Comparative Effectiveness PTSD Trial of Sequenced Pharmacotherapy and Psychotherapy in Primary Care
Phase: PHASE4
Conditions: PTSD
Sponsor: University of Washington

 
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COMPARATIVE EFFECTIVENESS PTSD TRIAL OF SEQUENCED PHARMACOTHERAPY AND 
PSYCHOTHERAPY IN PRIMARY CARE  
(STEPS) 
 
 
STUDY PROTOCOL 
VERSION 5 
6/27/24 
 
 
Principal Investigator - John Fortney, PhD  
Co-Principal Investigator – Debra Kaysen, PhD 
Co-Principal Investigator – Charles Engel, MD 
 
 
 
Supported by: 
Patient-Centered Outcomes Research Institute 
 PTSD-2019C1-15636  
 
 
 
 
 
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TABLE OF CONTENTS 
Page 
1 
PRÉCIS .......................................................................... Error! Bookmark not defined. 
1.1 Background and Significance .......................................................................................... 6 
1.2 Study Aims ...................................................................................................................... 6 
1.3 Study Description ............................................................................................................ 6 
2 
STUDY TEAM .......................................................................................................... 8 
2.1 Organizational Chart ....................................................................................................... 8 
2.2 Principal Investigator ...................................................................................................... 8 
2.3 Co-Principal Investigators ............................................................................................... 9 
2.4 Co-Investigators .............................................................................................................. 9 
2.5 Participating Study Sites ............................................................................................... 11 
3 
ACRONYMS .......................................................................................................... 12 
4 
STUDY OBJECTIVES ............................................................................................... 13 
4.1 Primary Objective ......................................................................................................... 13 
4.2 Secondary Objectives .................................................................................................... 13 
5 
BACKGROUND AND RATIONALE ........................................................................... 14 
5.1 Background [CI-1][HT-1][PC-1][RQ-1][RQ-3][RQ-5] ...................................................... 14 
5.2 Study Rationale ............................................................................................................. 17 
6 
STUDY DESIGN [PC-1][RQ-6] ................................................................................. 17 
7 
SELECTION AND ENROLLMENT OF PARTICIPANTS ................................................. 19 
7.1 Inclusion Criteria [CI-2] ................................................................................................. 19 
7.2 Exclusion Criteria [CI-2][IR-5][PC-2] .............................................................................. 19 
7.3 Study Enrollment Procedures ....................................................................................... 20 
8 
STUDY INTERVENTIONS ........................................................................................ 21 
8.1 Psychotherapy - Written Exposure Therapy (WET) ...................................................... 21 
8.2 Pharmacotherapy - Antidepressants ............................................................................ 24 
8.3 Treatment Sequences: .................................................................................................. 25 
8.4 Concomitant Interventions ........................................................................................... 26 
 
Allowed Interventions ........................................................................................... 26 
 
Required Interventions ......................................................................................... 26 
 
Prohibited Interventions ....................................................................................... 26 

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8.5 Adherence Assessment [IR-2][IR-5] .............................................................................. 26 
9 
STUDY PROCEDURES ............................................................................................ 27 
9.1 Schedule of Evaluations ................................................................................................ 27 
9.2 Description of Evaluations [CI-3][IR-6][MD-2][PC-1][PC-2][PC-3][RQ-6] ...................... 27 
9.3 Screening Evaluation ..................................................................................................... 28 
9.4 Enrollment, Baseline, and Randomization .................................................................... 28 
 
Enrollment ............................................................................................................ 28 
 
Baseline Assessments [IR-4] ................................................................................. 28 
 
Randomization ...................................................................................................... 29 
9.5 Follow-Up Evaluations [IR-4][RQ-6] .............................................................................. 29 
10 
SAFETY ASSESSMENTS .......................................................................................... 29 
10.1 Definitions of noncompliance, adverse events, serious adverse events and 
unanticipated problems: .............................................................................................. 29 
10.2 Expectedness ................................................................................................................ 31 
10.3 Determination of Unanticipated Serious Adverse Events ............................................ 31 
10.4 Reporting Serious and Continuing Non-Compliance and Unanticipated Serious 
Adverse Events ............................................................................................................. 33 
10.5 Safety Monitoring ......................................................................................................... 33 
11 
INTERVENTION DISCONTINUATION [MD-3] .......................................................... 34 
12 
STATISTICAL CONSIDERATIONS ............................................................................. 34 
12.1 General Design Issues ................................................................................................... 34 
12.2 Sample Size and Randomization ................................................................................... 35 
12.3 Interim analyses and Stopping Rules ............................................................................ 35 
12.4 Outcomes ...................................................................................................................... 36 
 
Primary outcome and endpoints: ......................................................................... 36 
 
Secondary outcomes ............................................................................................. 36 
 
Other Outcomes and Endpoints: .......................................................................... 36 
 
Contrasts ............................................................................................................... 37 
12.5 Data Analyses [IR-1] [HT-2][HT-3][RQ-4] ...................................................................... 37 
 
Moderator [CI-3][HT-2][HT-3][RQ-4] .................................................................... 38 
 
Assessment of Internal and External Validity [IR-5] ............................................. 38 
 
Handling of Missing Data [IR-5][MD-2] ................................................................. 39 
 
Sensitivity Analyses [MD-4] .................................................................................. 39 
12.6 Qualitative Data Collection, Management and Analysis .............................................. 39 
 
Qualitative Interviews [MM-1][MM-2][QM-1][QM-2][QM-4][RQ-6] ................... 39 
 
Qualitative Data collection [MM-1] ...................................................................... 39 
 
Qualitative Data Management and Analysis [MM-3][QM-1][QM-3][QM-4] ....... 40 

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DATA COLLECTION AND QUALITY ASSURANCE [IR-3] ............................................ 41 
13.1 Quality Assurance ......................................................................................................... 41 
 
Site Monitoring ..................................................................................................... 42 
 
Methods to prevent and monitor missing data [MD-1] ....................................... 43 
14 
PARTICIPANT RIGHTS AND CONFIDENTIALITY ....................................................... 44 
14.1 Institutional Review Board (IRB) Review ...................................................................... 44 
14.2 Data Use Agreements ................................................................................................... 45 
14.3 Informed Consent Forms .............................................................................................. 45 
14.4 Participant Confidentiality ............................................................................................ 46 
14.5 Study Discontinuation ................................................................................................... 48 
15 
ETHICAL CONSIDERATIONS ................................................................................... 48 
16 
COMMITTEES ....................................................................................................... 48 
17 
PUBLIC USE DATASET [IR-7] .................................................................................. 48 
18 
PUBLICATION OF RESEARCH FINDINGS [PC-4] ....................................................... 48 
 
 
 

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Summary of Changes from Previous Versions: 
 
Affected Section(s) Summary of Revisions Made to Version 
2 
Rationale 
1.3, 2.5, 7, 14.2 
Added two VA Medical Centers as sites. 
To increase recruitment 
7.2 
Revised definition of specialty mental 
health care for exclusion criterion. 
To increase recruitment 
8.5 
Added a data collection activity to the 4-
month and 8-month chart reviews. 
 
 
 
To collect data about 
receipt of trauma-focused 
psychotherapy in order to 
control for this in the data 
analysis. 
10.2 
Revised suicide ideation from a serious 
adverse event to increase in suicide 
ideation to an adverse event. 
Added suicide intention as a serious 
adverse event. 
To comply with IRB 
requirements. 
14.3 
Added the option to view a consent video 
rather than read the informed consent 
form. 
To decrease the burden of 
enrollment on staff. 
Affected Section(s) Summary of Revisions Made to Version 
3 
Rationale 
1.3, 2.5, 7, 14.2 
Added two Federally Qualified Health 
Centers as sites. 
To increase recruitment 
7.3 
Added opt-in texts to Federally Qualified 
Health Centers 
To increase recruitment 
7, 12.2, 12.5 
Reduced target sample size and 
recalculated power 
Renegotiated contract with 
PCORI 
1.3, 5.1, 7 
Corrected errors in target sample size 
Correct errors 
Affected Section(s) Summary of Revisions Made to Version 
4 
Rationale 
8.5 
Changed 90 days to 14 days for the 
timeframe for the pharmacotherapy 
adherence  
 
Changed 90 days to 4 months for the 
timeframe for psychotherapy adherence. 
To be consistent with the 
timeframe of the 
medication survey question 
 
To be consistent with the 
4-month follow-up period 
 
 

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1 
PRÉCIS 
 
1.1 
Background and Significance  
 
In primary care settings, PTSD frequently goes undetected and untreated.  When PTSD is 
diagnosed in primary care, treatment is usually inadequate and outcomes are poor.  This 
is highly problematic because many patients with PTSD prefer receiving care in primary 
care settings, and less than half are successfully referred to the specialty mental health 
setting. This is especially a concern for safety net primary settings such as Federally 
Qualified Health Centers and VA Medical Centers, where the prevalence of both past 
trauma exposure and PTSD are particularly high.  However, there are effective 
pharmacotherapy and psychotherapy treatments for PTSD that are feasible to deliver in 
primary care. Due to a lack of head-to-head comparisons between pharmacotherapy and 
psychotherapy protocols, clinical practice guidelines for PTSD provide contradictory 
recommendations about pharmacotherapy and psychotherapy. In particular, PTSD clinical 
practice guidelines have little to offer primary care providers because so few trials have 
been conducted in this setting.      
 
1.2 
Study Aims  
 
The proposed large pragmatic trial will compare, head-to-head, FDA approved 
antidepressant medications with a brief trauma-focused psychotherapy that is evidence-
based and feasible to deliver in primary care.  In addition, despite high treatment non-
response rates, very few trials have examined treatment sequencing and none have done 
so in the primary care setting.  For patients not responding to the initial treatment, the 
proposed research is powered to compare, head-to-head, alternative treatment 
sequences that are feasible to deliver in primary care.  The trial will: 1) compare 
outcomes among patients randomized to initially receive pharmacotherapy or brief 
psychotherapy, 2) compare outcomes among patients randomized to treatment 
sequences (i.e., switching and augmenting) for patients not responding to the initial 
treatment and 3) examine variation in treatment outcomes among different subgroups. 
 
1.3 
Study Description  
 
This multi-site trial will enroll 700 patients meeting clinical criteria for PTSD from 8 
Federally Qualified Health Centers and 8 VA Medical Centers.  Exclusion criteria will 
include those needing or already receiving specialty mental health care and those who 
could not logistically participate in the trial. The pharmacotherapy treatments are 
sertraline, fluoxetine, paroxetine and venlafaxine.  The psychotherapy treatment is 
Written Exposure Therapy.  Telephone and web surveys will be used to assessed 
outcomes (patient treatment engagement, self-reported symptom burden, health related 
quality of life, and recovery outcomes) at baseline, 4- and 8-months. Patients will be the 
unit of the intent-to-treat analysis.  Mixed-models (with multiple imputation to account 

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for missing data) will be used to test hypotheses.   

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2 
STUDY TEAM  
 
2.1 
Organizational Chart 
 
 
2.2 
Principal Investigator 
     
John Fortney, PhD 
Professor and Director 
Division of Population Health 
Department of Psychiatry and Behavioral Sciences 
School of Medicine, University of Washington 
206.685.6955 
 
fortneyj@uw.edu 
 
Research Career Scientist 
VA HSR&D Center of Innovation for Veteran-Centered and 
Value-Driven Care  
VA Puget Sound Health Care System  
206.764.2821 
john.fortney@va.gov 
 
Main responsibilities/Key roles: Dr. Fortney has overall 
responsibility for the study and is the investigator primarily in 
charge of the evaluation. 
Organizational Chart 
 

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2.3 
Co-Principal Investigators  
Charles Engel, MD, MPH 
Professor 
Division of Population Health 
Department of Psychiatry and Behavioral Sciences 
School of Medicine 
University of Washington 
ccengel@uw.edu 
  
Core Investigator 
VA HSR&D Center of Innovation for Veteran-Centered and 
Value-Driven Care  
VA Puget Sound Health Care System  
 
Main responsibilities/Key roles: Dr. Engel has overall 
responsibility for the pharmacotherapy comparator. 
 
Debra Kaysen, PhD 
Professor 
Division of Public Mental Health and Population Sciences 
Stanford University Medical Center 
dkaysen@stanford.edu 
650.725.5734 
 
Main responsibilities/Key roles: Dr. Kaysen has overall 
responsibility for the psychotherapy comparator. 
 
2.4 
Co-Investigators 
 
Joseph Cerimele, MD 
Division of Population Health 
Department of Psychiatry and Behavioral Sciences 
School of Medicine 
University of Washington 
206.221.4928 
cerimele@uw.edu 
 
Main responsibilities/Key roles: Dr. Cerimele has responsibility for 
the pharmacotherapy comparator and the evaluation of 
pharmacotherapy outcomes.  
 
 
 
 
 

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Deborah Bowen, PhD 
Department of Bioethics and Humanities 
University of Washington 
206.616.5601 
dbowen@uw.edu 
 
Main responsibilities/Key roles: Dr. Bowen is responsible for stakeholder 
engagement and qualitative data collection, management and analysis. 
 
