Improving Mind/Body Health and Functioning With Integrative Exercise
Phase: NA
Conditions: Stress Disorders, Post-Traumatic
Sponsor: VA Office of Research and Development

Study Protocol and Statistical Analysis Plan 
 
Title: Improving Mind/Body Health and Functioning with Integrative Exercise 
 
Date: August 7, 2023 
 
NCT ID: NCT02856412 
 
  

Study Application (Version 1.30)
1.0
General Information
*Enter the full title of your study:
Improving Mind/Body Health and Functioning with Integrative Exercise
 
 
*Enter the study alias:
VGX RR&D
* This field allows you to enter an abbreviated version of the Study Title to quickly identify this 
study.
 
 
2.0
Add departments
2.1 and Specify Research Location:
Is 
Primary? Department Name
UCSF - 
 - M_Psychiatry
133100
 
3.0
List the key study personnel: (Note: external and affiliated collaborators who 
are not in the UCSF directory can be identified later in the Qualifications of 
Key Study Personnel section at the end of the form)
3.1 *Please add a Principal Investigator for the study:
 
Neylan, Thomas MD
Select if applicable
Department Chair
Resident
Fellow
If the Principal Investigator is a Fellow, the name of the Faculty Advisor must be supplied below.
 
3.2 If applicable, please select the Research Staff personnel
 
A) Additional Investigators
Boyd, Jennifer E 
 Other Investigator
Chesney, Margaret A, PhD 
 Other Investigator
Cohen, Beth, MD, MA 
 Other Investigator
Gasper, Warren J 
 Other Investigator
Mehling, Wolf MD, MD 
N

 Other Investigator
O'Donovan, Aoife PhD, PhD 
 Other Investigator
Palyo, Sarah A 
 Other Investigator
Richards, Anne 
 Other Investigator
Strigo, Irina PhD, PhD 
 Other Investigator
B) Research Support Staff
Antonetti, Victor 
 Clinical Research Associate
Bertenthal, Daniel S 
 Data Manager
Cheng, David 
 Technician
Garcia Guerra, Sergio R 
 Clinical Research Associate
Goldstein, Lizabeth 
 Clinical Research Associate
Hlavin, Jennifer 
 Study Coordinator
Mayzel, Olga 
 Data Manager
Metzler, Thomas J 
 Biostatistician
Muratore, Laura 
 Study Coordinator
Phan, Jordan Dominique 
 Study Recruiter
Shumaker, Erik 
 Clinical Research Associate
Stenson, Emily P 
 Study Coordinator
West, Anna 
 Clinical Research Associate
Williams, Chanda 
 Clinical Research Associate
3.3 *Please add a Study Contact
 
Hlavin, Jennifer 
Muratore, Laura 
Neylan, Thomas MD 
The Study Contact(s) will receive all important system notifications along with the Principal 
Investigator. (e.g. The project contact(s) are typically either the Study Coordinator or the Principal 
Investigator themselves).
3.4 If applicable, please add a Faculty Advisor/Mentor:
 

3.5 If applicable, please select the Designated Department Approval(s)
 
Add the name of the individual authorized to approve and sign off on this protocol from your 
Department (e.g. the Department Chair or Dean).
4.0
 
Initial Screening Questions 
Updated April 2020 - Revised Common Rule (January 2018) Compliant / COVID-19 - 
v94
4.1  * 
:
PROJECT SUMMARY  (REQUIRED) Give a brief overview of this project (250 words or less). Tell us 
what this study is about, who is being studied, and what it aims to achieve. If you have an NIH 
Abstract, paste it here (Click on the orange question mark to the right for more detailed instructions):
Despite the considerable efforts of the VA to improve awareness of mental health 
problems and access to care, many returning veterans still report substantial 
barriers to seeking traditional mental health care. There is a large body of evidence 
demonstrating that aerobic exercise effectively improves many outcomes relevant to 
Posttraumatic Stress Disorder (PTSD) including; anxiety, depression, insomnia, 
cognition, and cardiovascular disease. In addition, there is a rapidly growing 
evidence base showing that aerobic exercise produces an increase in the growth of 
new neurons (e.g., neurogenesis) and increases the volume of the hippocampus 
which underscores the potential value of exercise for producing broad benefits to 
psychological health. Recognizing the promise that exercise might hold for attracting 
more veterans into care and improving overall health in veterans with PTSD, a team 
of investigators at the San Francisco Veterans Administration Medical Center 
(SFVAMC) developed a treatment protocol and completed a pilot study of 
Integrative Exercise (Aerobic exercise and Breath Training 3 weekly sessions over 
12 weeks) versus a waitlist control condition (CHR Protocol #12-09594).
Promising results from this trial have led us to the next step which is to conduct a 
definitive efficacy study of Integrative Exercise versus an active health education 
control condition: Illness Management and Recovery (IMR), also referred to as 
PTSD Recovery. The control condition will be matched on contact hours with 
treatment personnel. The goal of this revised proposal is to test if Integrative 
Exercise improves overall quality of life, PTSD symptoms, sleep quality, and 
measures of cardiovascular health in combat Veterans with chronic PTSD relative to 
the IMR/PTSD Recovery condition. Another goal is to test if improvements in quality 
of life are predicted by improvements in cardiovascular fitness as measured by 
exercise capacity on treadmill testing. Finally, the proposal will test if Integrative 
Exercise versus IMR/PTSD Recovery will produce greater improvements in 
additional health outcomes, including mood, subjective sleep quality, and PTSD 
symptoms. 
4.2  
 
* 
:
HUD DEVICE (REQUIRED) 
 
Does this application involve a Humanitarian Use Device (HUD):
No 
Yes, and it includes a research component 
Yes, and it involves clinical care ONLY 
4.3  * 
: 
TYPE OF RESEARCH (REQUIRED) 
(
Select the option that best fits your project Click the orange 
question mark to the right for definitions and guidance):

Biomedical research (including medical records review, biospecimen collection and/or use, 
other healthcare or health outcomes related activities, research database, biospecimen bank, 
or recruitment registry) 
Social, behavioral, educational, and/or public policy research 
Hybrid - includes aspects of BOTH types of research (check this option if your research is 
mainly social/behavioral but also involves specimen collection or blood draws to look at 
biological measures) 
4.4  * 
 
SUBJECT CONTACT: (REQUIRED) Does this study involve 
 contact or interactions with 
ANY
participants:
Yes (including phone, email or web contact) 
No (limited to medical records review, biological specimen analysis, and/or data analysis) 
4.5  
 
* RISK LEVEL: (REQUIRED) What is your estimation of the risk level, including all screening 
:
procedures and study activities
Minimal risk 
Greater than minimal risk 
4.6  * REVIEW LEVEL: (REQUIRED) Requested review level (Click on the orange question mark to the 
right for definitions and guidance):
Full Committee 
Expedited 
Exempt 
4.7  
 
* EXPEDITED REVIEW CATEGORIES: (REQUIRED) If you think this study qualifies for expedited 
 
 
review, select the regulatory categories that the research falls under: (check all that apply)
Category 1: Research using approved drugs or devices being used for their approved 
indications
Category 2: Collection of blood samples by finger stick, heel stick, ear stick, or venipuncture 
in certain populations and within certain amounts
Category 3: Prospective collection of biological specimens for research purposes by 
noninvasive means (e.g. buccal swabs, urine, hair and nail clippings, etc.)
Category 4: Collection of data through noninvasive, routine clinical procedures (e.g. physical 
sensors such as pulse oximeters, MRI, EKG, EEG, ultrasound, moderate exercise testing, etc. 
- no sedation, general anesthesia, x-rays or microwaves)
Category 5: Research involving materials (data, documents, records, or specimens) that have 
been or will be collected solely for nonresearch purposes
Category 6: Collection of data from voice, video, digital, or image recordings made for 
research purposes
Category 7: Research on individual or group characteristics or behavior or research employing 
survey, interview, oral history, focus group, program evaluation, human factorsevaluation, or 
quality assurance methodologies
* Does the collection of blood samples meet requirements outlined by HHS 
Office for Human Research Protections for Expedited Review Research 
: 
Category 2
(REQUIRED)
For healthy, nonpregnant adults who weigh at least 110 pounds the 
amounts drawn may not exceed 550 ml in an 8 week period and 
collection may not occur more frequently than 2 times per week;
From other adults and children, considering the age, weight, and 
health of the subjects, the collection procedure, the amount of blood 
to be collected, and the frequency with which it will be collected, the 

amount drawn may not exceed the lesser of 50 ml or 3 ml per kg in 
an 8 week period and collection may not occur more frequently than 2 
times per week
 Yes  
 No
4.9  
 
* DATA/SPECIMEN ANALYSIS ONLY: (REQUIRED) Does this study 
 involve records review and
ONLY
/or biospecimen analysis (do not check 'Yes' if this is a registry, research or recruitment database, or 
biospecimen repository):
  Yes  
  No
4.10  
 
* CLINICAL TRIAL: (REQUIRED)
Is this a clinical trial:
According to The World Health Organization (WHO) and the 
International Committee of Medical Journal Editors (ICMJE) a 
clinical trial is:
Any research study that prospectively assigns human participants or 
groups of humans to one or more health-related interventions to 
evaluate the effects on health outcomes.
ICMJE requires 
 of a clinical trial in a public database (such as 
registration
ClinicalTrials.gov) prior to enrollment, for eventual publication of results in 
member biomedical journals.
Public Law 110-85 requires that all investigators who perform 
Guidance: 
an 
 must ensure that the trial is registered on a 
applicable clinical trial
 
.
government web site called ClinicalTrials.gov
 
The FDA requires registration for 'applicable clinical trials,' defined 
as follows:
For any trials of drugs and biologics: controlled clinical investigations, 
other than Phase 1 investigations, of a product subject to FDA 
regulation.
For trials of biomedical devices: controlled trials with health outcomes 
of devices subject to FDA regulation, other than small feasibility 
studies, and pediatric post-market surveillance.
 
