifier: 563
• Study Type: interventional
• Target: 304
• Locations: 1 country
• Sites: 15

Brief 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.

Conditions

PTSD; Sleep Disorders

Keywords

Combat Trauma; Post traumatic stress disorder; PTSD; Sleep Disturbance; Trauma-Related Nightmares

Outcome Measures

Primary Outcomes (3)

• 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 Outcomes (10)

• Pittsburgh Sleep Quality Index

  This secondary outcome measure was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks (or early termination).

• CAPS Recurrent Distressing Dreams Item

  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

  This secondary outcome measure was administered at 6, 10, 14, 18, 22 and 26 weeks (or early termination).

• Total CAPS Score

  The total CAPS was administered at baseline, 6, 10, 18, and 26 weeks (or early termination).

• PTSD Checklist-Military Version (PCL-M) Score

  This secondary outcome was administered at baseline, 6, 10, 14, 18, 22 and 26 weeks to assess change in PTSD symptom severity.

Study Arms (2)

Prazosin Group

ACTIVE COMPARATOR

Subjects randomized to this arm will be on prazosin.

Drug: prazosin

Placebo Group

PLACEBO COMPARATOR

Subjects randomized to this arm will be on placebo.

Other: placebo

Interventions

prazosin DRUG

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.

Prazosin Group

placebo OTHER

"sugar" pill

Placebo Group

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.
• Psychotherapeutic treatment stable for at least 4 weeks prior to randomization.

You may not qualify if:

• Female participants must agree to use a reliable form of birth control during the study.
• 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.
• Allergy or previous adverse reaction to prazosin or other alpha-1 antagonist.
• 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.
• 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.
• 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).

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (15)

VA Medical Center, Loma Linda

Loma Linda, California, 92357, United States

Location

VA Medical Center, Long Beach

Long Beach, California, 90822, United States

Location

VA Palo Alto Health Care System

Palo Alto, California, 94304-1290, United States

Location

VA Medical Center, Miami

Miami, Florida, 33125, United States

Location

Atlanta VA Medical and Rehab Center, Decatur

Decatur, Georgia, 30033, United States

Location

VA Medical Center, Kansas City MO

Kansas City, Missouri, 64128, United States

Location

New Mexico VA Health Care System, Albuquerque

Albuquerque, New Mexico, 87108-5153, United States

Location

New York Harbor HCS

New York, New York, 10010, United States

Location

VA Medical Center, Durham

Durham, North Carolina, 27705, United States

Location

Salisbury VAMC

Salisbury, North Carolina, 28144, United States

Location

VA Medical Center, Providence

Providence, Rhode Island, 02908, United States

Location

WJB Dorn Veterans Hospital, Columbia

Columbia, South Carolina, 29209, United States

Location

VA Salt Lake City Health Care System, Salt Lake City

Salt Lake City, Utah, 84148, United States

Location

VA Puget Sound Health Care System Seattle Division, Seattle, WA

Seattle, Washington, 98108, United States

Location

Wlliam S. Middleton Memorial Veterans Hospital, Madison

Madison, Wisconsin, 53705, United States

Location

Related Publications (1)

• Raskind MA, Peskind ER, Chow B, Harris C, Davis-Karim A, Holmes HA, Hart KL, McFall M, Mellman TA, Reist C, Romesser J, Rosenheck R, Shih MC, Stein MB, Swift R, Gleason T, Lu Y, Huang GD. Trial of Prazosin for Post-Traumatic Stress Disorder in Military Veterans. N Engl J Med. 2018 Feb 8;378(6):507-517. doi: 10.1056/NEJMoa1507598.

  PMID: 29414272 RESULT

MeSH Terms

Conditions

Stress Disorders, Post-Traumatic; Sleep Wake Disorders; Parasomnias

Interventions

Prazosin

Condition Hierarchy (Ancestors)

Stress Disorders, Traumatic; Trauma and Stressor Related Disorders; Mental Disorders; Nervous System Diseases; Neurologic Manifestations; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Dr. Murray Rasknd
• Organization: VA Puget Sound Health Care System

Murray.Raskind@va.gov

(206) 764-2702

Study Officials

• Murray A. Raskind, MD

  VA Puget Sound Health Care System Seattle Division, Seattle, WA

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 18, 2007
• First Posted: September 20, 2007
• Study Start: January 6, 2010
• Primary Completion: February 28, 2013
• Study Completion: May 31, 2013
• Last Updated: May 1, 2018
• Results First Posted: June 18, 2014

Record last verified: 2018-03

Data Sharing

• IPD Sharing: Will not share

Locations

US (15)