Patrick Heagerty, PhD 
Department of Biostatistics 
University of Washington 
206.616.2720 
heagerty@u.washington.edu 
 
Main responsibilities/Key roles: Dr. Heagerty is the lead biostatistician on 
the evaluation team. 
 
Denise Sloan, PhD   
Professor 
Department of Psychiatry 
Boston School of Medicine 
 
Associate Director for Education 
National Center for PTSD 
VA Boston Healthcare System 
857.364.6333 
denise.sloan@va.gov 
 
Main responsibilities/Key roles: Dr. Sloan will train therapist and evaluate 
therapy fidelity. 
 
Brian Marx, PhD   
Professor 
Department of Psychiatry 
Boston School of Medicine 
bpmarx@bu.edu 
 
Deputy Director 
National Center for PTSD 
VA Boston Healthcare System 
857.364.6071 
brian.marx@va.gov 
 
Main responsibilities/Key roles: Dr. Marx will train therapist and evaluate 
therapy fidelity. 
 

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2.5 
Participating Study Sites  
 
Federally Qualified Health Centers 
 
East Arkansas Family Health Center 
 
West Memphis, Arkansas, United States, 72301 
Contact: Susan Ward-Jones    870-735-3842    swjones@eafhc.org    
 
Upper Great Lakes Family Health Center 
 
Gwinn, Michigan, United States, 49841 
Contact: Donald Similia    906-483-1325    Donald.Simila@UGLHealth.org    
 
Family Medical Center of Michigan 
 
Temperance, Michigan, United States, 48182 
Contact: Ed Larkins    734-847-3802    elarkins@familymedical.org    
 
Partnership Health Center, Montana 
401 Railroad St. W., Missoula, MT 59802 
Contact: Ellen Bluett    406-258-4442    ellen.bluett@mso.umt.edu 
 
Health Point, Washington 
955 Powell Ave SW, Renton, WA 98057  
Contact: Evan Oakes    425-277-1311    eoakes@healthpointchc.org 
 
Neighborhood Healthcare, San Diego 
425 N. Date St., Escondido, CA 92025 
Contact: Wendi Vierra    760-520-8340    wendi.vierra@nhcare.org 
 
Teche Action Board, Inc.  
1115 Weber Street, Franklin, LA 70538 
Contact: Karla Vappie  (337) 828-2550 EXT 2236   kvappie@tabhealth.org 
 
North Central Texas Community health care center, Inc. 
200 Martin Luther King, Jr. Boulevard, Wichita Falls, TX 76301 
Contact: Ellaheh Ebrahim  (940) 500-7065  eebrahim_md@chcwf.com 
 
VA Medical Centers 
 
VA Bedford Healthcare System 
Bedford MA, 01730 
Contact: Rosanne Schipani  781-687-2665   Rosanne.Schipani@va.gov 
 
VA Ann Arbor Healthcare System 
Ann Arbor, MI 48105 

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Contact: Rebeca Sripada   734-222-7432   Rebecca.Sripada@va.gov 
 
John L. McClellan Memorial Veterans Hospital 
North Little Rock, AR 72114 
Contact: Jacob Painter  501-257-1740   Jacob.Painter@va.gov 
 
Cincinnati VA Medical Center 
Cincinnati, OH 45220 
Contact: Nancy Nagel    513-861-3100 x5305   Nancy.Nagel@va.gov 
 
VA San Diego Healthcare System 
San Diego, CA 92161 
Contact: Leslie Morland 858-552-4324   Leslie.Morland@va.gov 
 
VA Portland Health Care System        
Portland, OR 97239 
Contact: Alan Teo 
503-220-8262-x52461   Alan.Teo@va.gov 
 
Ralph H. Johnson VA Medical Center 
109 Bee St, Charleston, SC 29401 
Contact: Wendy A. Muzzy  843-792-8068   muzzy@musc.edu 
 
Rocky Mountain Regional VA Medical Center 
1700 North Wheeling Street Aurora, CO 80045 
Contact: Bryann DeBeer   254-987-0341   Bryann.debeer@va.gov 
 
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ACRONYMS 
 
Acronyms 
AHRQ 
Agency Healthcare Research and Quality 
CHC  
Community Health Center 
CPT 
Cognitive Processing Therapy 
EHR 
Electronic Health Record 
OEF 
Operation Enduring Freedom 
OIF 
Operation Iraqi Freedom 
OND 
Operation New Dawn 
PCL  
PTSD Check List 
PCMHI 
VA Primary Care Mental Health Integration 
PE 
Prolonged Exposure Therapy 
PHQ-9  
Patient Health Questionnaire 
PTSD  
Posttraumatic Stress Disorder 
RCT 
Randomized Controlled Trial 
SAB  
Stakeholder Advisory Board 
SSRI 
Serotonin reuptake inhibitor 
SNRI 
Serotonin-norepinephrine reuptake inhibitor 
VA  
Department of Veterans Affairs 
WET 
Written Exposure Therapy 

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4 
STUDY OBJECTIVES 
 
4.1 Primary Objective 
 
To quantitatively compare engagement, self-reported PTSD symptom severity (primary 
outcome), quality of life, and recovery outcomes of primary care patients randomized to 
initially receive brief psychotherapy (WET) or their choice of the three SSRIs. 
• Primary Hypothesis 1a – Patients randomized to receive brief psychotherapy (Arm 
3) will have better outcomes than those randomized to an SSRI.     
 
4.2 Secondary Objectives 
 
For patients not responding to initial treatment, to quantitatively compare engagement, 
self-reported PTSD symptom severity (primary outcome), quality of life, and recovery 
outcomes of primary care patients randomized to: 1) switch from brief psychotherapy 
(WET) to their choice of the three SSRIs, 2) augment the SSRI with brief psychotherapy 
(WET), or 3) switch from one class of antidepressants (SSRI) to another class of 
antidepressants (SNRI - venlafaxine).  
• Primary Hypotheses 2a – Non-responders randomized to an SSRI augmented by 
WET will have better outcomes than those randomized to switching from an SSRI 
to an SNRI.  
• Exploratory Hypotheses 2b – Non-responders randomized to an SSRI augmented 
by WET will have better outcomes than those randomized to switching from WET 
to their choice of the three SSRIs. 
 
Aim 3: To quantitatively examine treatment heterogeneity among subgroups of primary 
care patients receiving pharmacotherapy and psychotherapy.  
• Primary Hypothesis 3a: Patient engagement, self-reported PTSD symptom 
severity, quality of life, and recovery outcomes will be poorer for: 1) veterans 
compared with non-veterans (controlling for combat exposure), 2) those with 
combat exposure compared with other types of traumas, 3) those currently 
prescribed benzodiazepines, 4) those taking SSRIs/SNRIs at study entry, and 5) 
those with self-reported substance use problems.  
• Primary Hypothesis 3b: Male gender, poor access, cannabis use, and preferring 
pharmacotherapy will be treatment moderators that reduce the differential 
effectiveness of psychotherapy compared to pharmacotherapy. 
 
Aim 4: To gain an in-depth understanding of patients’ treatment experience, qualitatively 
examine treatment acceptability, satisfaction, and engagement, as well as the perceived 
benefit (or lack thereof) of treatment for patients randomized to each arm.    
 

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5 
BACKGROUND AND RATIONALE  
 
5.1 Background [CI-1][HT-1][PC-1][RQ-1][RQ-3][RQ-5] 
 
Federally Qualified Health Centers - Federally Qualified Health Centers, more commonly 
known as “Community Health Centers” (CHCs), are America’s healthcare safety net and 
are key to addressing mental health disparities across the nation.  Nationwide, there are 
nearly 700 CHCs with over 10,000 clinic locations serving 26 million Americans [RQ-3].  
Virtually all (92%) CHC patients live at or below 200% of the Federal Poverty Level, and 
62% are racial/ethnic minorities.  Most CHCs do not have specialty mental health 
programs, but rather integrate mental health treatment into primary care using the 
Behavioral Health Consultant model that was developed at Cherokee Health Systems (a 
CHC in Knoxville TN).  Our Stakeholder Advisory Board (SAB) includes CHC patients, 
providers and administrators and we have collaborated with these stakeholders to better 
understand the delivery of PTSD services in CHCs and to plan this study [PC-1].  
  
VA Medical Centers (VAMCs) – The VA healthcare system is the largest healthcare system 
in the country with 1,243 health care facilities, including 170 VA Medical Centers and 
1,063 Community Based Outpatient Clinics serving more than 9 million Veterans per year 
[RQ-3].  Approximately 62% (1,218,857) of all Operation Enduring Freedom (OEF), 
Operation Iraqi Freedom (OIF), and Operation New Dawn (OND) veterans have used VA 
health care since 2001, and most (58.7%) have been treated for mental health disorders, 
including 393,139 for PTSD. Over a million Veterans (including those from previous 
wartime eras) receive service-connected compensation for PTSD.  The VA has trained 
thousands of its specialty mental health providers to deliver first-line psychotherapies for 
PTSD (Prolonged Exposure [PE] therapy and Cognitive Processing Therapy [CPT]) in 
specialty mental health clinics.  The VA has also integrated mental health treatment into 
primary care, termed Primary Care Mental Health Integration (PCMHI).  PCMHI programs 
run two models of integrated care in parallel, the Collaborative Care Management model 
and the Behavioral Health Consultant model. Our SAB includes four Veterans, PCMHI 
leadership, and we have collaborated with these stakeholders to plan this study [PC-1]. 
 
Prevalence and Disability - PTSD can develop in individuals exposed to traumatic events 
such as sexual assault, serious accidental injury, natural disasters or combat. It is 
characterized by flashbacks, nightmares, avoidance of situations that induce trauma 
memories, hypervigilance, anger, and sleep deprivation. The most prevalent trauma 
among women with  PTSD is sexual assault, and the most prevalent trauma among men 
with PTSD is combat. The one-year prevalence rate of PTSD is 4% in the general 
population, and 11.1% in primary care settings.  Prevalence is even higher in publicly-
funded safety-net clinics such as CHCs (20.7%) and the VA (24.5%).  PTSD is a devastating 
disorder and a significant contributor to disability/suicidality worldwide.  In primary care, 
79%-88% of patients with PTSD also go on to develop clinical depression, further 
contributing to disability and complicating treatment. Individuals with PTSD are more 
likely to engage in unhealthy behaviors such as tobacco use, drug use, alcohol misuse, 

15 
 
and have high rates of morbidity/mortality. PTSD negatively impacts marriages, 
educational attainment, and occupational functioning.  Providing effective treatments for 
PTSD in primary care settings has the potential to make an enormous impact on the 
quality of life for hundreds of thousands of Americans.  
 
Usual Care – According to the National Comorbidity Study Replication, only 34.4% of 
individuals with current PTSD receive specialty mental health care during the course of a 
year.  In a previous PCORI-funded large pragmatic trial (PCS-1406-19295), only 46.9% of 
CHC patients with PTSD offered telepsychiatrist or telepsychologist appointments actually 
engaged in treatment.  Even within the VA’s integrated system of care, only 44.6%-47.7% 
of veterans diagnosed with PTSD in primary care are successfully referred to specialty 
mental health.  Among, 50,000 OEF/OIF Veterans newly diagnosed with PTSD, only 27% 
had ≥9 specialty mental health encounters (8-9 visits are needed for PE or CPT to be 
effective), and those first diagnosed in primary care were half as likely to have ≥9 
encounters. The lack of engagement in specialty mental health care is highly problematic 
because only 13%-34% of patients receive adequate PTSD treatment in primary care (e.g., 
2 months of medications or evidence-based psychotherapy) and outcomes are poor.  For 
example, in a pragmatic trial of collaborative care for PTSD in VA primary care clinics, 
veterans in the usual care group showed no improvement in PTSD symptom severity (-1.3 
points on the Posttraumatic Diagnostic Scale) over the course of 12 months.  Likewise, in 
another pragmatic trial of collaborative care for PTSD in Department of Defense primary 
care clinics, active duty service members in the usual care group showed no improvement 
in PTSD symptom severity (-3.5 points on the Posttraumatic Diagnostic Scale). 
    
Conceptual Framework [CI-1] – Lack of access and engagement in specialty mental health 
treatment is clearly driving poor PTSD outcomes.  To close this engagement gap, more 
patients with PTSD need access to effective treatments in primary care settings. We 
conceptualize access to care as the potential ease of having encounters with healthcare 
providers.  Integrating PTSD treatment into primary care improves geographical (i.e., 
travel), temporal (e.g., wait time), financial (e.g., co-pays) and cultural (e.g., stigma) 
access.  However, even in primary care settings, poor access may be a negative treatment 
moderator for psychotherapy because it requires more visits than pharmacotherapy, and 
thus involves greater travel burden, more time commitment, and higher co-pays [HT-1]. 
Patients with poor access to primary care may have less frequent psychotherapy 
encounters than those with good access, and infrequent visits reduces the effectiveness 
of trauma-focused psychotherapies.  Our conceptualization of patient engagement is 
participating sufficiently in a treatment plan to potentially experience a therapeutic 
effect.  Treatment engagement depends on patient perceptions about access to care, and 
their perceived need for and expectations from treatment.  With good access and 
adequate engagement, individuals have the opportunity to receive high quality care and 
improved outcomes.  
 