 
For additional information on the ClinicalTrials.gov registration process at 
UCSF and the definition of a clinical trial for purposes of registration, visit 
 
the ClinicalTrials.gov section of the UCSF Clinical Research Resource 
HUB.
 
 
 Yes  
 No
 - 'NCT' number for this trial:
Clinical Trial Registration
NCT02856412
4.11  * 
: 
CLINICAL TRIAL PHASE (REQUIRED) Check the applicable phase(s):

Phase 0
Phase 1
Phase 1/2
Phase 2
Phase 2/3
Phase 3
Phase 4
Not Applicable
4.12  
: 
* INVESTIGATOR-INITIATED (REQUIRED) Is this an investigator-initiated study:
 Yes  
 No
 of the 
 to 
The UCSF IRB recommends use
Virtual Regulatory Binder
manage your study.
4.13  * 
 
CORONAVIRUS RESEARCH: (REQUIRED) Does this study involve research on coronaviruses (COVID-
19, SARS, MERS or other):
  Yes  
  No
4.15  
 
*
 
CANCER: (REQUIRED) Does this study involve cancer (e.g., the study involves patients with cancer 
or at risk for cancer, including behavioral research, epidemiological research, public policy research, 
specimen analysis, and chart reviews):
  Yes  
  No
4.16  * 
 
RADIATION EXPOSURE: (REQUIRED) Does your protocol involve any radiation exposure to patients
/subjects 
 from 
 
for 
 purposes (e.g., x-rays, CT-scans, DEXA, CT-
EITHER
standard care OR 
research
guided biopsy, radiation therapy, or nuclear medicine including PET, MUGA or bone scans):
  Yes  
  No
4.17  SCIENTIFIC REVIEW: If this study has undergone scientific or scholarly review, please indicate 
which entity performed the review (check all that apply):
Cancer Center Protocol Review Committee (PRC) (Full approval is required prior to final IRB 
approval for cancer-related protocols.)
CTSI Clinical Research Services (CRS) Advisory Committee
CTSI Consultation Services
Departmental scientific review
Other:
 
* Specify Other: (REQUIRED)
SFVAMC
4.18  
 
* STEM CELLS: (REQUIRED) 
 
Does this study involve
 
human stem cells (including iPS cells and adult 
stem cells), gametes or embryos:
No 
Yes, and requires IRB and GESCR review 
Yes, and requires GESCR review, but NOT IRB review 

4.19  
 
 
*
 
FINANCIAL INTERESTS: (REQUIRED) Do you or any other responsible personnel (or the spouse, 
 
 
registered domestic partner and/or dependent children thereof) have financial interests related to 
 
this study:
  Yes  
  No
5.0
 Funding
5.1  
 
* FEDERAL FUNDING: (REQUIRED) Is this study currently supported in whole or in part by Federal 
funding, 
, OR has it received 
 Federal funding in the past:
even by a subcontract
ANY
 Yes  
 No
5.2  
 
* 
Is this project linked in any way to the Department of Defense (DoD):
DoD INVOLVEMENT: 
(REQUIRED)
  Yes  
  No
5.3  
 
SPONSORS: Identify all sponsors and provide the funding details. If funding comes from a 
 
Subcontract, please list only the Prime Sponsor:
External Sponsors:
 
View 
Details
Sponsor Name
Sponsor Type
Awardee 
Institution:
Contract 
Type:
Project 
Number 
UCSF 
RAS 
System 
Award 
Number 
("A" + 
6 
digits) 
US Dept of 
Veterans Affairs 
01 
SF VAMC 
Research 
Office 
Grant 
 
 
Sponsor Name:
US Dept of Veterans Affairs 
Sponsor Type:
01 
Sponsor Role:
Funding
CFDA Number:
 
Grant/Contract Number:
 
Awardee Institution::
SF VAMC Research Office 
Is Institution the Primary 
Grant Holder:
Yes 
Contract Type:
Grant 
Project Number:
 
UCSF RAS System Award 
Number ("A" + 6 digits):
 
Grant Number for Studies Not 
Funded thru UCSF:
 
Grant Title:
 
PI Name:
(If PI is not the same as 
identified on the study.)
 

Explain Any Significant 
Discrepancy:
 
Other Funding Sources and Unfunded Research - Gift, Program, 
Departmental or other Internal Funding (check all that apply):
Funded by gift (specify source below)
Funded by UCSF or UC-wide program (specify source below)
Specific departmental funding (specify source below)
Unfunded (miscellaneous departmental funding)
Unfunded student project
6.0
 Sites, Programs, Resources, and External IRB Review
6.1    
  
 (check all that apply): 
 UCSF AND AFFILIATED SITES
*
(REQUIRED)  
UCSF Benioff Children's Hospital Oakland (BCHO)
UCSF Cancer Center Berkeley
UCSF Cancer Center San Mateo
UCSF China Basin clinics and facilities
UCSF Helen Diller Family Comprehensive Cancer Center
UCSF Langley Porter Psychiatric Institute (LPPI)
UCSF Medical Center at Mission Bay (Benioff Children's Hospital, the Betty Irene Moore 
Women's Hospital, Bakar Cancer Hospital, or outpatient clinics)
UCSF Mount Zion
UCSF Parnassus (Moffitt-Long hospital, dental clinics or other outpatient clinics)
UCSF Other Sites (including Laurel Heights and all the other sites outside the main hospitals 
and clinics)
Fresno - UCSF Fresno OR Community Medical Center (CMC)
Gladstone Institutes
Institute on Aging (IOA)
Jewish Home
SF Dept of Public Health (DPH)
SF VA Medical Center (SF VAMC)
Vitalant (formerly Blood Centers of the Pacific and Blood Systems Research Institute)
Zuckerberg San Francisco General (ZSFG)
Research involving the SF VAMC: P
 
lease thoroughly review the
webpage 
Working with the SF VAMC 
and/or consult the VA 
Research Office (
 or (415) 221-4810 x6425) 
V21SFCHRPP@va.gov
 to submitting your application to the IRB and:
prior
, identify who is 
If this study involves both UCSF and the VA
serving as the VA PI under 'Descriptions of Study 
Responsibilities' in the 'Qualifications of Investigators' section 
at the end of this form
Include the additional required VA forms in the Study 
Documents section of the Initial Review Submission Packet 
form
6.2  
At what locations will study visits and activities occur:
LOCATIONS: 
IMR/PTSD Recovery and Integrative Exercise Groups:

Subjects can participate in
 assessments and treatment classes from their own homes. 
 all
Informed consent, diagnostic interview/assessments, and medical screen will take place remotely 
and are conducted over the phone or via videoconferencing. Self-report questionnaires can be 
completed from the participant's own device via Qualtrics or on paper through the mail or secure 
messaging (e.g., Azure RMS, Myhealthevet). Neurocogntive testing will be completed remotely 
from the participant's own device via Millisecond Inquisit. Treatment classes will be held remotely. 
Integrative Exercise classes are held using videoconferencing. PTSD Recovery classes are held 
primarily over videoconferencing; however, if technological issues arise, participants may attend 
class using VANTS phone lines.
 
For our clinical trial, no participant will be required to complete any assessment in-person at the 
SFVA Medical Center; however, if circumstances permit, local participants may be given the 
option to complete pre-treatment, post-treatment, and 6 month follow up assessments in-person 
at the SFVA Medical Center (e.g, self-reports, clinical interivew, neurocognitive testing). They 
may also be given the option to complete the blood draw, urine screen, and FMD procedures in-
person at the SFVAMC for additional compensation. 
 
6.3  
Will any study procedures or tests be conducted off-site by non-UCSF 
OFF-SITE PROCEDURES: 
personnel:
 Yes  
 No
Please identify which procedures may be done off-site:
For our fully-remote clinical trial, subjects can participate in
 assessments and treatment 
 all
classes from their own homes. Informed consent, diagnostic interview/assessments, and medical 
screen will take place remotely and are conducted over the phone or via videoconferencing. Self-
report questionnaires can be completed from the participant's own device via Qualtrics or on 
paper through the mail or secure messaging (e.g., Azure RMS, Myhealthevet). Neurocogntive 
testing will be completed remotely from the participant's own device via Millisecond Inquisit. 
Treatment classes will be held remotely. Integrative Exercise classes are held remotely using 
videoconferencing. PTSD Recovery classes are held remotely over videoconferencing; however, if 
technological issues arise, PTSD Recovery participants may attend class using VANTS lines.
 