Psychotherapy – Trauma-focused psychotherapies are the first-line treatment for PTSD, 
but are often burdensome to patients and must be delivered by highly trained therapists, 

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usually only available in specialty mental health treatment settings.  Treatment drop-out 
from trauma-focused psychotherapies delivered in specialty mental health care settings is 
extremely high both in pragmatic trials and routine care ranging from 28.3%-47.8%.  
Recent meta-analyses have found that drop-out rates are higher for evidence-based 
trauma-focused therapies (PE and CPT) than for present centered therapy [RQ-1].  
Effective and engaging therapies that are available and feasible to deliver are needed in 
primary care settings [RQ-5].  WET is a brief (i.e., five 40-minute sessions) trauma-focused 
therapy where patients write about their traumatic experience following scripted 
instruction.  While retaining the core exposure element of other trauma-focused 
psychotherapies, WET does not require patient homework between sessions and requires 
considerably less therapist time, training and supervision.  This makes WET ideal for 
delivery in primary care settings [RQ-5].  In contrast to the high drop-out rates for PE and 
CPT, drop-out rates for WET have ranged from 6.4%-14%.  In a trial conducted in a civilian 
population, WET was significantly (p<0.001) more effective than waitlist control, with 
between group effect sizes of 3.49 and 2.18 at the 6 week and 18 week assessment, 
respectively. In a non-inferiority trial comparing 5 sessions of WET to 12 sessions of CPT, 
WET was found to be non-inferior to CPT. Drop-out rates were significantly (p<0.001) 
lower for WET (6.3%) than for CPT (39.7%).  This highlights the patient-centeredness of 
WET compared to other trauma-focused psychotherapies [RQ-5].  WET is recommended 
as a first line treatment in the VA/DOD PTSD Clinical Practice Guidelines. 
 
Pharmacotherapy – SSRIs and SNRIs are widely prescribed for patients with PTSD [RQ-5]. 
Two thirds (66.3%) of patients receive an SSRI or SNRI during the first year after PTSD 
diagnosis, with the most prescribed SSRIs being sertraline (23%), fluoxetine (11%) and 
paroxetine (7%) and the most common SNRI being venlafaxine (9%).  According to meta-
analyses, there is good evidence for the efficacy of the two FDA approved SSRIs for PTSD 
(paroxetine and sertraline) and the pharmacologically similar fluoxetine, as well as one 
SNRI (venlafaxine)[RQ-1; RQ-5].  A large meta-analysis of depression studies suggests that 
among these drugs, paroxetine and venlafaxine have greater side-effect profiles than 
sertraline and fluoxetine, and that paroxetine and venlafaxine have greater 
discontinuation rates than placebo or other antidepressants [RQ-1].  However, according 
to a recent systematic review, the frequency of adverse events associated with these 
medications remains poorly characterized for patients with PTSD [RQ-1].  Also, although 
meta-analysis suggests that the effect sizes for these medications are smaller than the 
effect sizes of trauma-focused psychotherapies, there are few head-to-head comparisons 
of pharmacotherapy and psychotherapy [RQ-1]. There are no head-to-head comparisons 
of pharmacotherapy and psychotherapy for PTSD conducted in the primary care setting.  
8. Non-response and Treatment Sequencing - According to meta-analysis, 41% of patients 
with PTSD do not respond to initial pharmacotherapy [RQ-1].  For non-responders, meta-
analysis suggests that augmentation with a second medication is not effective [RQ-1].72  
However, there is insufficient evidence to recommend for or against switching to another 
medication or augmentation with psychotherapy [RQ-1].  For non-response to 
psychotherapy, there is also insufficient evidence to recommend for or against switching 
to or augmenting with pharmacotherapy [RQ-1]. 

17 
 
  
Treatment Heterogeneity [HT-1] – Meta-analyses suggest that veterans are more 
resistant to PTSD treatment, but there are no trials with sufficient numbers of veterans 
and non-veterans to make head-to-head comparisons, nor to disentangle veteran status 
with gender and combat exposure [RQ-1].  One small head-to-head trial of 
pharmacotherapy versus psychotherapy demonstrated that those preferring 
pharmacotherapy but receiving psychotherapy had worse psychotherapy outcomes [HT-
1].  The same study found that current cannabis use is associated with poorer adherence 
to psychotherapy but not to pharmacotherapy [HT-1]. Meta-analysis suggests that trials 
with more women have larger treatment effects, and this moderation effect appears to 
be larger for psychotherapy than pharmacotherapy [RQ-1; HT-1].  One small trial found 
that men and women had similar outcomes immediately after completing trauma-
focused psychotherapy, but men had worse long-term outcomes [HT-1].    
 
5.2 Study Rationale 
 
 The PCORI-AHRQ review specifically highlighted the lack of evidence about the 
comparative effectiveness of psychotherapy and pharmacotherapy for PTSD, and clinical 
practice guidelines for PTSD provide contradictory recommendations [RQ-1]. In particular, 
PTSD clinical practice guidelines have little to offer primary care providers because so few 
trials have been conducted in this setting, despite the fact that most people with PTSD do 
not receive specialty mental health treatment.  Consequently, primary care providers are 
unsure about which PTSD treatments to offer their patients, and often resort to referral 
or prescribing benzodiazepines.  The proposed pragmatic trial will determine whether the 
best initial choice of treatment is an SSRI or a brief trauma-focused psychotherapy that is 
feasible to deliver in primary care [RQ-3].  In addition, despite high treatment non-
response rates, very few trials have examined treatment sequencing and none have done 
so in the primary care setting.  For patients not responding to the initial treatment, the 
proposed trial is powered to compare, head-to-head, alternative treatment sequences 
that are feasible to deliver in primary care.  Specifically, for patients failing an SSRI, the 
proposed trial will determine whether a different class of antidepressant (SNRI) should be 
recommended next or whether the SSRI should be augmented with brief trauma-focused 
psychotherapy [RQ-3].  Moreover, because the answers to these questions may depend 
on the characteristics of the patient, our large diverse sample will allow us to identify 
clinically meaningful treatment effect modifiers such as veteran versus civilian status, 
gender, concurrent drug use and patient treatment preferences.  The PCORI-AHRQ review 
specifically highlighted the lack of evidence about whether treatment effectiveness 
differed by patient characteristics such as type of trauma exposure and co-occurring 
conditions [RQ-1]. 
 
6 
STUDY DESIGN [PC-1][RQ-6] 
 
Overview: As described in Figure 1, the proposed large pragmatic trial will have three 
arms.  Patients will initially be randomized to an SSRI (either sertraline, fluoxetine or 

18 
 
paroxetine based on patient preference and treatment history) or WET in a 1:1:2 
allocation.  The estimated 41% of patients failing to respond to the initial treatment will 
receive the second treatment in the sequence.  Non-responders randomized to Arm 1 will 
have the SSRI augmented by WET.  Non-responders randomized to Arm 2 will be switched 
from the SSRI to venlafaxine. Non-responders in Arm 3 will be switched from WET to an 
SSRI. Treatment will be delivered by primary care and integrated care staff at CHCs and 
VAs per recommendation for pragmatic trials [IR-5].  Encounters will be billed for by CHCs 
and recorded as normal workload by VAs. 
Engagement Approach:  As we have done successfully in our ongoing PCORI-funded 
pragmatic trial and for the development of this application, we have assembled a 
Stakeholder Advisory Board (SAB) to inform all aspects of the research from development 
to dissemination [PC-1].  Consumer members will include existing members of our current 
advisory board as well as new members selected from CHC patients enrolled in our 
ongoing PCORI trial (four veterans and four civilians).  Policy/providers on the SAB will 
include existing members of our current advisory board (including two CHC Executive 
Directors, and a Senior Advisor at the National Association of Community Health Centers) 
and two new members (Director of the VA National Center for PTSD, and the Director of 
VA’s PCMHI initiative). The consumers will meet every other month and the 
provider/policy members will join the meeting quarterly. We will facilitate ample 
opportunities for co-learning and foster a shared vision for and bidirectional commitment 
to the study.  In addition to formal meetings, a qualitative researcher (Co-I Bowen) will 
reach out to consumer members individually to ensure their voice is heard.  SAB 
members who can accept consultation will receive reasonable consulting fees.  Based on 
consumer feedback from our first SAB meeting we made important modifications and 
refinements to the treatment arms.  For the pharmacotherapy treatments, we now allow 
providers/patients to choose from a class of antidepressants (SSRIs) rather than requiring 
a specific antidepressant (paroxetine) as was approved in the LOI [PC-1].  This 
modification to the treatment comparator was approved by a Senior Program Officer at 
PCORI.  We also made refinements to the psychotherapy protocol, allowing it to be 
delivered in six, 30-minute sessions (instead of five 40-minute sessions) to accommodate 
PCMHI session length performance metrics [PC-1].  The consumer members of the SAB 
also chose outcomes that were relevant to them [RQ-6] and helped revise the plans for 
delivering the treatment via interactive video during the COVID-19 pandemic [PC-1]. 
 
 
 
 
 
 

19 
 
7 
SELECTION AND ENROLLMENT OF PARTICIPANTS  
 
Study Setting and 
Population:  This 
multi-site trial will 
enroll 700 patients 
meeting clinical 
criteria for PTSD from 
8 CHCs and 8 VA 
sites.  CHC sites were 
chosen because of 
their large size 
and/or successful 
participation in past 
trials.  VA sites were chosen based on a data extract conducted by retired SAB member 
Dr. Pomerantz that identified large PCMHI programs with both psychologist and social 
worker therapists (needed to estimate therapist effects). Because only 11%-18% of 
primary care patients with PTSD are diagnosed/detected, all primary care patients will be 
screened for PTSD annually.  Universal screening for PTSD in primary care is standard in 
VA.  The 12 rural CHCs participating in our ongoing PCORI-funded trial successfully 
screened for PTSD and identified 2,802 patients with a positive PTSD screen in a 2.5 year 
period. Not all eligible patients were recruited to keep enrollment evenly distributed over 
time. We will use the new five-item PC-PTSD-5 screener which has excellent sensitivity 
(95%) and specificity (85%).    
 
7.1 Inclusion Criteria [CI-2] 
• Screen positive for PTSD (PC-PTSD-5 score ≥3) 
• Meet PTSD diagnostic Criteria A on the Short Trauma Questionnaire 
• Have high PTSD severity (PCL-5 score>33) 
 
7.2 Exclusion Criteria [CI-2][IR-5][PC-2]  
 
Following Thorpe’s recommendations for conducting pragmatic trials, patient exclusion 
criteria will be kept to an absolute minimum [PC-2; IR-5]. Patients will primarily be 
excluded for logistical reasons, or because they would be more appropriately treated in 
specialty mental health settings.   
 
Patients will be excluded based on the following criteria: 
 
• Patient has a diagnosis of schizophrenia, schizoaffective disorder, bipolar disorder, 
or dementia 
• Patient is currently being prescribed venlafaxine 
• Patients with a new prescription for any psychotropic medication in the past 8 
Figure 1:  Three Arm Sequenced Treatment Study Design 

20 
 
weeks, including dose changes   
• Patient has received specialty mental health services in past 2 months, OR patient 
has a future appointment for specialty mental health services OR patient/provider 
prefers referring to specialty mental health setting.  Specialty mental health is 
defined as seeing a mental health specialist in a non-co-located setting OR 
sessions are less frequent than every 2 weeks AND sessions are longer than 50 
minutes in duration.   
• Provider does not believe that study participation is in the best interest of the 
patient 
• Patient is pregnant 
• Patient is terminally ill 
• Patient not planning to use clinic during next 8 months 
• Patient is a prisoner 
• Patient does not speak English or Spanish 
• Patient is younger than 18 years of age 
• Patient has impaired decision-making capacity and is unable to participate in the 
informed consent process  
• Patient cannot attend in person or interactive encounters 
 
Current use of psychotropic medications: We will allow patients to be on a stable dose of 
any psychotropic medication (including benzodiazepines) for 8 weeks [PC-2]. We define 
psychotropic medications as any antidepressant, antianxiety, antipsychotic, antimanic, 
sedative-hypnotic, other CNS depressant (e.g., muscle relaxers), opioid analgesic, lithium 
compound, or other mood stabilizers. Maintaining a stable dose will require that patients 
have not undergone any change in dose or frequency of administration during the period 
based on patient history and medical record review. Patients on a stable does of a 
selective serotonin reuptake inhibitor who meet the above eligibility criteria will be 
eligible for participation in the trial.  In practice, many clinicians prescribing and patients 
taking medications for PTSD would consider a medication change or introducing 
psychotherapy if symptoms are elevated (PCL-5 >33) despite 8 weeks of stable PTSD 
pharmacotherapy. We believe it is important for the trial to include patients facing this 
common clinical scenario so as to equip clinicians and patients with data on which to 
inform this common treatment decision.  Because we would have more power to detect 
treatment heterogeneity if 50% of patients were not taking SSRIs/SNRIs at baseline, we 
now propose to prioritize enrollment of patients not taking SSRIs/SNRIs. 
 
7.3 Study Enrollment Procedures  
 
To foster trust among potential study participants and facilitate patient recruitment/ 
retention, CHC/VA staff will recruit and consent patients. As we have done in the past, 
participating CHCs will obtain a Federal Wide Assurance (FWA) designating our Central 
IRB as having oversight of human subjects protection, allowing CHC staff to be fully 
engaged in research activities. VA staff research activities will be overseen by the VA’s 

21 
 
Central IRB.  The PI will train all CHC/VA staff in the recruitment and consenting 
processes, allowing for local flexibility in language and procedures to account for 
variations in community culture and clinical workflow. Once the patient is consented, 
CHC/VA staff will upload contact and screening information and signed consent forms to 
our survey group’s web-interface, and the patient will be immediately randomized. Two 
recruitment approaches will be used: 1) handoffs during the encounter and 2) telephone 
outreach after the encounter.  Patients screening positive for PTSD are expected to have 
a warm handoff to an integrated mental health provider who will administer the Short 
Trauma Questionnaire (from PDS-5) and the PCL-5 (both clinically appropriate following a 
positive PTSD screen).  If the patient meets these two inclusion criteria, they will be 
consented by the designated staff member at the end of the encounter.  Patients 
screening positive for PTSD who are not recruited during the encounter can also be 
contacted by staff afterward.  Potentially eligible patients not recruited during an 
encounter will be identified by chart review or query of the electronic health record and 
contacted by staff via telephone.  CHC patients with a positive PC-PTSD-5 screen or a 
PTSD diagnosis in the electronic health record will be sent a short opt-in text about the 
trial directing interested patients to call a UW researcher.  The text will be sent by the 
CHC.  The UW researcher will use the recruitment script and then assess interested 
patients for eligibility.  Eligible patients will be consented either by CHC staff or the UW 
researcher.  VA patients will be sent an opt-out card 10 days prior to being contacted by 
phone and only those not opting out will be contacted.  Once the patient is consented, 
CHC/VA staff will indicate the patient’s consent on our survey group’s web-interface by 
uploading a PDF of the consent form, and the patient will be immediately randomized. If 
informed consent cannot be obtained in person, we will conduct the informed consent 
process over televideo or telephone.  For CHC patients, e-Consent forms would be signed 
securely in a REDCap project hosted at UW.  Clinic staff would be able to email or text a 
link to the e-Consent form.  For VA  patients, e-Consent forms will be distributed and 
signed using DocuSign, the VA’s only approved e-Consenting platform.  For patients who 
are unable to electronically sign the e-Consent form, we will mail written informed 
consent documents to be returned with postage paid return envelopes, or allow signed 
consent forms to be dropped off at the clinic.  For faster turnaround, we may also use VA 
Rights Management Services (RMS) or MyHealtheVet secure transmission using 
encrypted email with subsequent return of wet signatures.  A progress note describing 
study participation and randomization status will be generated for CHC/VA staff to enter 
into the EHR in order to notify primary care providers and therapists that the patient has 
been enrolled and randomized.  
 
8 
STUDY INTERVENTIONS  
8.1 
Psychotherapy - Written Exposure Therapy (WET) 
The previously tested protocol for WET involves one 60 minutes session, followed by four 
40-minute sessions (for a total of 5 sessions). The first session includes psychoeducation 
about symptoms of PTSD, provides a treatment rationale for approaching the trauma 
memory, and discusses the use of writing as a means of doing so. At the suggestion of 

22 
 
SAB member Dr. Pomerantz, we modified the protocol to be six sessions of 30 minutes 
each to account for the 30-minute session limit in the VA PCMHI setting (see WET 
protocol in Appendix). In sessions 2-6, patients will write about the memory of their worst 
traumatic event for 20 minutes, with a focus on details of the event and thoughts and 
feelings that occurred during the event. Patients are directed to write about the same 
trauma memory during each session. The therapist leaves the room while the patient 
writes. After returning the therapist inquires whether the patient experienced any 
difficulties, and addresses these with the patient. Based on feedback from our SAB, we 
will allow patients to audio-record their narratives if they are not comfortable writing. 
The therapist reads the narrative between sessions to make sure instructions were 
followed. Feedback about the narrative is provided to the patient at the beginning of 
sessions 3-6. This feedback is used to prompt the patient for writing in the current session 
(e.g., "You did a great job writing about the details of the event but you didn't write about 
the emotions you felt during the event. It is important for you to write about the 
emotions you felt during the event in today's writing session.") The session ends with the 
therapist instructing the patient to allow themselves to experience any trauma-related 
memories, images, thoughts, and feelings in the interval between sessions. 
 
Interactive Video - In the VA, therapists will use VA Video Connect for televideo based 
encounters.  If necessary, the VA research assistant can work with the local Telehealth 
Coordinator to send others VA-issued WiFi-enabled tablets.  In CHCs, prescribers will use 
whichever HIPAA compliant televideo platform they have adopted (e.g. Zoom, Updox, 
Doxy.me, OTTO) for televideo encounters.  During the session therapists will keep their 
video on during the entire writing time and be available if the patient has questions or 
needs support throughout the session. The therapist will mute their microphone while 
the patient is writing, so as not to distract them with ambient noise. The therapist may 
also ask the patient to move their camera so the therapist  can observe them writing, just 
to ensure that they are engaged and on track and to facilitate trauma processing. It is 
critical that WET be delivered with fidelity in making the transition to televideo delivery. 
This includes three main elements that need to be preserved: measurement-based care, 
writing instructions and writing materials, and handling of the trauma narrative. 
Measurement-based care: Measurement-based care presumes that therapists are 
getting updated information regarding the patient’s distress (subjective units of distress, 
SUDS) prior to writing the exposure and after writing the exposure to inform their care 
and treatment plan. Changes in subjective distress are discussed with the patient as an 
indicator of progress, and as a measure of fear extinction. Tracking of SUDS ratings also 
can be used to graph symptoms and share this using screen sharing with patients or 
graphs can be sent to patients via secure messaging so they can see their own treatment 
progress. Lastly, these distress ratings are used to inform conversations regarding Written 
Exposure Therapy implementation during case consultation. SUDS ratings are collected 
verbally in session whether treatment is in-person or delivered via telehealth, thus there 
is no adaptation needed for telehealth delivery for this treatment element. Materials: 
Unlike most evidence-based therapies for PTSD, the number of materials necessary for 
Written Exposure Therapy delivery are relatively limited. Patients will need access to the 

23 
 
writing instructions during the session. The preferred solution is to provide this packet of 
session-by-session instructions for the 6 sessions in advance via regular mail or as an in-
person pickup. If this is not possible the patient packets can be provided in advance via 
secure messaging. If that is not possible the therapist can share their screen with the 
instructions during the appointment or copy and paste the instructions into a chat box 
during the appointment to share with the patient during the session. Patients will need to 
have access to lined paper and a writing implement to write the trauma narrative. Typing 
the narrative or audio recording the narrative are not recommended strategies for 
completing the narrative. If there is an overriding clinical reason for typing or audio-
recording the trauma narrative for a particular patient (e.g., literacy or disability) that will 
be tracked at the session level as a fidelity modification. Unlike in-person delivery of 
Written Exposure Therapy, there can be a temptation for patients to modify the 
narratives between sessions with televideo delivery as they retain the narrative. 
However, it is important to stress to patients that they should not edit or add to the 
narrative after the session. Written trauma narrative: The last challenge with adapting 
Written Exposure Therapy to televideo delivery is for the patient to share the written 
narrative with the therapist. This means that it is critical that the patient be able to get 
the narrative to the therapist in advance of the next session. Either having the patient 
read the therapist the narrative or having the patient type the narrative changes the 
intervention and would be seen as protocol deviations. At the same time, an essential 
part of treatment is for the therapist to review the narrative and provide feedback to the 
patient.  Note that written narratives are not intended to be entered into the medical 
record, but rather are to be destroyed after therapy is complete. The preferred method 
for getting the narrative from the patient to the therapist will be for the patient to send 
the narrative via secure messaging. The narrative can be transferred either by scanning it 
with a smartphone scanning app (or printer scanner) or taking a photo of it, and then 
including it as an attachment to the secure message. In the VA, there is an existing patient 
portal system (My HealtheVet) for secure message transfer and we have secured patient 
training materials to instruct veterans on how to use this system. If necessary, a VA 
research assistant will help the veteran enroll in My HealtheVet and learn how to use the 
secure messaging system.  For the CHCs, they will choose to either use their electronic 
health record’s patient portal or a portal we will host at the University of Washington.  
This portal will be based on REDCap and patients will be able to securely upload a 
scanned file or photo to a location that only their therapist will be able to access.  If the 
patient does not have the ability to scan or photograph the narrative, the patient can 
hold the written narrative up to the camera and the therapist can use screen capture to 
save the image. This option is not ideal as the image may be more difficult to read due to 
image degradation. The therapist must also make sure the screenshot image is de-
identified and is stored in a secure location on their computer. Another option is to have 
the patient mail the narrative to the therapist at the clinic. This is less preferred due to 
both security concerns about mailing narratives, as well as concerns that the narrative 
may not reach the therapist in time for them to review the material prior to the next 
session. 

24 
 
8.2 
Pharmacotherapy - Antidepressants  
Step One Pharmacotherapy – Our choice of pharmacotherapy for Arms 1 and 2 was based 
on discussions with consumer and provider stakeholders. The consensus of stakeholders 
was for initial randomization to a ‘choice of SSRI’ comparator. Consumer stakeholders 
strongly preferred that their providers present them with medication options. Providers 
also strongly preferred options to account for patient’s treatment history (i.e., failed SSRI 
trials due to side-effects or lack of efficacy). Individuals randomized to this SSRI 
comparator will receive one of three SSRIs (sertraline, paroxetine, or fluoxetine) based on 
patient preference and treatment history. From a scientific perspective, these three SSRIs 
appear to have similar effect sizes and thus, testing them as an antidepressant class is 
likely to yield similar treatment effects as testing them each separately.  If anything, there 
may be a somewhat larger, but more realistic, effect as recent research suggests that 
giving patients with PTSD their preferred treatment improves subsequent treatment 
engagement (adherence, follow-up) and outcomes. In this condition, providers will assess 
each patient’s history of SSRI treatment, including responses, and side-effects. If a patient 
experiences problematic side effects after taking their choice of SSRI, the provider may 
switch them to another of the SSRI options during the first 8 weeks of follow-up. At 
baseline, some primary care patients may be prescribed benzodiazepines, 
anticonvulsants, and/or atypical antipsychotics, though according to meta-analyses there 
is little evidence of their efficacy.  For patients taking these medications at enrollment we 
will provide psychiatric consultation to the prescriber about the risks and benefits of 
discontinuation.   
 
Patients on any antidepressant (including SSRIs) at enrollment who are randomized to a 
pharmacotherapy arm will be cross-tapered over four weeks to fluoxetine, sertraline or 
paroxetine (i.e., the old drug will be tapered down while the new drug is tapering up). 
Because patients will be randomized immediately after consenting, those randomized to 
a pharmacotherapy arm may have their prescription changed the same day they are 
consented and before the baseline survey can be completed.  Therefore, for the purpose 
of the cross-taper, current SSRI use will be identified by the primary care provider via the 
EHR rather than by patient survey.  Specifically, current antidepressant use will be defined 
as having been prescribed an antidepressant (any dose) for more than a month.  Primary 
care providers will verify the patient has been taking the medication before implementing 
the cross-taper protocol.  Primary care providers will be given instructions for tapering 
schedules for each medication.  Patients will receive written instructions from their 
provider (developed for the trial). We will also recommend to providers a phone or clinic 
follow-up visit at two and four weeks to support patient adherence. We will also assess 
common side-effects and discontinuation symptoms (described below) via patient survey 
at baseline and at both the 4- and 8-month follow-up assessments. Of note, because 
patients will be cross-tapering SSRIs and discontinuation symptoms are typically limited 
to 4 weeks or less, we anticipate discontinuation symptoms will affect relatively few if any 
patients.  Finally, these cross-tapering procedures will also be followed for those patients 
failing to respond to the initial treatment who are switched to another medication. 

25 
 
 
Interactive Video - Prescribers will have the option of conducting in-person (office-based) 
or televideo (office-based or home based) encounters with patients and occasional 
telephone (home-based) encounters.  In the VA, prescribers will use VA Video Connect for 
televideo based encounters.  If necessary, the VA research assistant can work with the 
local Telehealth Coordinator to send others VA-issued WiFi-enabled tablets.  In CHCs, 
prescribers will use whichever HIPAA compliant televideo platform they have adopted 
during the COVID-19 pandemic (e.g. Zoom, Updox, Doxy.me, OTTO) for televideo 
encounters.  Patients will use personal devices including desktops, laptops, tablets or 
smartphones or Medicaid-issued smartphones.  A survey of the CHC teams indicated that 
many patients would likely use their smartphone.  Three quarters (76.1%) of patients 
screening positive for PTSD in CHCs and recruited into a PCORI-funded trial reported 
owning a smart-phone, and only 15.6% reported that lack of access to a computer, tablet, 
or smartphone with a reliable internet connection interfered with getting the healthcare 
they needed. These televideo platforms allow CHC staff to send patients a link to the 
videoconferencing session via email or text, or for patients to enter an ID directly into a 
website/app. These HIPAA compliant televideo platforms also have virtual waiting rooms 
so that patients cannot interrupt another patient’s encounter. 
8.3 
Treatment Sequences:   
Based on the results of the 4-month follow-up survey (see below), we will classify patients 
as responders or non-responders to treatment.  Specifically, we will compare the baseline 
and 4-month follow-up PCL-5 scores.  Those not experiencing a clinically significant 
change (defined as <10 point change on the PCL-5) will be classified as non-responders to 
treatment.  We conservatively expect 40% will not respond to treatment.  
 