6.4  RESEARCH PROGRAMS: Check any UCSF research programs this study is associated with:
Cancer Center
Center for AIDS Prevention Sciences (CAPS)
Global Health Sciences
Immune Tolerance Network (ITN)
Neurosciences Clinical Research Unit (NCRU)
Osher Center
Positive Health Program
6.5  * CTSI CRS SERVICES: (REQUIRED) Will this study be carried out at one of the UCSF Clinical Research 
 units or utilize 
:
Services (CRS)
CRS services
 Yes  
 No
 can be found at:
The CRS budget request form
 https://crs.ucsf.edu
/sites/g/files/tkssra726/f/CRS%20Budget%20Request%
. Follow the 
 
20Form_Final_8.14.20%20Restricted%20Version.docx
instructions on the form to submit.
6.6  * MULTI-CENTER TRIAL: (REQUIRED) Is this a multi-center or multi-site research trial:

By 
' we mean a study where the protocol is developed 
'multi-center trial
by an lead investigator, an industry sponsor, consortium, a disease-group, 
etc.,and multiple sites across the nation or in different countries participate 
in the trial. The local sites do not have any control over the design of the 
protocol.
  Yes  
  No
6.8  OTHER SITE TYPES: Check all the other types of sites not affiliated with UCSF with which you are 
cooperating or collaborating on this project:
Do NOT check any boxes below if this is a multi-center clinical 
trial, UCSF is just one of the sites, and neither UCSF nor one of its 
faculty-linked affiliates (SF VAMC, Gladstone, ZSFG) are the 
coordinating center.
Other UC Campus
Other institution
Other community-based site
Foreign Country
Sovereign Native American nation (e.g. Navajo Nation, Oglala Sioux Tribe, Havasupai, etc.)
6.14  * RELYING ON AN EXTERNAL IRB: (REQUIRED) Does this application include a request to rely on an 
external IRB (a central IRB (other than the NCI CIRB) or an external IRB (other UC campus, 
commercial, or institutional):
  Yes  
  No
7.0
 Research Plan and Procedures
7.1  
Describe the hypothesis or what the study hopes to prove:
HYPOTHESIS: 
Hypothesis 1a: Subjects randomized to Integrative Exercise will have a 
greater improvement in quality of life as measured by the WHOQOL-BREF 
psychological domain compared to subjects randomized to IMR/PTSD 
Recovery.
Secondary Hypothesis 1b: Subjects randomized to Integrative Exercise 
versus IMR/PTSD Recovery will have greater improvements in cardiovascular 
health as measured by exercise capacity on the treadmill test.
Exploratory Hypotheses: Subjects randomized to Integrative Exercise versus 
IMR/PTSD Recovery will have greater improvements in additional health 
outcomes, including mood, subjective measures of sleep quality, and 
brachial artery flow mediated vasodilation. These outcomes will be used to 
examine the internal consistency of the effects of treatment on the primary 
WHOQOL-BREF outcome.
Hypothesis 2a: Participants randomized to Integrative Exercise will demonstrate greater 
improvements in PTSD symptoms as measured by the CAPS score compared to those 
in the IMR/PTSD Recovery control group. 
7.2  
List the specific aims:
AIMS: 

Aim 1: To determine whether a 12-week course of Integrative Exercise therapy produces 
significant pre-post improvements in quality of life as measured by the World Health Organization 
Quality of Life (WHOQOL-BREF) and associated psychological and physical health outcomes 
relative to the Illness Management and Recovery (IMR)/PTSD Recovery condition.
 
Aim 2: To determine whether Integrative Exercise produces significant pre-post improvements in 
PTSD symptoms as measured by the CAPS score relative to the IMR/PTSD Recovery condition.
 
7.3  
Briefly describe the study design (e.g., observational, interventional, randomized, placebo-
DESIGN: 
controlled, blinded, cross-over, cross-sectional, longitudinal, pharmacokinetic, etc.):  
Subjects with full PTSD will be recruited to participate in a parallel-groups trial. 104 subjects will 
be randomly assigned to one of two groups: a 12-week course of Integrative Exercise [IE] or 12-
week Illness Management and Recovery (IMR)/PTSD Recovery class.
 
A stratified randomization strategy will be deployed to help ensure that the 2 conditions do not 
differ for subjects who are or are not engaged in current treatment for PTSD. Drs. Mehling and 
Boyd, who have extensive experience with delivering IE and IMR/PTSD Recovery respectively, will 
rate recorded sessions and independently rate adherence.
 
Participants will complete baseline assessments prior to randomization. Subjects will them be 
randomized to either the IE or IMR/PTSD Recovery classes.
 
Integrative Exercise treatment involves a combination of aerobic and strength training exercises 
as well as concentration training based on mindful breathing techniques. Subjects will exercise 3 
times weekly, with each total workout being approximately 60 minutes in length.
 
The control condition will involve 36 hours of health education using the Illness and Management 
and Recovery (IMR)/PTSD Recovery program which is mandated by the Uniform Mental Health 
Services directive to be a component of PRRCs at each VA medical center. The IMR/PTSD 
Recovery control condition, sometimes referred to as Wellness Management and Recovery, is an 
educational curriculum focused on helping clients more effectively manage their illnesses to 
pursue their personal recovery goals.
 
After the 12-week intervention, participants will repeat the basline assessments. Measures of 
subjective sleep quality, PTSD symptoms, mood states – particularly depression, and quality of 
life (QOL), will be obtained in all subjects (Integrative Exercise and IMR/PTSD Recovery) at 
baseline, weeks 4 & 8, and again following the end of 12 weeks. Subjects randomized to 
Integrative Exercise will be asked to rate their satisfaction with the intervention (i.e., acceptability 
and feasibility and comparison with other PTSD treatments that participants may have 
experienced in the past) at the end of 12 weeks.
 
Subjects in both conditions will have repeat clinical assessments at 6 months to examine 
durability of treatment gains.
 
 
7.4  
 Briefly provide the background and significance of this study (e.g. 
BACKGROUND AND SIGNIFICANCE:
 
why is this study needed) (space limit: one half page):
If this is a first in humans study, please summarize the safety data from 
the animal studies. For pediatric drug or device studies, please identify if 
this is the first study in pediatric populations.  
Background and Significance:
Given that aerobic exercise has been found to improve brain health and neurogenesis
, cognitive 
10
function
, mood
, sleep
, and cardiovascular health
, there is a strong rationale to determine 
11
12
13
14
if exercise may be an effective rehabilitative intervention for Veterans with combat related PTSD. 
Our group has also demonstrated that individuals with PTSD have lower rates of exercise 
compared to others without PTSD of the same age and sex
, suggesting they may particularly 
15
benefit from a focus on exercise. Despite the high acceptance of exercise therapy for PTSD found 
in one study
, and the considerable advantage of a treatment lacking stigma, to date there are 
16
no reported controlled trials for exercise in any population with PTSD.

 
 
7.5  
Briefly summarize any preliminary studies relevant to your proposed 
PRELIMINARY STUDIES: 
research 
:
(space limit: one half page)
In our pilot study (CHR Protocol #12-09594), we enrolled a total of 46 (9 
women) veteran participants. Twenty-one subjects were assigned to 
exercise and 25 to the wait list. Note, randomization was conducted from 
block randomization lists from 4 strata defined by gender and age. We had a 
total of 9 dropouts: 5 from the Integrative Exercise (IE) group and 4 from 
the Wait List (WL) group. All 5 subjects from the IE group and 2 from the 
WL group dropped out in the first week after randomization and were lost to 
follow-up. One of the subjects who dropped from WL immediately following 
randomization indicated they elected to enroll in a fitness program outside of 
the research setting. We have 38 total completers (21 WL and 16 IE). 
 
There are strong converging lines of evidence that exercise can have positive effects on 
multiple functional domains relevant to PTSD: psychological and physical heath, sleep, 
and cardiovascular health. We have developed a novel protocol integrating the best 
elements of aerobics, strength training, and mindfulness-based breath training. We 
currently have a dedicated study team in place and with our success at recruitment and 
engagement, we are poised to complete a new definitive efficacy trial with an active 
control condition that will have sufficient power to properly evaluate whether an exercise 
intervention improves quality of life and broad measures of psychological and physical 
health in combat Veterans with PTSD. Because of the strengths of our team in PTSD-
related comorbidities and clinical trials, we are in a unique position to test if exercise has 
positive effects on quality of life, psychological health, sleep, and cardiovascular fitness. 
It is our position that positive results in all of these domains would greatly enhance the 
attractiveness of this intervention to returning warfighters with PTSD and attract more 
Veterans into treatment. Further, the empiric data obtained from this project will help 
inform policy regarding therapeutics that serve the rehabilitation mission of RR&D.
 