Arm 1:  Patient failing to respond to an SSRI will be switched to venlafaxine.  Venlafaxine 
was chosen as the sequenced treatment comparator for patients who are not responsive 
to SSRIs. Venlafaxine was chosen because 1) venlafaxine is pharmacologically different 
than SSRIs, with an adjunctive “selective norepinephrine” boost in addition to serotonin 
reuptake inhibition, and 2) venlafaxine is an evidence-based option for PTSD that 
relatively few primary care patients with PTSD will have been prescribed in the past.  We 
chose not to include venlafaxine in the initial set of treatment options because: 1) 
discontinuation rates are somewhat higher for venlafaxine than for other antidepressant 
medications [RQ-1], 2) the risk of increased blood pressure (already a common problem 
with primary care patients) at high therapeutic dosages, and 3) primary care providers 
typically have less experience prescribing SNRIs than SSRIs. 
 
Arm 2:  Patient failing to respond to an SSRI will be augmented with WET. 
 
Arm 3:  Patient failing to respond to WET will be switched to an SSIR. 
 
For patients failing to respond, the patient will be prompted to contact the clinic to 
discuss a treatment change and the telephone number of clinic will be provided.  We will 

26 
 
also contact the clinic to have them schedule an appointment for the next assigned 
treatment.  We anticipate that some patients failing treatment will not change treatment 
plans and that some patients responding to treatment will change treatment plans (i.e., 
contamination).  We will record this and examine the impact of contamination bias in a 
sensitivity analysis. 
 
8.4 Concomitant Interventions 
 Allowed Interventions 
Patients may engage in any treatment that is available to them at any time and 
remain enrolled in the trial.  
 Required Interventions  
None 
  Prohibited Interventions 
None 
 
8.5 Adherence Assessment [IR-2][IR-5] 
 
Patient Adherence - Engagement/adherence will be measured using standard questions 
about appointment attendance and medication adherence.  For pharmacotherapy, 
adherence will be measured as the proportion of days taking the prescribed dosage of 
medication in the previous 14 days (0-14 divided by 14 as an upper limit).  For 
psychotherapy, adherence will be measured as the proportion of WET sessions attended 
in the previous 4 months (0-6 divided by 6 sessions as an upper limit). Thus, regardless of 
treatment condition, adherence will be measured on a scale from 0 to 1, allowing 
comparison across treatment arms. 
 
Provider Intervention Fidelity [IR-2] – Fidelity is the degree to which the intervention is 
implemented as specified by the protocol. Following Thorpe’s recommendations for 
maximizing the external validity of pragmatic trials, fidelity will be monitored, but not 
artificially controlled [IR-5]. For psychotherapy, CHC therapists will use a checklist for each 
patient encounter and upload that to a portal hosted by UW (REDCap project).  For 
psychotherapy, VA therapists will use a checklist embedded into the progress note for 
each patient encounter and the information will be obtained via chart review and entered 
into the portal hosted by UW (REDCap project). The checklists will record the delivery of 
the core elements of WET (e.g., whether writing assignments were completed),  the type 
of therapist (e.g., licensed clinical social worker, psychologist PhD) delivering WET, 
whether sessions were conducted face-to-face, or over interactive video or audio-only 
phone, and how the written narrative was made available to the therapist.  For 
pharmacotherapy, clinic staff will review the medications list in the EHR and record which 
medication(s) were prescribed to the patient, and the type of prescriber (e.g., primary 
care physician, nurse practitioner, psychiatrist) in our survey group’s web-interface. For 

27 
 
psychotherapy, clinic staff will review the EHR and record whether the patient received 
another type of trauma-focused psychotherapy (Prolonged Exposure, Cognitive 
Processing Therapy, or Eye Movement Desensitization and Reprocessing) and total 
number of encounters.  As we have done successfully in the past, during the follow-up 
surveys we will ask patients about their adherence to the psychotropic medications they 
were prescribed. Likewise, we will ask patients how many WET sessions they attended.  
 
9 
STUDY PROCEDURES 
 
9.1 
Schedule of Evaluations 
 
 
Intake 
Baseline 
4 Month 
Follow-Up 
8 Month 
Follow-up 
Post Study  
Clinician Assessment 
of Inclusion Criteria 
X 
 
 
 
 
Telephone Survey 
 
X 
X 
X 
 
Qualitative Interview 
 
 
 
 
X 
 
9.2 Description of Evaluations [CI-3][IR-6][MD-2][PC-1][PC-2][PC-3][RQ-6] 
 
A telephone or web survey will be administered at baseline (pre-treatment), at 4-month 
follow-up (post initial treatment) and 8-month follow-up (post sequenced treatment for 
non-responders) [CI-3]. The patient telephone/web survey will be administered in English 
or Spanish (depending on patient preference) by the Social and Economic Sciences Center 
at Washington State University. All surveys will be administered by masked interviewers 
[IR-6] using the Computer Assisted Telephone Interviewing system. The survey group will 
make up to 10 phone call attempts to contact each patient, and reminder letters, emails 
and texts will be sent prior to the follow-up surveys [PC-2; MD-1].  All baseline interviews 
will be completed within 30 days of the target date.  All follow-up interviews will be 
completed within 3 weeks before or after the target date, and follow-up rates are 
expected to be >80% [MD-1]. Study participants recruited from the VA will be 
compensated $50 for completing each of the three interviews (baseline, 4-month follow-
up, 8-month follow-up) and study participants recruited from CHCs will be compensated 
$30, $50 and $40 for completing each interview. [PC-2; MD-1]. If patients are willing, 
contact information about friends and relatives will be collected at baseline, and these 
individuals will be consulted if the patient cannot be located for follow-up [PC-2; MD-1]. 
This data collection approach is consistent with Thorpe’s recommendations for 
conducting pragmatic trials because it does not require patients to make frequent clinic 
visits to complete research assessments, thus minimizing patient burden and attrition 
bias [PC-2; IR-5].  In addition, because surveys will be completed independently of 
treatment, outcomes will be measured for patients dropping out of treatment [PC-2].  
Prior to fielding the survey, each question will be evaluated by SAB consumer members 
for understandability and face validity [PC-1]. The outcome domains and instruments 
were selected in consultation with SAB members [PC-1][RQ-6].    

28 
 
9.3 
Screening Evaluation 
 We will use the five-item PC-PTSD-5 screener which has excellent sensitivity (95%) and 
specificity (85%).  All sites (Federally Qualified Health Centers and VA Medical Centers) 
routinely screen for depression at primary care visits using the 9-item PHQ-9 depression 
screener and the VA routinely screens for PTSD using the five-item PC-PTSD-5.  The PC-
PTSD-5 will be administered along with the depression screen by a nurse or physician 
assistant or administered by the social worker or psychologist for those patients referred 
to the Behavioral Health Consultant. Primary care providers typically refer patients 
screening positive who will administer the Short Trauma Questionnaire (from PDS-5) and 
the 20-item PTSD Checklist for DSM-5 (PCL-5) as part of routine care.  These three 
instruments (PC-PTSD-5. Short Trauma Questionnaire and PCL-5) are used to determine 
inclusion criteria eligibility.  All three instruments are short and are used routinely by 
Behavioral Health Consultants.   
9.4 
Enrollment, Baseline, and Randomization 
 Enrollment 
Patients are considered to have enrolled after they have completed the informed 
consent AND their information (identifying information and documentation of 
eligibility criteria) has been entered into the research portal.   
 
 Baseline Assessments [IR-4] 
• Demographics and insurance 
• Social Support (ESSI) 
• Medication Adherence (Written for STEPS) 
• Side Effects (Written for STEPS) 
• Health Related Quality of Life (VR-12) 
• Recovery Goals (RAS) (not dominated by symptoms sub-scales) 
• Criteria A Trauma Exposure (Short Trauma Questionnaire from PDS-5 at pre-
baseline eligibility assessment) 
• PTSD Symptoms (PCL-5 at pre-baseline eligibility assessment) 
• Depression (PHQ-9) 
• Sleep (PSQI-A) 
• Generalized Anxiety (GAD-7) 
• Alcohol Use (AUDIT-C) 
• Drug Use (DAST10) 
• Beliefs About Mental Health Treatment (EASI)  
• Service Utilization  
•  Treatment History (NCS-R) 
•  Perceived Need (NCS-R) 
•  Treatment Preference (Written for STEPS) 
• Access to Care (Assessment of Perceived Access to Care - APAC)  

29 
 
• Mobile Devices (Pew Survey) 
• Health Literacy – Short Test of Functional Health Literacy in Adults (3 item 
screener)  
 
 Randomization 
Randomization will be conducted at the patient level immediately before being 
administered the baseline research assessment. Randomization will be stratified 
by site so that equal numbers of patients will be allocated to the three arms at 
each site to avoid bias due to site-level variation in patient casemix and protocol 
fidelity and by SSRI/SNRI use at study entry to ensure that these more treatment 
resistant patients are allocated equally across the three study arms.  
Randomization will be blocked.  We will use blocks of 4, 6, or 8, the size of which 
will be randomly determined to prevent local CHC/VA staff from guessing the next 
treatment group assignment.  
 
9.5 
Follow-Up Evaluations [IR-4][RQ-6] 
• Medication Adherence (Written for STEPS) 
• Side Effects (Written for STEPS) 
• Antidepressant Discontinuation Symptoms (Written for STEPS) 
• PTSD Symptoms (PCL-5) 
• Health Related Quality of Life (SF12V) 
• Recovery Goals (RAS) (not dominated by symptoms sub-scales) 
• Depression (PHQ-9) 
• Sleep (PSQI-A) 
• Generalized Anxiety (GAD-7) 
• Alcohol Use (AUDIT-C) 
• Drug Use (DAST10) 
• Service Utilization (Written for STEPS) 
• Satisfaction (ECHO) 
 
10 
SAFETY ASSESSMENTS  
10.1 Definitions of noncompliance, adverse events, serious adverse events and 
unanticipated problems: 
• Noncompliance: any action or activity associated with the conduct or oversight of 
research involving human subjects that fails to comply with applicable regulations, the 
IRB’s Handbook, and/or the determinations and requirements of the IRB. 
Noncompliance may range from minor to serious; be unintentional or willful; and may 
occur once, sporadically, or continuously.  
o Protocol Violations - an accidental or unintentional change to, or 
noncompliance with the IRB-approved procedures (e.g., the protocol, informed 

30 
 
consent document, recruitment process or study materials) without prior IRB 
approval. Protocol violations generally increases risk and/or decrease the 
benefit; affect the subject’s rights, safety or welfare and/or the integrity of the 
research data.  
 
• Serious Noncompliance: any action or omission in the conduct or oversight of 
research involving human subjects that affects the rights and welfare of subjects, 
increases risk to subjects, or compromises the scientific integrity or validity of the 
research. 
 
• Continuing Noncompliance: a pattern of repeatedly failing to comply with applicable 
regulations, the IRB’s Handbook, and/or the determinations and requirements of the 
IRB that may affect subjects’ rights and welfare, increase risk to subjects, or may 
compromise the scientific integrity or validity of the research. Continuing 
noncompliance also includes frequent instances of minor noncompliance or failure to 
respond to a request to resolve an episode of noncompliance. 
 
• Adverse Event - Any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory 
finding), symptom, or disease temporally associated with the subject's participation in 
the research, and does not imply any judgment about causality. 
 
• Serious adverse event - Any adverse event temporally associated with the subject’s 
participation in research that meets any of the following criteria: 
o Results in death 
o Is life-threatening (places the subject at immediate risk of death from the 
event as it occurred) 
o Requires inpatient hospitalization or prolongation of existing hospitalization 
o Results in a persistent or significant disability/incapacity 
o Any other adverse event that, based upon appropriate medical judgment, may 
jeopardize the subject’s health and may require medical or surgical 
intervention to prevent one of the other outcomes listed above.  
 
• Unanticipated Problems - Unanticipated problems involving risks to subjects are 
defined as any incident, experience, or outcome that meets all of the following 
criteria:  
o Unexpected in terms of nature, severity and risks as described in the consent 
form  
o Related or possibly related to participation in the research  
o Suggests that research participation places subjects at a greater risk of harm, 
including physical, psychological, economic, or social harm, than was 
previously known or recognized 
 

31 
 
10.2 Expectedness 
There are numerous risks that are anticipated for this population of patients with PTSD 
and potential other comorbid mental health and substance use disorders.  These risks are 
both study-related and non-study-related.   
• Anticipated study-related risks associated with evaluation activities include:  
• psychological distress due to survey questions 
• potential loss of confidentiality 
 
Study participants will be more likely to be started on or switched to FDA approved 
antidepressant medications or have their dosages increased than non-study participants.  
Likewise, study participants randomized to an arm with a Written Exposure Therapy 
treatment component will write about their traumatic events.  
Therefore, anticipated study-related risks associated with clinical activities include:  
• anticipated side-effects 
• psychological distress related to writing trauma narrative  
 
Because of the severity and comorbidity of addiction and mental illness in our study 
population, it also anticipated that study participants will experience the following non-
study related events. 
• Adverse Events and Serious Adverse Events with a relatively high degree of 
frequency: 
• Increase in suicide ideation (Adverse Event) 
• Suicide intent (Serious Adverse Event) 
• Suicide attempt (Serious Adverse Event) 
• Death by suicide (Serious Adverse Event) 
• Accidental overdose (Serious Adverse Event) 
• Emergency department visits and/or hospital admissions (Serious Adverse Event) 
 
10.3 Determination of Unanticipated Serious Adverse Events 
Serious Adverse Events that are unanticipated must be reported to the IRB, DSMB and 
PCORI.  To determine whether the event is an unanticipated Serious Adverse Event it 
must be 1) unexpected, 2) related or possibly related to the research AND 3) suggests 
greater risk of harm than was previously thought.  The flow chart below provides an 
algorithm for determining whether an Adverse Event or Serious Adverse Event represents 
an unanticipated problem that needs to be reported under Health and Human Services 
regulations at 45 CFR part 46. 

32 
 
 
Step 1: Assessing whether an adverse event is unexpected - The vast majority of adverse 
events occurring in the context of research are expected in light of (1) the known 
toxicities and side effects of the treatments, 2)  the expected natural progression of 
subjects’ underlying diseases, disorders, and conditions, and 3) subjects’ predisposing risk 
factor profiles for the adverse events. An Adverse Event is unexpected if the event occurs 
in one or more subjects participating in a research protocol, the nature, severity, or 
frequency of which is not consistent with either: 
• The risk of the Adverse Event is described in the informed consent document  
OR 
• The expected natural progression of any underlying disease, disorder, or condition of 
the subject(s) experiencing the Adverse Event and the subject’s predisposing risk 
factor profile for the adverse event.  
 
Step 2: Assessing whether an adverse event is related or possibly related to 
participation in research - Adverse events may be caused by one or more of the 
following: 
• The procedures involved in the research 
• An underlying disease, disorder, or condition of the subject; or 

33 
 
• Other circumstances unrelated to either the research or any underlying disease, 
disorder, or condition of the subject.  
Determinations about the relatedness of Adverse Events to participation in research 
commonly result in probability statements that fall along a continuum between 
definitely related to the research and definitely unrelated to participation in the 
research.  Possibly related to participation in the research is the critical threshold for 
determining whether a particular Adverse Event represents an unanticipated 
problem.  Possibly related is defined as “a reasonable possibility that the Adverse Event 
may have been caused by the procedures involved in the research. 
 
Step 3: Assessing whether an Adverse Event suggests that the research places subjects 
at a greater risk of harm than was previously known or recognized - An Adverse Event 
places subjects at greater risk of harm if the event is Serious (a Serious Adverse Event is 
defined above).  
10.4 Reporting Serious and Continuing Non-Compliance and Unanticipated Serious Adverse 
Events 
Serious and Continuing Non-compliance, as well as Adverse Events that are unexpected, 
related or possibly related to participation in research, and serious warrant consideration 
of substantive changes in the research protocol or informed consent process/document 
or other corrective actions in order to protect the safety, welfare, or rights of subjects.  
Adverse events that are unexpected and related or possibly related to participation in the 
research, but not serious, may also warrant consideration of substantive changes in the 
research protocol or informed consent process. An unanticipated Adverse Event or 
Serious Adverse Event will warrant consideration of substantive changes in the research 
protocol or informed consent process or other corrective actions in order to protect the 
safety, welfare, or rights of subjects or others.  Examples of corrective actions or 
substantive changes that might need to be considered in response to an unanticipated 
problem include:  
• Changes to the research protocol initiated by the investigator prior to obtaining IRB 
approval to eliminate apparent immediate hazards to subjects; 
• Modification of inclusion or exclusion criteria to mitigate the newly identified risks; 
• Implementation of additional procedures for monitoring subjects; 
• Suspension of enrollment of new subjects; 
• Suspension of research procedures in currently enrolled subjects; 
• Modification of informed consent documents to include a description of newly 
recognized risks; and 
• Provision of additional information about newly recognized risks to previously 
enrolled subjects. 
 
10.5 Safety Monitoring 
 

34 
 
A Data and Safety Monitoring Board (DSMB) has been established for STEPS.  The DSMB is 
responsible for safeguarding the interests of study participants, assessing the safety and 
clinical effectiveness of the treatment comparators, ensuring data quality, and for 
monitoring the overall conduct of the study. 
 
The DSMB is an independent group providing recommendations to the Principal 
Investigator (Dr. Fortney) and Co-Principal Investigators (Drs. Kaysen and Engel).  The 
DSMB is required to provide recommendations about starting, continuing, and stopping 
the study.  The Principal Investigator is responsible for forwarding these 
recommendations to PCORI.  In addition, the DSMB is asked to regularly monitor the data 
from the study, review and assess the performance of its operations, and make 
recommendations, as appropriate, to Drs. Fortney, Kaysen and Engel. 
 
11 
INTERVENTION DISCONTINUATION [MD-3] 
 
Patients may withdraw from the intervention and/or the evaluation at any time with or 
without their primary care provider’s approval.  The reason for withdrawal or termination 
will be recorded. 
 
12 
STATISTICAL CONSIDERATIONS  
 
12.1 General Design Issues  
 
The trial has three arms.  Patients will initially be randomized to an SSRI or WET in a 1:1:2 
allocation.  Non-responders randomized to Arm 1 will have the SSRI augmented by WET.  
Non-responders randomized to Arm 2 will be switched from the SSRI to venlafaxine. Non-
responders in Arm 3 will be switched from WET to an SSRI.  
  
• Aim 1: To quantitatively compare engagement, self-reported PTSD symptom severity 
(primary outcome), quality of life, and recovery outcomes of primary care patients 
randomized to initially receive brief psychotherapy (WET) or their choice of the three 
SSRIs. 
o Primary Hypothesis 1a – Patients randomized to receive brief psychotherapy 
(Arm 3) will have better outcomes than those randomized to an SSRI (Arms 1 and 
2).  
 
• Aim 2: For patients not responding to initial treatment, to quantitatively compare 
engagement, self-reported PTSD symptom severity (primary outcome), quality of life, 
and recovery outcomes of primary care patients randomized to: 1) switch from brief 
psychotherapy (WET) to their choice of the three SSRIs, 2) augment the SSRI with 
brief psychotherapy (WET), or 3) switch from one class of antidepressants (SSRI) to 
another class of antidepressants (SNRI - venlafaxine).  
o Primary Hypotheses 2a – Non-responders randomized to an SSRI augmented by 
WET (Arm 1) will have better outcomes than those randomized to switching from 

35 
 
an SSRI to an SNRI (Arm 2).  
o Exploratory Hypotheses 2b – Non-responders randomized to an SSRI augmented 
by WET (Arm 1) will have better outcomes than those randomized to switching 
from WET to their choice of the three SSRIs (Arm 3). 
 
• Aim 3: To quantitatively examine treatment heterogeneity among subgroups of 
primary care patients receiving pharmacotherapy and psychotherapy.  
o Primary Hypothesis 3a: Patient engagement, self-reported PTSD symptom 
severity, quality of life, and recovery outcomes will be poorer for: 1) veterans 
compared with non-veterans (controlling for combat exposure), 2) those with 
combat exposure compared with other types of traumas, 3) those currently 
prescribed benzodiazepines, 4) those taking SSRIs/SNRIs at study entry, and 5) 
those with self-reported substance use problems.  
o Primary Hypothesis 3b: Male gender, poor access, cannabis use, and preferring 
pharmacotherapy will be treatment moderators that reduce the differential 
effectiveness of psychotherapy compared to pharmacotherapy. 
 
12.2 Sample Size and Randomization 
 
With 350 patients randomized to pharmacotherapy (Arms 1 & 2) and 350 randomized to 
psychotherapy (Arm 3) and assuming a 20% attrition rate and α significance level of 0.05, 
we will have 80% power for Hypothesis 1 to detect mean differences of 0.24 standard 
deviations (effect size), or 4.08 points on the PCL-5 our primary outcome.   With 175 
patients in each arm, and conservatively assuming a 40% treatment non-response rate, 
and 20% attrition rate, we will have 80% power for Hypothesis 2a to detect means 
differences of 0.47 standard deviations, or 7.99 points for the PCL-5 score.  For the 
heterogeneity analyses of current versus no SSRI/SNRI use at baseline we will have 80% 
power to detect differences in treatment effects comparing those subjects with and 
without SSRIs at baseline of 0.52, 0.48and 0.47 standard deviations depending on the 
proportion of patients not taking SSRIs at study entry (30%, 40% or 50%).   Assuming that 
30% of patients are not taking SSRIs/SNRIs at study entry, we will have 80% power to 
detect difference in treatment effects of 8.84 on the PCL-5.   Because we would have 
more power to detect treatment heterogeneity if 50% of patients were taking 
SSRIs/SNRIs at baseline, we now propose to prioritize enrollment of patients not taking 
SSRIs/SNRIs.  If 50% of patients were taking SSRIs/SNRIs at baseline, we will have 80% 
power to detect differences in treatment effects of 7.99 on the PCL-5.  
 
12.3 Interim analyses and Stopping Rules 
 
No interim analyses are planned to compare intervention superiority or to stop the trial 
based on differences in the clinical effectiveness of the primary outcomes or safety across 
arms.   
 
Potential Serious Adverse Events include suicide attempt or suicide completion and life-

36 
 
threatening medication side-effects, however these are not considered to be 
Unanticipated Serious Adverse Events because they are not related to participation in the 
research. We will perform semi-annual analysis of accruing safety data. Specifically, the 
DSMB will discuss each serious adverse event to determine if it was study related.  
Because suicide attempts, suicide completions and life-threatening medication side-
effects are rare events, it is not feasible to compare observed serious adverse event rates 
with expected rates based on published data.  Specifically, there would not be sufficient 
power to compare observe and expected rates statistically.  The DSMB will be asked to 
review all information associated with serious adverse events and then make a decision 
as to whether the study should be modified, continued or stopped.  
 
12.4 Outcomes  
 
 Primary outcome and endpoints:  
 
For Hypothesis 1a, the primary outcome is PTSD symptom severity at the 4-month 
follow-up as measured by the PCL-5.    
 
For Hypothesis 2a, the primary outcome is PTSD symptom severity at the 8-month 
follow-up as measured by the PCL-5.    
 
 Secondary outcomes   
 
• 
Side Effects (Written for STEPS) at 4- and 8-months 
• 
Antidepressant Discontinuation Symptoms (Written for STEPS) at 4- and 8-
months 
• 
Health Related Quality of Life (SF12V) at 4- and 8-months 
• 
Recovery Goals (RAS) (not dominated by symptoms sub-scales) at 4- and 8-
months 
• 
Depression (PHQ-9) at 4- and 8-months 
• 
Generalized Anxiety (GAD-7) at 4- and 8-months 
 
 
 
 Other Outcomes and Endpoints: 
  
• Sleep (PSQI-A) at 4- and 8-months 
• Alcohol Use (AUDIT-C) at 4- and 8-months 
• Drug Use (DAST10) at 4- and 8-months 
• Treatment Engagement: Medication Adherence (Written for STEPS) and 
Therapy Visits (Written for STEPS) at 4- and 8-months 
• Service Utilization (Written for STEPS) at 4- and 8-months 
• Satisfaction (ECHO)  

37 
 
 
 Contrasts 
The primary contrast is being randomized at baseline to receive brief 
psychotherapy (Arm 3) versus being randomized to an SSRI (Arms 1 and 2) for the 
full sample.  
The secondary contrast is being randomized to an SSRI augmented by WET (Arm 1) 
versus being randomized to switching from an SSRI to an SNRI (Arm 2) for those 
not responding to the initial treatment.  
 
12.5 Data Analyses [IR-1] [HT-2][HT-3][RQ-4]  
 
Patients will be the unit of the intent-to-treat analysis. The clustering of patients within 
sites may cause outcomes to be correlated across patients treated in the same site. To 
account for intra-class correlation and stratified randomization, healthcare system and 
SSRI/SNRI use at study entry will be included as fixed effects. Generalized linear models 
will be specified with the appropriate distribution and link functions to match the 
dependent variable (e.g., linear for the symptom change score, binomial for adverse 
events).  To examine contamination bias, we will conduct a per-protocol sensitivity 
analysis that excludes patients who received a treatment other than the one to which 
they were assigned.  
 