 
7.6  
Is this a treatment study, i.e. does this study intend to provide treatment 
* TREATMENT PROTOCOL: 
to individuals with a medical or psychological condition: (REQUIRED)
 Yes  
 No
7.7  
 Does this study involve any procedures, lab tests or imaging studies that 
* BILLABLE PROCEDURES:
have a CPT code and could be billable to patients, their insurance, Medi-Cal, Medicare, or any other 
entity (answer 'Yes' even if the study is going to pay for all the procedures): (REQUIRED)
  Yes  
  No
, send 
If you are not sure if your study involves billable procedures
an email to the 
 for help 
UCSF Office of Clinical Research (OCR)
answering this question.
7.8  
Types of research activities that will be carried out. Check all that 
 COMMON RESEARCH ACTIVITIES: 
*
apply and describe in more detail in the 'Procedures / Methods' section: (REQUIRED)
Interviews, questionnaires, surveys
Educational or cognitive tests

Focus groups
Social media-based research activities
Observation
Fitness tests or other exertion activities
Use of mobile health apps or other apps
Collection of data from wearable tech such as Fitbit, Apple Watch, Garmin, motion actigraphs, 
etc.)
Non-invasive imaging or testing (MRI, EEG, pulse oximetry, etc.)
Imaging procedures or treatment procedures that involve radiation (x-rays, CT scans, CT-
guided biopsies, DEXA scans, MUGA or PET scan)
Administration of contrast agent
Randomization to one intervention versus another
Use of placebo
Biopsy conducted solely for research purposes
Sham surgical procedure
None of the above
7.9  
PROCEDURES / METHODS: 
* 
(REQUIRED)
Describe the research methods and study activities taking place at each site 
(e.g. what will participants be asked to do and what will members of the 
study team do?). If there will be multiple participant groups or study sites, 
explain what will happen with each group or study sites.
 
If some of the activities would occur even if the person were not in the 
study, as in the case of treatment or tests performed for diagnostic 
purposes, clearly differentiate between those activities that will be 
done solely for research purposes and those that are happening as 
part of routine care.
 
Please call our office at 415-476-1814 and ask to speak to someone on the 
Expedited Review team if you need help differentiating between what parts 
are research and what parts aren't.
Informed Consent
Written or electronic informed consent will be obtained by study personnel prior to the first 
diagnostic screening appointment and prior to the start of any study related procedures.
 
Screening and Eligibility Assessments
The following procedures will be started after informed consent is obtained:
Clinicial Assessment & Questionnaires: To determine study eligibility and to obtain 
baseline assessment, a diagnostic interview will be conducted. A trained clinical 
interviewer will conduct a diagnostic assessment using the scales listed in the Clinician 
Administered Assessments section below. The diagnostic assessments will be audio 
recorded.
Medical Evaluation: All potential participants will meet with the study doctor who will 
review their medical and surgical history as well as concurrent medications. Participants 
will be asked about knee symptoms and/or other relevant previous injuries that could be 
exacerbated by exercise.  All participants will complete the Physical Activity Readiness 
Questionnaire (American College of Sports Medicine [ACSM guidelines] to be cleared to 
exercise.  If needed, each subject will perform a graded exercise test (ASCM guidelines) to 
assess functional capacity.
Optional Screening and Eligibility Assessment
Blood Draw: Subjects will 
 be required to complete a blood draw for inclusion in this 
NOT
100% remote clinical trial; however, if circumstances permit, local participants may be 
given the option to have their blood drawn for additional compensation. Blood will be 
collected at the CTSI Clinical Research Center at the SF VA Medical Center. No more 
than 61.5 ml (or 12 teaspoons) of blood will be drawn.

Routine lab tests: This will include a serum chemistry panel, liver function tests, 
thyroid functions, complete blood count, and differential, total cholesterol, HDL-
cholesterol, LDL-cholesterol, triglycerides, glucose, hemoglobin A1c, a urine 
toxicology screen, and potentially other markers. 
Research analyses: The blood will also be used to study chemicals, enzymes, and 
genes related to PTSD. The blood will be stored at the SFVAMC in Dr. Thomas 
Neylan’s -80 freezer (building 8; room 4) for future analysis.
Pre-treatment Assessments
Participants who are eligible following all Screening Assessments will be asked to complete Pre-
treatment Assessments.
Self-Report Questionnaires: All Questionnaires listed in the Instruments section will be 
completed via Qualtrics or on paper through the mail or secure email messaging (e.g., 
Azure RMS, Myhealthevet). If circumstances permit, participants may be given the option 
to complete questionnaires on-site at the SFVAMC.
Neurocognitive Testing: All neurocognitive tests listed in the Instruments section will be 
completed remotely via Millisecond Inquisit. If circumstances permit, participants may be 
given the option to complete neurocognitive testing on-site at the SFVAMC.
Optional Pre-treatment Assessment
Brachial flow-mediated dilation (FMD) test: Subjects will 
 be required to 
NOT
complete the FMD test for inclusion in this 100% remote clinical trial; however, if 
circumstances permit, local participants may be given the option to complete this test for 
additional compensation.
Brachial Artery Flow-Mediated Dilation will be performed by a trained vascular 
technician.  Flow mediated dilation (FMD) will be measured with standard 
procedures using an occlusion cuff and doppler ultrasound.  Staff will attach the 
occlusion cuff to the participants’ upper arm, initiate supra-systolic cuff occlusion 
for five minutes, and then terminate occlusion and measure brachial artery 
response with ultrasound for 60 seconds post occlusion.  Subjects will be asked to 
rate the blood pressure cuff on : a) its intensity (by indicating the maximum 
sensation of pain on a scale from –10/“Neutral” to +10/“Extremely Painful” with 0/
“Pain threshold” as the midpoint); and b) its affect (on a scale from –10/“Extremely 
Pleasant” to +10/“Extremely Unpleasant” with 0/“Unpleasantness Threshold” as the 
midpoint) using a visual analogue scale [182].
Note: we will be asking participants who take blood pressure medications (including alpha 
1 blockers, nitrates, or other blood pressure medications) to hold their medications until 
after they complete the FMD test. They will also be instructed to fast the morning of the 
procedure and to avoid nicotine and caffeine at least 4 hours prior to the test. Breakfast 
will be provided immediately after this fasting procedure.
Note: we will be asking female participants to report any known pregnancy.
 
Randomization
Participants will be randomized to either 12 weeks of Integrative Exercise or 12 weeks of IMR
/PTSD Recovery. Participants will complete the Commitment to Attend Exercise/PTSD Recovery 
Classes prior to starting remote classes.
 
12-week Integrative Exercise (IE) Therapy condition: The exercise program will be 12 
weeks in duration, involving a combination of aerobic and strength training exercises as well as 
concentration training based on mindful breathing techniques from yoga and mindfulness 
approaches recommended by Dr. Hoge (Hoge, 2010). Subjects will exercise 3 times weekly, with 
each total workout being approximately 60 minutes in length. All exercise will be supervised and 
documented by a trained professional in order to validate adherence and allow for program 
replications by others as part of an intervention program for PTSD. 
 
The exercise program is designed with the following overall characteristics: it can be reproduced 
indoors as well as outdoors; it can be done in a group setting with participants at various fitness 
levels; it can also be performed alone; it does not require a club membership or machines; it is 
accessible to combat veterans of all socio-economic and educational levels; it is safe to veterans 
with injuries; it is sufficiently different from usual fitness center programs to be attractive to 
combat veterans; it can be recorded on an MP3 recorder for use in a private home.
 
While the overall goals of the exercises are to increase strength and cardiovascular fitness, 
participants will practice and refine the following exercise skills/techniques: nose breathing, 
mental focus/mindfulness, body scanning, rhythmic limbering, dynamic constant resistance, 
plyometics, and isometric resistance.
 

12-week Illness Management and Recovery (IMR)/PTSD Recovery condition: The control 
condition will involve 36 hours of health education using the Illness and Management and 
Recovery (IMR)/PTSD Recovery program
 which is mandated by the Uniform Mental Health 
89
Services directive to be a component of PRRCs at each VA medical center. The IMR/PTSD 
Recovery control condition, sometimes referred to as Wellness Management and Recovery, is an 
educational curriculum focused on helping clients more effectively manage their illnesses to 
pursue their personal recovery goals. The IMR/PTSD Recovery workbook has detailed adherence 
checklists which filled out by research staff at the end of each session. The 11 modules include 
the following topic areas which have been adapted for use in PTSD: recovery, practical facts 
about PTSD, stress-vulnerability, building social support, medications for PTSD, drug and alcohol 
use, reducing relapse, coping with stress, coping with persistent symptoms, getting needs met in 
the VA healthcare system, and living a healthy lifestyle
.
61, 89
 
4 and 8-week Self-Report Assessments
All participants will complete the following self-report assessments at 4 weeks and 8 weeks after 
beginning the study intervention: PTSD Checklist (PCL), Insomnia Severity Index (ISI), Pittsburgh 
Sleep Quality Index (PSQI), The Pittsburgh Sleep Quality Index Addendum for PTSD (PSQI-A), 
The Symptom Checklist-90-R (SCL-90-R), Godin Leisure-Time Exercise Questionnaire, Five Facet 
Mindfulness Questionnaire (FFMQ), Multidimensional Assessment of Interoceptive Awareness 
(MAIA), and The World Health Organization Quality of Life (WHOQOL-BREF).
 
Post-treatment 12-week assessments
Several of the procedures completed during Screening and Eligibility and pre-treatment will be 
repeated:
Clinician Assessment & Questionnaires: See above for description
Self-Report Questionnaires: See above for description
Neurocognitive Testing: See above for description
Optional Post-treatment 12-week assessments
If circumstances permit, local participants may be given the option to complete the below 
procedures for additional compensation:
Blood Draw: See above for description. The same amount of blood may be collected as at 
baseline: 61.5 ml (or 12 teaspoons)
Brachial flow-mediated dilation (FMD) test: See above for description
 
Post-treatment 6 month assessments: 
All pariticipants will complete the following assessments 6 months after completing the study 
intervention:
Clinician Assessment & Questionnaires: See above for description.
Self-Report Questionnaires: See above for description.
Neurocognitive Testing: See above for description
7.10  
: To what extent, if any, do the planned research procedures differ 
STANDARD CLINICAL PRACTICE
from the care that people would otherwise receive at this institution or the study site if not being 
done locally:
 
Integrative Exercise is not a standard treatment for PTSD, but there is emerging evidence that it 
is helpful. The other condition, Illness Management and Recovery/PTSD Recovery has been used 
in PTSD, but also is not a standard treatment.
7.11  
List all questionnaires, surveys, interview, or focus group guides that will be used for 
INSTRUMENTS: 
this study:
If the instruments are not complete or not available because they will be 
developed as part of this study, describe the basic content or include an 
outline and submit the final versions to the IRB with a modification for 
approval prior to use.

1.  
2.  
3.  
4.  
5.  
6.  
7.  
8.  
9.  
The following assessments will be utilized in all subjects at baseline and after the 12-week 
treatment period, and at the 6-month follow-up period. All of the instruments involving a clinical 
rater will be conducted by an evaluator who will not be conducting the treatment and will be kept 
blind to treatment assignment. Subjects will be instructed prior to the assessment at 12 weeks 
and 6 months not to disclose their treatment assignment to the interviewer.
The World Health Organization Quality of Life (WHOQOL-BREF)
: The WHOQOL-BREF 
51, 52
instrument comprises 26 items, which measure the following broad domains: physical 
health, psychological health, social relationships, and environment. The WHOQOL-BREF is 
a shorter version of the original WHOQOL-100 instrument and is more convenient for use 
in large research studies or clinical trials. The Psychological Domain, our primary outcome, 
is derived from 6 items which index body image, negative & positive feelings, self-esteem, 
spirituality, and cognition. Each item has 5 response options with higher scores denoting 
higher psychological health. The mean score of items within each domain is used to 
calculate the domain score. Mean scores are then multiplied by 4 in order to make 
transformed domain scores to a range of 4-20 comparable with the scores used in the 
WHOQOL-100.
Structured Clinical Interview for DSM-5-Research Version (SCID-5-RV,
). The SCID will 
64
be repeated after the 12-week treatment period.
Clinician Administered PTSD Scale for DSM-5 (CAPS-5,
). The CAPS-5 is a 30 item scale 
65
that provides both a dimensional and categorical measure of PTSD. The CAPS-5 will 
determine lifetime and current PTSD. The CAPS-5 items are rated with a single severity 
score that incorporates both frequency and intensity PTSD-related symptoms. In addition 
to assessing the 20 DSM-5 PTSD symptoms, questions target the onset and duration of 
symptoms, subjective distress, impact of symptoms on social and occupational 
functioning, improvement in symptoms since a previous CAPS administration, overall 
response validity, overall PTSD severity, and specifications for the dissociative subtype 
(depersonalization and derealization)
.
65
Life Stressor Checklist-Revised (LSC-R): Structured clinical interview for lifetime exposure 
to stressful life events 
. This structured clinical interview for lifetime exposure to 
66
stressful life events will be used to characterize the type of trauma exposure and age of 
occurrence(s) of different traumas in all subjects.
Addiction Severity Index Lite (ASI-Lite)
: The ASI-Lite Composite Score for Alcohol Use 
67
will provide a secondary measure of past month alcohol use severity, and the ASI-Lite 
number of years of alcohol use will provide a marker of lifetime alcohol use. The ASI-Lite 
Composite Score for Drug Use will provide a secondary measure of past month non-
alcohol substance use severity, and the ASI-Lite number of years of drug use will provide 
a marker of lifetime non-alcohol substance use. The ASI-Lite is a valid and reliable 
standardized research interview to assess the occurrence and severity of alcohol and non-
alcohol substance abuse. The ASI-Lite includes questions about the frequency, duration, 
and severity of problems over the subject’s lifetime and in the past 30 days.
Smoking status
 is a two-question categorical measure employed by the Centers for 
68
Disease Control and Prevention National Health Interview Survey, and categorizes 
individuals into one of three groups: (a) "Never smokers", adults 18 or over who have 
smoked fewer than 100 cigarettes in their lifetime; (b) "Former smokers", adults who have 
smoked at least 100 cigarettes in their lifetime but are not smoking at time of interview; 
and (c) "Current smokers", adults who have smoked at least 100 cigarettes over their 
lifetime and who are still smoking at time of interview.
Number of pack years
 is a two-question continuous measure of smoking that utilizes the 
68
number of cigarettes per day multiplied by the number of years of smoking to calculate 
pack years of smoking.
Five Facet Mindfulness Questionnaire (FFMQ)
: The FFMQ is a 39-item questionnaire 
69, 70
derived from a factor analysis of other mindfulness questionnaires. It assesses five facets 
of mindfulness: observing, describing, acting with awareness, non-judging and non-
reactivity to inner experience which represent elements of mindfulness as it is currently 
conceptualized. Items are rated on a Likert scale ranging from 1 (never or very rarely 
true) to 5 (very often or always true). The FFMQ has been shown to have good internal 
consistency (alpha coefficient range .72 to .92) in several samples and significant 
relationships in the predicted directions with domains related to mindfulness
. The 
69, 70
FFMQ allows a detailed assessment of changes as a function of mindfulness and therefore 
will be used as a secondary outcome.
Godin Leisure-Time Exercise Questionnaire
: is a validated brief inventory assessing 
71, 72
sedentary, work, recreational, and aerobic activity in a typical week. This metric will be 
used to measure time spent in vigorous activity and will serve multiple purposes: a) It will 
be used to test if randomization effectively balances levels of baseline vigorous activity 
across the two groups; b) It will be used as a manipulation check to ensure that subjects 
randomized to IE engage in more vigorous activity after randomization than subjects 

10.  
1.  
2.  
3.  
4.  
5.  
1.  
2.  
3.  
1.  
2.  
3.  
randomized to IMR/PTSD Recovery; c) It will be used as a secondary predictor of 
treatment response.
The Physical Activity Self-Efficacy scale (PASE)
: The PASE will be used as an exploratory 
73
measure of  perceived confidence to continue exercising in the face of competing day-to-
day conditions.
 
 
The following measures will be obtained in all subjects at Pre-treatment, week 4, week 8, and 
after 12 weeks, and at the 6 month follow-up period:
PTSD Checklist for DSM-5 (PCL-5)
. The PCL-5 is a validated self-report rating scale for 
74
assessing PTSD symptoms. It consists of 20 items that correspond to the DSM-5 
symptoms of PTSD.
Symptom Check-List-90-Revised (SCL-90-R) [147]. The SCL-90-R is a standard self-report 
measure of general psychopathology. Scored for nine primary dimensions and three 
summary indices, the SCL-90-R manual reports extensive reliability and validity data.
Sleep and Alertness Assessment Methods:
Pittsburgh Sleep Quality Index (PSQI)
. This self-report measure provides a subjective 
75
assessment of sleep quality, sleep latency, sleep duration, sleep efficiency, sleep 
disturbances (including nightmares), use of sedative-hypnotics, and daytime energy. This 
index is now widely used and has been validated by polysomnography. The PSQI will be 
our main measure of sleep quality.
PSQI- PTSD Addendum (PSQI-A)
. The PSQI-A assesses disruptive nocturnal behaviors 
76
related to PTSD, such as hot flashes, nightmares, and episodes of terror during sleep. The 
total score ranges from 0 (normal) to 21 (severe). The PSQI-A has demonstrated good 
internal consistency and convergent validity. The PSQI-A will be secondary measure of 
sleep quality that will be used in exploratory analyses.
Insomnia Severity Index (ISI): The ISI is a valid and reliable self-report measure
 that is 
77
a more specific index of perceived insomnia severity, as compared to the widely used PSQI 
measure which captures sleep disturbances of all types. The internal consistency of the ISI 
was found to be excellent (Cronbach’s = 0.74) and has been validated with both sleep 
diary and polysomnography
. The ISI will be secondary measure of sleep quality that will 
77
be used in exploratory analyses.
The following neurocognitive tests will be obtained via Millisecond Inquisit in all subjects at the 
Pre-treatment, Post-treatment, and 6 month follow-up period:
Short Arrow Flanker Test
List Learning Test
Letter number sequence Test
If circumstances permit and a subject elects to complete neurocognitive tests on-site at the 
SFVAMC, subjects willl complete the following neurocognitive tests:
Flanker Inhibitory Control and Attention Test
Oral Symbol Digit Test
Rey Auditory Verbal Learning Test (Rey AVLT)
Attach any unpublished instruments in the 'Other Study Documents' 
section of the Initial Review Submission Packet form after 
completing the study application. Published instruments should 
NOT be attached.
7.12  
Are you drawing any blood or collecting other biosamples (e.g. tissue, 
* BIOSPECIMEN COLLECTION: 
buccal swabs, urine, saliva, hair, etc.) for analysis under this protocol and/or storage for future 
research: (REQUIRED)
 Yes  
 No
Could this study generate genetic data that may be broadly shared (e.g., submitted to 
* 
NIH in compliance with Genomic Data Sharing (GDS)/Genome-Wide Association 
 requirements): 
Studies (GWAS)
(REQUIRED)
  Yes  
  No