Hypothesis Testing [IR-1] – Primary Hypothesis 1 will be tested by comparing the 280 
patients randomized to WET (Arm 3) completing the 4-month follow-up to the reference 
group specified as the 280 patients randomized to Arms 1 and 2 completing the 4-month 
follow-up.   Primary Hypotheses 2a will be tested by comparing the ~56 non-responding 
patients randomized to Arm 1 (augmenting SSRI with WET) completing the 8-month 
follow-up to the ~56 non-responding patients randomized to Arm 2 (switching from SSRI 
to SNRI) completing the 8-month follow-up.  Similarly, Exploratory Hypothesis 2b will be 
tested by comparing the ~56 non-responding patients randomized to an SSRI augmented 
by WET (Arm 1) to the ~56 non-responding patients randomized to switching from WET 
to their choice of the three SSRIs (Arm 3).  To test Hypothesis 3a we will add the 
explanatory variables of interest (veteran/civilian status, combat vs other trauma 
exposure, prescribed benzodiazepines at baseline, and baseline substance use problems) 
to the regression testing Primary Hypothesis 1 (n=560 completing the 4- month follow-
up) [HT-2; HT-3; RQ-4].    
Exploratory Subgroup Analysis – To examine whether the results of the primary hypotheses 
testing are sensitive to the mode of delivery (face-to-face vs interactive video), we will 
dichotomously categorize study participants as mostly receiving interactive video encounters if 
the number of interactive video encounters is greater than or equal to the number of face-to-
face encounters.  This “effect modifier” will be calculated separately for the first 4-month follow-
up period and the second 4-month follow-up period.  The impact of this effect modifier will be 
assessed using the same regression specification that was used to test Primary Hypotheses 1a 
(Patients randomized to receive brief psychotherapy (Arm 3) will have better outcomes than 

38 
 
those randomized to an SSRI (Arms 1 and 2)), 2a (Non-responders randomized to an SSRI 
augmented by WET (Arm 1) will have better outcomes than those randomized to switching from 
an SSRI to an SNRI (Arm 2)), and 2b (Non-responders randomized to an SSRI augmented by WET 
(Arm 1) will have better outcomes than those randomized to switching from WET to their choice 
of the three SSRIs (Arm 3)).  The effect modifier will be specified as both a main effect and as an 
interaction effect. A significant negative main effect will be interpreted as a risk factor for 
experiencing a smaller overall treatment effect for those patients having mostly interactive video 
encounters.  The significance of the interaction effect will be used to determine whether mode of 
delivery is an effect modifier.  A significant negative interaction term will be interpreted as 
interactive video as being a risk factor for experiencing a smaller psychotherapy effect and 
significant positive interaction term will be interpreted as a risk factor for experiencing a smaller 
pharmacotherapy effect.   
 
 Moderator [CI-3][HT-2][HT-3][RQ-4] 
Moderator Analyses (Treatment Heterogeneity Effect) - For the treatment moderator 
Hypothesis 3b, we will use the method developed by the MacArthur Foundation [HT-2; 
RQ-4].  The treatment moderator analysis will also be conducted using the 4-month 
follow-up outcomes data and will compare the 280 patients randomized to WET (Arm 3) 
completing the 4-month follow-up to the reference group specified as the 280 patients 
randomized to Arms 1 and 2 completing the 4-month follow-up.  The moderator variables 
will represent the pre-baseline time period and will not change over time [CI-3].  The 
moderator analysis will use the same regression specification that was used to test 
Primary Hypothesis 1.  The hypothesized moderators will be added as a group as both 
main effects (if they were not already specified as covariates in the regressions used to 
test Hypothesis 1) and as interaction effects (with Arm 3).  The significance of the 
interaction effects will be used to determine whether the patient characteristic is a 
treatment moderator.  A negative interaction term will be interpreted as a risk factor for 
experiencing a smaller psychotherapy effect and positive interaction term will be 
interpreted as protective factor for not experiencing a smaller psychotherapy effect.  The 
presence of significant treatment moderators will be interpreted as evidence of 
treatment heterogeneity, and subgroup specific treatment effects will be estimated with 
associated confidence intervals and displayed using a funnel plot to characterize the 
degree of heterogeneity.  We will specify one regression equation (n=560) that 
simultaneously examines the following potential moderators of interest, male gender, 
poor access, cannabis use, and preferring pharmacotherapy over psychotherapy [HT-3]. 
The choice of moderators was determined by clinical judgement and prior empirical 
evidence (see section D.9) [HT-1].  
    
 Assessment of Internal and External Validity [IR-5] 
To assess for internal validity, we will compare the demographic and clinical 
characteristics of study participants randomized to the three arms [IR-5]. 
 

39 
 
To assess for external validity, we will calculate enrollment refusal rates and track reasons 
for refusal [IR-5].   
 Handling of Missing Data [IR-5][MD-2] 
Because we are collecting comprehensive survey data, we should be observing most 
important baseline predictors of missingness at follow-up.  We will compare the baseline 
characteristics of patients with and without missing outcome data [IR-5].  We will impute 
missing data for those with missed follow-ups to account for attrition bias rather than 
dropping observations with missing data [MD-2].  This approach assumes that data a 
missing at random (i.e., the probability of missing depends on observed data, but not 
unobserved data).   This assumption cannot be tested.     
 
 Sensitivity Analyses [MD-4] 
Because the missing at random assumption cannot be tested, we will conduct sensitivity 
analyses that consider plausible forms of non-ignorable missing outcome data, and the 
sensitivity of regression estimates to departures from missing at random mechanisms 
[MD-4]. The regression results generated by the imputed data based on the missing at 
random assumption and the missing not at random assumption will be compared to 
determine the sensitivity of our missing at random assumption.   
 
12.6    Qualitative Data Collection, Management and Analysis 
 
 Qualitative Interviews [MM-1][MM-2][QM-1][QM-2][QM-4][RQ-6]  
 
Because the patient’s treatment experience is a critical outcome that the survey 
instruments may not adequately capture, we also propose to conduct semi-
structured qualitative interviews with patients [RQ-6; QM-1]]. Sample: Qualitative 
interviews will be conducted with a purposively selected sample of patients (n≈60) 
[QM-2]. Patients will be recruited at the end of their 8-month follow-up interview 
[QM-1; MM-1]. The aim is to achieve maximum variation in the patient sample so 
that we have the broadest understanding of patient experiences. Initially, patients 
will be sampled to achieve variation in treatment arms and level of engagement 
[QM-2; QM-4; MM-2]. As we conduct interviews, we will analyze the data in order 
to refine the interview guide and begin to identify preliminary themes or findings. 
As qualitative findings become available, we may make minor revisions to the 
interview guides and consider new directions with regard to sampling [QM-2]. This 
iterative process (moving between sampling, data collection and analysis) will 
allow us to use early findings to target recruitment and monitor for saturation (the 
point at which no new findings are emerging from the interviews).  
 
 Qualitative Data collection [MM-1] 
 

40 
 
All interviews will be conducted by phone. Patients will be audio-consented by the 
qualitative investigator or a trained research assistant just prior to the interview. 
Interviews will be conducted using interview guides that will be developed during 
the course of the study in partnership with our SAB. The purpose of the interviews 
will be to gain an in-depth understanding of why treatments were found to be 
more or less effective and for which types of patients [MM-1].  Therefore, we will 
initially focus our patient interviews on the fit between the patient and the 
treatment, treatment preferences, access, engagement and perceived helpfulness 
of treatment. However, we will also pursue other issues that emerge naturally 
during the interviews and incorporate them into our interview guides.  Thus, the 
inductive qualitative data collection, coding, analysis, and interpretation will be 
integrated activities, thus ensuring that the interpretation of findings is well 
grounded in the data. Qualitative findings will help us interpret why patients 
randomized to Arm 1, Arm 2 or Arm 3 had better outcomes [MM-1].  
 
 Qualitative Data Management and Analysis [MM-3][QM-1][QM-3][QM-4]  
Audio recordings of the interviews will be transcribed and entered verbatim, 
along with any observation field notes, into a qualitative data analysis and 
management software package (Atlas.ti) that enables researchers to mark blocks 
of text with thematic codes, explore relationships among codes, and between 
codes and participant groups [QM-1]. Our qualitative expert and a trained 
research assistant will analyze the transcripts and notes [QM-3]. We will follow 
the 5-phase analysis strategy described by Crabtree and Miller (describing, 
organizing, connecting, corroborating/legitimizing, representing) [QM-1].  To 
accomplish the describing and organization steps we use an immersion-
crystallization approach in which the team reads and discusses the data 
(immersion) to identify key findings (crystallization) [QM-3]. We will develop an 
initial set of inductively derived categories that tag or mark critical segment of 
data. These analytical categories will likely reflect the broad range of 
characteristics noted above, as well as others that emerge through the data 
analysis process.  After consensus is reaching on these tagging conventions, what 
we often refer to as codes, a codebook will be established. To ensure consistency 
in data analysis, the team will meet regularly to discuss the discrepancies and 
emerging findings.  After all of the data has been reviewed once, the team will 
begin a comparative analysis, where categories of tagged text (codes) are 
analyzed to identify cross-cutting patterns. For the connecting phase, we will 
compare our findings to the survey results [MM-3]. For the corroborating/ 
legitimizing phase, we will present our findings to the SAB to confirm/disconfirm 
or refute insights [QM-4]. For the representing phase, we will meet with the SAB 
to discuss the best ways of sharing understandings and interpretations that are 
meaningful to our target audience.  
 

41 
 
13 
DATA COLLECTION AND QUALITY ASSURANCE [IR-3] 
 
 
 
13.1 Quality Assurance  
 
For the telephone survey, the case disposition for each study participant will be tracked in 
the research portal maintained by Washington State University. Contact information will 
be checked for completeness by project assigned clinic site coordinators and by UW 
project managers. For each study participant, their contact history will be documented 
and recorded. Washington State University employs an interviewer dialing protocol using 
a computer assisted telephone interview CATI system that will provide for up to ten for 
every telephone number in telephone survey samples. Contacts by telephone are tracked 
in the CATI’s sample administration disposition system.  
 
Supervised Interviewing - Interviewer performance is monitored to provide feedback and 
ensure adherence to standardized survey interview scripts. Interviewers are scored and 
assessed for quality interviewing and standardized performance. Interview performance 
reports are produced through the CATI system. Survey monitors and survey supervisors 
monitor 5% to 10% of interviews and score performance and evaluate interviewers 
throughout the course of the project. Monitors are able to listen to the interviews on the 
telephone and to observe the data being entered by the interviewer as the interview is 
being conducted.  The monitoring process focuses on the interviewer’s use of probing and 
feedback phrases, accuracy in reading questions and recording responses, rapport with 
respondent, and ability to persuade respondents to complete the interview.  Immediate 
feedback is given to each interviewer who is monitored, on his/her performance during 
the interview.  Supervisors use reports to work with individual interviewers to improve 
Data Flowchart 
 
 

42 
 
cooperation rates, productivity rates, and overall performance of interviewers on the 
surveys. 
 
CATI Controls - The CATI system provide computer screen display for viewing each 
question and coded response options. Prior to the start of interviewing the CATI 
programmed questionnaire is tested in multiple ways to ensure question branching 
matches the ended pathway as designated in the final WORD version of the 
questionnaire. The branching is tested by the programmer, the study director, the survey 
supervisors, survey interviewers, and survey sponsor for accuracy. Pretesting with mock 
interviews helps test the interview flows as intended aurally. Scenario testing and 
question by question testing is conducted to make sure all response option coding 
instructs desired question branching. The CATI system controls the progress and routing 
through the survey interview. At each question response options are coded and only 
possible response options are allowed for entry by the interviewer. This controls for entry 
error by interviewers. Error is also reduced by thorough training on the questionnaire 
with an experienced survey supervisor prior to interviewing. All interviewers on 
monitored, performance scored, and provided with feedback on performance during 
calling and specifically on the project surveys. In the event that survey questions are 
missed inadvertently respondents are recalled to verify or recollect the data.  
 
Questionnaire Data Quality Review - The data are extracted from pretest interviews and 
for interviews to ensure that data is generated for every variable in the survey. A 
frequency listing showing each question and its response options, the number of 
responses and percentages of responses are printed and reviewed by SESRC and UW 
project directors for accuracy. Each question is also reviewed for the occurrence of 
missing data. Since the survey and all questions are voluntary, a small number of missing 
responses are not uncommon. Early review of the survey responses allows for early 
intervention if a larger than expected frequency of missing or nonresponsive data are 
discovered. The survey will also be reviewed for outliers on numeric variables and 
strategies can be implemented to help counter missing or outlier data if it is found to 
occur. As much as possible strategies will be implemented to prevent missing responses. 
Examples of these strategies include allowing for “don’t know”, and “refused” responses 
so that interviewers can progress with the interviews. With the coding of “don’t know” 
responses, strategies such as an alternative question with prespecified categorical 
response can be used to help respondent that expresses they can’t be precise and the 
interviewer encourages best estimates. Other options include providing open ended 
follow-up questions to explore why a respondent cannot provide an answer.  
 