Please check the Resource Sharing Plan section of your funding 
notice. You will not be able to share the data as required by your 
funding agency if the consent form doesn't include the required 
language.
7.13  
Briefly summarize the methods and types of analyses that will be 
STATISTICAL METHODS: 
performed:
Study groups will be described in terms of baseline characteristics (including demographic and 
clinical measures, and baseline levels of the outcome variables) using appropriate summary 
statistics. Distributions of clinical measures and outcomes will be examined for presence of 
outliers and need for outcome transformations. The primary analyses will be 
intent-to-
unadjusted 
treat analyses, with all subjects randomized included in the analyses. Only the stratification 
factor, concurrent PTSD treatment status, will be included as a covariate in the primary analysis. 
Other baseline factors that remain unbalanced after randomization and are related to the 
outcomes will be analyzed in a separate sensitivity analysis to assess the robustness of the 
. All available time point data from any dropouts will be included in the analyses, 
primary analysis
using mixed models to accommodate the missing data. Residuals will be examined to ensure 
model assumptions are met. If we find violation of distributional assumptions, we will consider (1) 
transformations of or alternative distributions for the outcomes, and (2) bootstrapped 95% CI on 
the estimated intervention effect. If outliers are found, we will determine if data errors were 
overlooked during cleaning and check their influence via removal. The frequency and timing at 
which outcomes are obtained varies by measure.  Some key measures, including the CAPS and 
the Exercise Treadmill Test, are measured at two time points, pre- and post-treatment, while self-
report measures such as the WHOQOL, PCL and PSQI are measured at four time points.  All of 
these outcomes will be analyzed with linear mixed models (LMM’s).  Measures with more than two 
measurement occasions make full use of the LMM strategy, whereas LMM’s for pre-post measures 
reduce to ANCOVA as a special case, except for the added flexibility of modeling heterogeneous 
group variances.  In analyses with intermediate time points, a number of modeling choices must 
be made, including whether to treat the time variable as continuous or categorical, the form of 
the within-subjects correlation matrix, and whether to allow for heterogeneity of variance across 
groups and/or time points.  The best fitting model will be selected according to likelihood ratio 
tests (for nested models) or the Bayesian Information Criterion (BIC; for non-nested models) 
before examining any coefficients or test statistics. The LMM is an unbiased intent-to-treat 
analysis under assumptions of Missing At Random (MAR).  Any baseline clinical measures that 
  However, the 
correlate with dropout will be added to the models in a sensitivity analysis.
possibility of informative missingness (i.e., missingness related to the missing outcome or other 
unmeasured variables) cannot be tested but also cannot be ruled out.  Therefore, besides our 
primary LMM analytic strategy, we propose another sensitivity analysis for departure from MAR, 
based on copy reference (CR) imputation
. In this procedure, post-dropout data in the 
90, 91
treatment group are multiply imputed from a model that assumes that treatment arm dropouts 
revert to the control group trajectory at a rate determined by the within-control group correlation 
structure.  In the limiting case of participants who drop out of the treatment arm immediately 
after baseline, their imputed trajectory follows that of the control group.  Dropouts from the 
control group are imputed from the control group only model based on baseline data and any 
observed time points before dropout.  Multiply-imputed data sets are analyzed with the LMMs as 
proposed, with the estimates combined using Rubin’s rules. The effect is to reduce the estimated 
difference between groups at end of trial, and yields a more conservative effect estimate than the 
LMM without imputation.
                                                                                     
7.14  
List only the 5-10 most relevant references (a separate bibliography can be attached 
REFERENCES: 
 
for reference purposes if this study involves novel approaches, agents, or an emerging technology 
that the IRB may not be familiar with):
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participation in a mindfulness program for veterans with posttraumatic stress disorder: a 
randomized controlled pilot study. 
 
, 14-27 (2013).
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47.        Polusny, M.A.
 Mindfulness-Based Stress Reduction for Posttraumatic 
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Military-Related PTSD: A Review of Randomized Clinical Trials. 
 
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8.0
 Biospecimen Collection and/or Bank Administration
8.1  
(check all that apply): 
TYPE OF SPECIMENS 
* 
(REQUIRED)
Blood (provide amount below)
Tissue (describe below)
Other type of biospecimen, such as sputum, cerebrospinal fluid, buccal swabs, etc. (describe 
below)
Existing/archival materials (name source below)
Briefly describe the types of biospecimens that will be collected. Provide the 
amount of blood, if applicable. For leftover/existing/archival material, 
identify the source:
Participants may be asked to provide both urine and blood samples. Approximately 61.5 ccs 
(around 12 teaspoons) of blood will be drawn. The blood will be stored at the San Francisco VA 
Medical Center.
8.3  
(check all that apply): 
SPECIMENS ARE: 
* 
(REQUIRED)
Leftover specimens from a clinical diagnostic or therapeutic procedure
Specimens collected for research purposes only (including extra samples taken during a 
clinical procedure)
Other
8.4  
 
: Will any specimens or portions of specimens be retained after the study is 
* FUTURE SPECIMEN USE
over for possible use in future research studies: (REQUIRED)

 Yes  
 No
8.5  
Consent for retaining specimens for future research 
SPECIMEN BANKING - CONSENT METHOD: 
* 
studies will be obtained via (check all that apply): (REQUIRED)
Specimen section within a main research study consent form
Separate specimen consent form
UCSF surgical consent form with tissue donation brochure
8.6  
Indicate where specimens will ultimately be stored: 
 SPECIMEN DESTINATION: 
*
(REQUIRED)
Indicate where specimens will be sent if they will not 
Outside Entities: 
remain at UCSF (choose at least one; check all that apply):
Cooperative group bank
NIH
Other university or collaborator
Industry sponsor
Other
N/A - all specimens will remain at UCSF
Specify to what institution, cooperative group, or company specimens will 
be transferred:
Blood will be stored at the SFVAMC in Dr. Thomas Neylan’s -80 freezer (building 8; room 4) for 
future analysis. 
: If specimens will remain at UCSF, in what kind of 
Internal Storage
facility will they reside (choose at least one; check all that apply):
UCSF repository/bank being established under this protocol
Existing UCSF specimen repository/bank with IRB approval
National cooperative group bank housed at UCSF
Other location at UCSF (please describe)
N/A - no specimens will be retained at UCSF facilities
8.7  
Will direct identifiers be associated with 
SPECIMENS SENT OUTSIDE UCSF - IDENTIFIABILITY: 
specimens or shared with other researchers and/or outside entities:
Yes 
No 
N/A - Specimens will not be shared with others 
9.0
 Drugs and Devices
9.1  
Are you 
 any drugs and/or biologics that are either 
* DRUGS AND/OR BIOLOGICS: 
STUDYING
approved or unapproved: (REQUIRED)
  Yes  
  No
If you have questions about FDA requirements for drug or device 
research, you can send an 
to request a consult.
email 

 
Note: This question is frequently answered incorrectly. If any drugs 
or biologics, approved or unapproved, are being administered under 
this protocol, you should check 'Yes' unless you are 
 sure 
absolutely
that NONE of the drugs are part of the research protocol. Tip: Ask 
the PI or the sponsor if you are not sure how to answer this 
question.
9.3  
: Are you 
 any medical devices, in vitro diagnostics, or assays that are 
* MEDICAL DEVICES
STUDYING
 
either approved or unapproved:(REQUIRED)
  Yes  
  No
If you have questions about FDA requirements for drug or device 
research, you can send an email to request a consult.
10.0
 Sample Size and Eligibility Criteria
10.1  
 
How many people will you enroll:
ENROLLMENT TARGET: 
104
 If there are multiple participant groups, indicate how many people will be 
in each group:
104 subjects will be randomized so that approximately 52 will be assigned to each of the 2 study 
groups: IMR/PTSD Recovery and Integrative Exercise.
 