 Site Monitoring 
For each site, we will run biweekly report that provides aggregate counts of the following 
data points: 
• # Patients meeting inclusion criteria 
o # Patients meeting exclusion criteria 

43 
 
 # Patient has a diagnosis of schizophrenia, schizoaffective disorder, 
bipolar disorder, or dementia 
 # Patient is currently being prescribed venlafaxine 
 # Patients with a new prescription for any psychotropic medication in the 
past 8 weeks, including dose changes   
 # Patient has received specialty mental health services in past 2 months, 
OR patient has a future appointment for specialty mental health services 
OR patient/provider prefers referring to specialty mental health setting.  
Specialty mental health is defined as seeing a mental health specialist in a 
non-co-located setting OR sessions are less frequent than every 2 weeks 
OR sessions are longer than 30 minutes in duration.   
 # Provider does not believe that study participation is in the best interest 
of the patient 
 # Patient is pregnant 
 # Patient is terminally ill 
 # Patient not planning to use clinic during next 8 months 
 # Patient is a prisoner 
 # Patient does not speak English or Spanish 
 # Patient is younger than 18 years of age 
 # Patient has impaired decision-making capacity and is unable to 
participate in the informed consent process  
 # Patient cannot attend in person or interactive encounters 
 # Patients not assessed for eligibility 
o # Eligible patients not enrolled 
 # Unable to contact 
 # Refused 
• Reason for refusal 
o # Eligible patient consented  
 
These site reports will be used to monitor the various steps in the recruitment process.  
For sites recruiting fewer patients than expected, these reports will be used to identify 
problems in the recruitment process (e.g., not screening patients for PTSD, not 
attempting to recruit patients, patients refusing to participate). 
 Methods to prevent and monitor missing data [MD-1] 
 
Retention in the evaluation will be monitored and controlled.  The goal for retention in 
the evaluation (i.e., completion of the 4- and 8-month follow-up telephone surveys) will 
be >80%.   Standard interviewing times will include early evenings and weekends.  The 
dialing protocol requires 10 valid call attempts: two morning attempts, two afternoon 
attempts, and six evening attempts at different hours of the evening.  Reminder letters, 
texts and emails about follow-up interviews will be sent out to patients a month in 
advance and patients will be called two weeks prior to their scheduled interview to 
determine whether the interview needs to be rescheduled. We will also include a $5 bill 

44 
 
in the reminder letter. Another reminder letter will be mailed after 5 phone attempts.  
Study participants will be compensated financially for completing each of the three 
interviews (baseline, 4-month follow-up, 8-month follow-up).  The survey will be 
administered in either English or Spanish depending on the preference of the study 
participant.  We will monitor survey progress through reports posted on-line. These 
reports will show the number of completed interviews and the number of interviewer 
hours for the project on a daily basis as well as cumulative totals and project goals. To 
monitor interviewer performance, we use the reports produced by our CATI system 
providing individual and overall totals for interviewing by interviewer and by project, for 
any time period selected.  Data Collection uses these reports to work with individual 
interviewers to help improve the cooperation rate, productivity rate and overall 
performance of that individual on a project. There will be a regular established 
communication between SESRC and UW to make notification for study participants that 
have inaccurate or no longer working telephone numbers. SESRC will monitor the survey 
progress through reports (i.e. case level disposition reports and productivity reports). 
SESRC will communicate survey progress and outcomes through on-line and/or periodic 
reporting. These reports will show the number of completed interviews for each survey 
wave.  When study participants are lost to follow-up, SESRC will document the reason 
why the follow-up was not completed (e.g., refused, unable to contact, etc.).   
 
Retention in treatment (for the two treatment comparators TCC and TER) will be 
monitored but not controlled.   Qualitative interviews will be conducted with patients 
who did and did not engage in treatment in order to identify the reasons why some 
patients did not initiate or dropped out of care.   
 
14 
PARTICIPANT RIGHTS AND CONFIDENTIALITY  
 
14.1 Institutional Review Board (IRB) Review 
 
There are 2 IRBs providing oversight for the STEPS Trial.   
 
• University of Washington IRB  
o Review of adverse events 
o Evaluation Activities  
 Telephone/web survey 
 Qualitative interviews 
 Data analysis 
o Federal Wide Assurance for CHCs 
 Eligibility assessment 
 Chart review 
 Informed consent 
 Clinical activities 
 
Four universities are ceding oversight of research activities to the University of 

45 
 
Washington IRB: 
• Washington State University 
• University of Michigan IRB  
• Oregon Health & Science University 
• Stanford University  
 
• VA Central IRB  
o Clinical activities at VA Medical Centers 
o Review of adverse events 
o Eligibility assessment 
o Chart review 
o Clinical activities 
 
In addition to the VA Central IRB, the local Research & Development offices will provide 
regulatory oversight for each VA Medical Center site.   
 
14.2 Data Use Agreements 
Each of the eight VA Medical Center sites and the University of Washington (on behalf of 
all sub-contractors) will sign a Data Use Agreement.   This Agreement establishes the 
terms and conditions under which the VA Medical Center will provide and the University 
of Washington will use data for the STEPS trial. 
 
14.3 Informed Consent Forms 
 
Community Health Center (CHC) staff will obtain informed consent for three reasons.  
First, the local CHC staff are in the best position to explain the study to the patient using 
language that is familiar to them.  Second, local CHC staff are in the best position to 
understand the patients’ medical care context and to answer questions about how the 
study could impact that care.  Third, patients have trust in the local CHC staff and feel 
comfortable asking questions or expressing concerns.  To avoid coercion the patient’s 
primary care provider will not be involved in obtaining informed consent. Following a 
positive PTSD screen, CHC staff will talk with the patient and their provider to assess 
study eligibility prior to engaging the patient in the informed consent process. CHC staff 
will approach patients screening positive for PTSD after the screening has taken place.  
The informed consent process may take place the same day the patient visited the clinic.  
If there is not an opportunity to engage the patient in the informed consent process on 
the same day as their visit, CHC staff will telephone the patient and schedule a time for 
them to come back to the clinic to undergo informed consent.   
 
The consent form will be available in English and in Spanish. The CHC staff member 
trained to obtain informed consent will find a private location to conduct the informed 
consent process.  The staff member will explain the informed consent process and then 
give the patient time to read the consent form.  The staff member will offer to read the 
consent form to the patient.  CHC patients will also have the option of viewing a video 

46 
 
instead of reading the consent form.  After the patient has read the consent form, the 
staff member will give the patient the opportunity to ask questions and then assess the 
patient’s understanding of the purpose of the study, the procedures and the risks and 
benefits.  Once the consent form has been signed, the staff member will make two copies 
and give one to the patient.  The other will be stored in a locked cabinet locally.  A pdf of 
the scanned signed consent form will be uploaded to the research portal at Washington 
State University.  If informed consent cannot be obtained in person, we will conduct the 
informed consent process over televideo or telephone.  E-Consent forms would be signed 
securely in a REDCap project hosted at the University of Washington (UW).  
 
A progress note describing study participation and randomization status will be generated 
for CHC staff to enter into the EHR in order to notify the PCP that the patient has been 
enrolled and randomized.  
 
14.4 Participant Confidentiality  
 
Washington State University   
 
In developing survey procedures, Washington State University follows the code of 
professional ethics and practices of the American Association for Public Opinion Research.  
That code states that "Unless the respondent waives confidentiality for specified uses, we 
shall hold as privileged and confidential all information that might identify a respondent 
with his or her responses.  We shall also not disclose or use the names of respondents for 
non-research purposes unless the respondents grant us permission to do so."  To that 
end, all interviewers and employees at Washington State University are trained regarding 
professional ethics and confidentiality and in understanding their role as a professional 
researcher with regard to keeping interviews confidential and to act in ways that will not 
introduce bias or compromise research objectives.   
 
Furthermore, to ensure that survey respondents cannot be identified from their survey 
responses Washington State University will follow federal guidelines for protection of 
human subjects, and will adopt the following procedures: 
• Will maintain two separate files in separate locations. One file will contain the 
survey administration files, which include subject identifiers such as phone 
number and individual names. The second file will contain the survey responses. 
These two files will be linkable with a study ID.  
• Will keep all computer records on password protected computers in locked offices 
and all paper files in locked file cabinets in locked offices. No data collected from 
respondents will be stored on laptops or portable devices. 
• Will encrypt all files sent via email or on external devices to the Sponsor’s study 
coordinators. 
 
 
Data Protection – Washington State University has facilities that ensure data protection 

47 
 
and disaster recovery practices. All the data files have primary storage on SESRC’s data 
collection servers residing within  Washington State University’s Departmental Server 
Facility. One server is a file server that is used to store information and documents for 
current and archived projects. A second server is used to host the organization website, 
collect and store data from surveys, as well as to serve as a web and database server.  A 
third server is used as a printer server.  All three servers are used as DNS servers (Domain 
Name Server).  We also have three dedicated web servers for management of file backup 
and survey data collection. Backup servers are connected to each of the main network 
servers at each location, and are available if either of the main local area networks fails.  
A RAID array of hard drives is used for backup of daily interviewing data and is currently 
set for RAID. Thus, survey data is written simultaneously to multiple servers and drives to 
ensure backup of each interview as it is being conducted.   Interview data is stored on 
both the main and backup servers as it is collected.   Additionally, a daily backup is 
created at the end of each day’s calling at 11 p.m. every evening, and is stored on the 
server hard drives.  Once a month, all of the daily files are backed-up again on a compact 
disk (CD) and archived for later retrieval if necessary. The facility has restricted access to 
authorized personnel only, with 24-hour video surveillance and registered electronic key 
access.  The facility also is equipped with humidity and temperature controls, exclusive air 
conditioning, a Halon fire detection and suppression system and Uninterrupted Power 
Source (UPS).  Servers sit behind  Washington State University’s firewall system at all 
times and all machines are protected with the latest Symantec Antivirus software.  In case 
of system failure, all servers are running on a RAID array, mirroring working drives. In 
addition, nightly backups of all data are created and archived using a synthetic-fulls 
procedure on a 90-day and 14-day rotation.  In addition to  Washington State University’s 
Departments Server Facility monitoring, the survey unit maintains its own remote server 
monitoring software designed to give notice to our network administrators in the case of 
attempted intrusion, system overloads or system failure.   
 
University of Washington 
 
All study staff will be trained by the Principal Investigator on the protection of 
participants’ rights, especially in areas relevant to confidentiality.  All staff will 
acknowledge in writing that they will abide by the University’s and current study’s rules 
and procedures pertaining to the rights of participants, confidentiality, and data safety in 
general.  They will acknowledge that any lapse could result in disciplinary action or 
termination.  In addition, the proposed project will adhere to the following general rules 
of data safety:  1) all staff will sign a written commitment to maintain an atmosphere of 
confidentiality, which will include not discussing confidential study information with 
anyone outside the study team and not attempting to learn the identity of an individual 
participant; 2) all questionnaire data will be marked only by a non-identifying ID number; 
3) all identifying information (consent forms, contact information for follow-up 
interviews) will be kept separate from data gathered from participants and kept double-
locked, either in locked cabinets in locked rooms or in password-protected files in 
password-protected computers or systems; 4) all questionnaire data gathered from 

48 
 
participants will be kept double locked; 5) non-study personnel will at no time be 
permitted to view identifying information; 6) all electronic data containing identifiers will 
be maintained with password protection.  The following data sources will contain patient 
identifiers: consent forms, and participant locator forms.  Consent forms will have the 
signature of the participant.  Locator forms will contain the participant’s name, study ID, 
medical record #, current address and phone number, as well as the addresses and 
telephone numbers of contacts.  For survey data, each study participant will be given a 
unique, but non-identifying number.  No names or other identifying information will 
appear in the survey data.  Electronic copies of the interview data will be stored on a 
secured (password protected) server and files are backed up each night by UW IT.  
 
14.5 Study Discontinuation  
 
The STEPS trial can be discontinued by the University of Washington IRB or the VA Central 
IRB.    
 
15 
ETHICAL CONSIDERATIONS 
 
The 1979 The Belmont Report and 1991 Publication of the Common Rule guide the ethical 
principles being followed by the STEPS trial.  
 
The 1996 Health Insurance Portability and Accountability Act (HIPAA) Privacy Rule guides 
the protocols for sharing patient health information between organizations.   
 
16 
COMMITTEES 
 
• Executive Council 
• Stakeholder Advisory Board 
• Data and Safety Monitoring Board 
 
17 
PUBLIC USE DATASET [IR-7] 
 
The Patient Centered Outcomes Research Institute requires that all funded studies 
generate a public use de-identified dataset and data dictionary.  This Open Science Data 
Repository has not yet been created, but the Inter-university Consortium for Political and 
Social Research (ICPSR) at the University of Michigan has been funded to create such a 
repository.  The public use de-identified dataset and data dictionary for STEPS will be 
furnished to this repository in the format required. 
   
18 
PUBLICATION OF RESEARCH FINDINGS [PC-4] 
 
Publication of the results of this trial will be governed by the Executive Council and 
written publication guidelines for the STEPS investigators. 
 

49