We estimate that we will have to consent 208 individuals to undergo the initial screening and 
eligibility assessment, in order to enroll 104 eligible subjects.
10.3  
Explain how and why the number of people was chosen. For multi-site 
SAMPLE SIZE JUSTIFICATION: 
studies, this is referring to the number that will be enrolled across all sites:
Power Analysis: Our pilot data on WHOQOL-BREF, PTSD symptoms and METS units in response 
to exercise treatment are promising, but we are reluctant to base our power calculations entirely 
on effect sizes derived from pilot data, as these tend to be far too imprecise 
.  Rather we have 
93
powered the study to detect clinically meaningful effects on our primary variables.  We conducted 
our power calculations for measures obtained at only pre- and post-treatment time points, 
because these are key outcomes and because the two time point case represents a lower bound 
for power when outcomes are measured more frequently.  We used simulation (2000 replications 
each at multiple effect sizes) under the LMM to estimate power. Because our interest is in 
between-group differences in treatment outcomes, it is both appropriate and intuitive to express 
effect sizes in terms of standardized group differences at outcome.  These are calculated from 
LMM-based marginal means and variances of post-treatment outcomes adjusted for baseline 
outcome measures. In the special cases where the LMM reduces to classical ANOVA-type models, 
these effect size estimates are identical to Cohen’s d, and they have the same interpretation in 
more complex models. Our proposed total sample size of 80 completers yields power of 80% at 
alpha = .05 to detect standardized effects (model-estimated differences between the two groups 
at Week 12) of d = .5, assuming within-participant correlations of .7, which is a somewhat 
conservative correlation compared to our pilot data (r = .8) and previous experience in our lab. 
Using standard deviation estimates from similar patient populations studied in our lab, we 
estimate that an effect size of d = .5 translates to a difference in CAPS scores of approximately 8 
points, WHOQOL scores of 1.3 points, and METS scores of 2.7 units, which we believe are 
clinically meaningful effects and which are somewhat smaller than observed in our pilot 
data.  There are no existing effect size estimates for calculating power for the mediation 
hypothesis, Hyp. 1c, and our pilot data sample is too small to provide reasonable estimates of 
mediation effects, as these depend on the relationship among several coefficients each of which is 
estimated with considerable error in a small sample.  However, taking the point estimates of our 
pilot treatment effects on WHOQOL and CAPS at face value, we will have 80% power to detect a 
mediation effect of approximately 40% of the total effect of treatment on WHOQOL and 22% of 

1.  
2.  
the total effect on CAPS scores, using the method of Vittinghoff, Senn, and McCullough
.  The 
94
mediation effects estimated from our pilot data are approximately 18% for both WHOQOL and 
CAPS, but with 95% C.I.’s ranging from -25% (i.e., an effect in the wrong direction) to more than 
60%, so these estimates provide little information.  Still, our proposed sample size will be able to 
detect a fairly substantial mediation effect if it exists, and a smaller effect is not likely to be 
clinically important.
10.4  
Eligible age ranges: 
* 
 AGE RANGE: 
PARTICIPANT
(REQUIRED)
0-6 years
7-12 years
13-17 years
18-64 years
65+
10.5  
 Data will be collected from or about the following types of people (check all 
STUDY POPULATIONS:
* 
 
that apply): (REQUIRED)
Inpatients
Outpatients
Family members or caregivers
Providers
People who have a condition but who are not being seen as patients
Healthy volunteers
Students
Staff of UCSF or affiliated institutions
None of the above
10.6  
Check the populations that may be enrolled: 
SPECIAL SUBJECT GROUPS: 
* 
(REQUIRED)
Children / Minors
Adult subjects unable to consent for themselves
Adult subjects unable to consent for themselves (emergency setting)
Subjects with diminished capacity to consent
Subjects unable to read, speak or understand English
Pregnant women
Fetuses
Neonates
Prisoners
Economically or educationally disadvantaged persons
None of the above
10.7  
 Briefly describe the population(s) that will be involved in this study. Include 
INCLUSION CRITERIA: 
anyone that data will be collected from or about (e.g. patients, healthy controls, caregivers, 
providers, administrators, students, parents, family members, etc.):
Inclusion Criteria:
Male and Female veterans between the ages of 18-75 who are physically able to 
participate in an exercise program.
Meet criteria for of at least 3 months duration, as indexed by the Clinician Administered 
PTSD Scale for DSM-5 (CAPS-5). Participants may either meet full criteria as determined 
by the CAPS-5 or receive a score of equal to or greater than 23.
10.8  
 List any exclusion criteria (e.g. reasons why someone would not be included 
EXCLUSION CRITERIA:
in the study):

1.  
2.  
3.  
4.  
5.  
6.  
7.  
8.  
9.  
Exclusion Criteria:
History of any psychiatric disorder with active psychosis or mania in the past 5 years.
 
Severe drug or alcohol use disorder within the past 6 months as assessed by the 
Structured Clinical Interview for DSM-5. Participants with moderate drug or alcohol use 
disorder will be reviewed on a case-by-case basis.
 
Prominent suicidal or homicidal ideation.
 
Currently exposed to recurrent trauma or have been exposed to a traumatic event within 
the past 3 months.
 
Pregnant, have a clinically significant neurologic disorder, systemic illness affecting CNS 
function, and/or physical disabilities making it impossible to use exercise equipment.
 
History of seizures in the past 5 years.
 
Any acute coronary event (i.e., Myocardial Infarction) in the past 6 months.
 
Moderate to severe Traumatic Brain Injury (any history of head trauma associated with 
the onset of persistent cognitive complaints, neurological symptoms, or loss of 
consciousness > 30 minutes).
 
Subjects who, in the opinion of the investigator, are otherwise unsuitable for a study of 
this type.
      10. Subjects who do not have access to an electronic device that will support telehealth 
participation (e.g., smart phone, laptop, desktop   computer).
      11.  Subjects who do not have private space in their residence to participate in telehealth 
classes.
We will not exclude patients with PTSD who are currently receiving individual or group therapy or 
patients who are currently taking antidepressant or anti-anxiety medication, but will apply the 
following criteria: patients must have been in treatment for at least 2 months, meet symptomatic 
criteria for inclusion, and do not have plans to discontinue treatment during the course of the trial.
10.9  
Do any study activities take place on any 
* RESEARCH CONDUCTED ON PATIENT CARE WARDS: 
patient care units including inpatient wards, peri- or post-operative care units, operating rooms, or 
 
in the Emergency Department at UCSF Health medical facilities: (REQUIRED)
  Yes  
  No
10.11  
Does your protocol or study involve any of the following patient 
EMERGENCY DEPARTMENT: 
* 
related activities in the emergency department (e.g. subject identification, recruitment, consent, 
blood draws, specimen retrieval, involvement of ED staff (nursing, tech, and/or physician), or any 
other ED based procedures): (REQUIRED)
 
  Yes  
  No
11.0
 Recruitment and Consent
11.1  
Is this a competitive enrollment clinical trial? By competitive 
* COMPETITIVE ENROLLMENT: 
enrollment, we mean that sites who do not enroll participants early may not get to participate at all: 
(REQUIRED)  
  Yes  
  No

11.2  
 
What kinds of methods will be used to identify potential 
* SUBJECT IDENTIFICATION METHODS: 
participants for recruitment (check all that apply): (REQUIRED)
Review of patients' conditions, history, test results, etc. (includes patients seen in clinic, 
scheduled for surgery, a procedure, imaging, or tests, or seen in the Emergency Department 
as well as searching through medical record data for possible cohort identification)
Already approved recruitment registry
Re-contact of participants from the investigators' previous studies
Referrals from colleagues (attach the 'Dear Colleague' letter or other recruitment materials 
you will provide to colleagues)
Referrals from the community / word of mouth
Advertisements (flyers, brochures, radio or t.v. ads, posting on clinical research sites or social 
media, presentation of the study at community events/media, etc.)
Online recruiting tool (describe below)
CTSI Recruitment Services unit
Posting on UCSF Clinical Trials, ClinicalTrials.gov or other publicly available clinical trial website
Other method (describe below)
Attach your recruitment materials (e.g., flyers, ads, recruitment 
letter templates, email text, etc.) in the Other Study Documents 
section of the Initial Review Submission Packet Form.
* Provide details about the subject identification methods: (REQUIRED)
We will mail out an invitation letter, brochure, and response postcard (a self-
addressed, stamped envelope will be included for the subject to return the response 
postcard) to a large numbers of veterans who meet broad criteria, based on 
diagnostic codes in veteran health records. After patients have had the opportunity 
to mail in the postcard (after two weeks) or have initiated contact with us 
themselves, we will provide them with additional study information over the phone 
and, if interested, we will continue with screening procedures.
 
We may also request a similar list of veterans from the DoD, in order to reach 
veterans who may not yet be registered with the VA. The same mailing procedures 
as described above will be followed for this group of veterans.
 
All letters, postcards and brochures used in the mailings above will be submitted for 
IRB approval before mailing.
 
ResearchMatch
ResearchMatch.org will be utilized as a recruitment tool for this protocol. ResearchMatch.org is a 
national electronic, web-based recruitment tool that was created through the Clinical & 
Translational Science Awards Consortium in 2009 and is maintained at Vanderbilt University as an 
IRB-approved data repository. UCSF is part of the ResearchMatch network, so UCSF researchers 
are allowed to use this registry with IRB approval.
 
How it works: Anyone residing in the United States can self-register as a potential research 
volunteer on ResearchMatch.com. Once registered, volunteers’ coded information becomes part of 
a pool of data that researchers can search through when looking for people to contact about their 
studies. The researchers then send a recruitment message (attached to this submission) to 
potentially eligible volunteers through ResearchMatch's secure web system. After receiving the 
recruitment email from ResearchMatch, the volunteer can click a button to release their contact 
information to the researcher if they want to learn more about the study. All volunteer 
information is kept confidential until the volunteer decides to release it.
 Did all the participants of previous studies provide permission to be 
*
contacted for future studies: (REQUIRED)
 Yes  
 No
11.3  * SEARCHING OF MEDICAL RECORDS: (REQUIRED)

Whose patients are they:
Investigators' own patients or patients seen within the same practice
Patients not under the care of the investigators
How and by whom will records be accessed and searched (check all that 
apply):
Self-search in APeX or other medical records source
Self-search using UCSF's Research Cohort Selection Tool
CTSI Consultation Service Recruitment Services
UCSF Academic Research Services (ARS)
University of California Research Exchange (UC ReX)
Other method (describe below)
Describe the other ways medical records may be accessed and searched to 
identify prospective participants:
We will request from from the VA a list of veterans who meet broad criteria, based 
on diagnostic codes in veteran health records. 
11.4  
How, when, and by whom will eligibility for recruitment be 
DETERMINATION OF ELIGIBILITY: 
determined:
Eligibility will be determined as follows:
 
Phone Screen and Phone Verbal Consent
Interested individuals, responding to recruitment efforts, can call  the study recruiter for more 
information. Before study personnel provide information about the study, individuals will be given 
the option to have their information stored in our recruitment database (CHR Protocol #12-
09158)  so they may be contacted by program staff regarding other studies they may be eligible 
for. Study personnel will then provide information about the study.  If a potential subject is 
interested in participating, he or she will be asked a series of eligibility questions.  If he/she 
meets initial requirements for eligibility and is interested in participating, the potential participant 
will be invited for a remote appointment with the study team, where further eligibility procedures 
will take place.
 
Eligibility Procedures 
Once informed consent has been obtained, potential subjects will meet remotely with the clinical 
interviewer and the study doctor.  Data from the clinical interview and medical screen will be 
reviewed in conference with Dr. Neylan & study staff.  Eligibility to be enrolled will be determined 
by the inclusion and exclusion criteria noted above.
11.5  
Who initiates contact (check all that apply): 
INITIATION OF CONTACT: 
* 
(REQUIRED)
Investigators/study team
UCSF recruitment unit (e.g. CTSI Consultation Services)
Potential participant
Other (explain below)
Provide details about how contact is initiated:
TrialFacts will use an online advertising campaign to recruit participants on 
behalf of our study. Veterans who see our promotional materials and who 
are interested in our clinical trial will complete prescreen questionnaires 
through TrialFacts.org website. All promotional materials and prescreen 
questionnaires used by TrialFacts will be submitted for IRB approval before TrialFacts 
recruiting begins. 
 

TrialFacts will send Veterans who are a potential fit for our study (as indicated by their 
prescreen questionnaire responses) and who choose to complete a phone screen 
with research support staff a calendar invitation, a confirmation email, as well as email 
and text message reminders. 
 
 
Contact may be initiated through ResearchMatch.org. How it works: Anyone residing in 
the United States can self-register as a potential research volunteer on ResearchMatch.com. Once 
registered, volunteers’ coded information becomes part of a pool of data that researchers can 
search through when looking for people to contact about their studies. The researchers then send 
a recruitment message (attached to this submission) to potentially eligible volunteers through 
ResearchMatch's secure web system. After receiving the recruitment email from ResearchMatch, 
the volunteer can click a button to release their contact information to the researcher if they want 
to learn more about the study. All volunteer information is kept confidential until the volunteer 
decides to release it.
11.6  
 (check all that apply): 
HOW IS CONTACT INITIATED:
* 
(REQUIRED)
In person
Phone
Letter / email
Website or app
Other (explain below)
Attach the telephone recruitment script in the Other Study 
Documents section of the Initial Review Submission Packet Form. If 
potential participants will initiate contact, attach the telephone 
screening script that will be used to provide more information about 
the study and determine if callers are eligible to participate.
Attach the recruitment letter or email template in the Other Study 
Documents section of the Initial Review Submission Packet Form.
11.7  
Based on the checkboxes you chose above, please provide a narrative 
RECRUITMENT PLAN: 
describing your recruitment plan. We want to know:
Who is conducting the search for potential participants, and how?
How are potential subjects being approached for recruitment? By whom, and when?
If there will be more than one participant group (e.g. patients, healthy controls, caregivers, family 
members, providers, etc.), provide details about the recruitment plans for each group. 
(Recommended length - 100-250 words)
Recruitment Strategies: Recruitment methods and media will include flyers; 
in-person presentations; website advertisements; internet postings/boards; 
a study-specific webpage; informational letters; newspaper advertisements; 
print newsletters; press releases or advertisements in print, internet, 
television and radio; public service announcements; public notice-board 
postings; contact with and referral from relevant clinicians; social media, 
pamphlets; postcards, mailings; informational sessions about the research. 
In clinical settings, care providers will also be given informational materials 
to distribute to potential candidates.
The above mentioned recruitment strategies will also take place at social 
service agencies; community mental health clinics; community organizations
/events, including recreational and wellness centers; local professional 
organizations; residential treatment facilities; consenting support and 

recovery centers; local hospitals and healthcare systems; insurance 
providers; regional employee assistance programs; religious organizations; 
cultural centers; public transportation vehicles and stations; social clubs; 
and local universities.
Additionally, we will mail out an invitation letter, brochure, and response 
postcard (a self-addressed stamped envelope will be included for the subject 
to return the response postcard) to large numbers of Veterans who meet 
broad criteria, based on diagnostic codes in Veteran health records. We will 
contact patients after they have had the opportunity to mail in the postcard 
(after two weeks). (Before mailing this letter and postcard will be submitted 
for approval by the IRB.) Staff will contact Veterans via phone call, text 
message from a VA issued, password protected and encrypted cellular 
phone.  Study staff will also use a VA issued cellular phone to send text 
messages and VA email to send messages with information about the study 
to Veterans with whom study staff have established contact.  Text messages 
sent by study staff will be discreet and use the minimum language necessary 
to communicate information about the study.  Email Text messages will 
include the option to opt-out of further contact and messages will not 
include personally identifiable information or personal health information. 
Interested candidates who respond to recruitment solicitation will initiate 
contact with the Stress and Health Research Program directly via phone, will 
be given an overview of the study and its enrollment requirements, and will 
be initially screened by telephone.  
Additionally, recruiters will access a pool of shared participants utilizing a 
password protected database  which is described in depth in approved CHR 
Protocol #12-09158.  Particiants in this database have previously agreed to 
be contacted about additional research.
If a potential participant is interested and meets initial requirements for 
participation, he/she will be invited for an appointment with a trained staff 
member from the Stress and Health Research Program. This remote 
appointment will entail meeting with trained research personnel who will 
describe the study in detail, address any questions/concerns and obtain 
written or electronic informed consent for study participation. After informed 
consent has been obtained, the initial evaluation interview, and other 
procedures to determine eligibility will then be conducted.
In addition to the recruitment plans described above, we will be using an 
online recruitment service provider (TrialFacts.org) to recruit potential 
participants. To recruit for this study, TrialFacts has created study-specific 
promotional materials that will be used in their online advertising 
campaigns. Participants who are interested in our clinical trial will answer a 
series of prescreen questionnaires to assess whether they are a potential fit. 
Participants who sign up to participate in the study and pass the online 
screening questionnaire are then asked to book an appointment for a phone 
screen with our research staff. These participants will choose a specific time 
slot to be contacted by our research staff for their phone screening call. 
TrialFacts will send the participant a calendar invitation, a confirmation 
email, as well as email and text message reminders. Research staff will 
contact these interested candidates directly and will provide an overview of 
the study and its enrollment requirements and will conduct an initial phone 
screen. 

 We may use ResearchMatch.org to recruit potential 
ResearchMatch:
participants. We will send out a recruitment message to potentially eligible 
volunteers. Volunteers who are interested in being contacted will click a 
button to release their contact information to our research team if they wish 
to learn more about the study. Our research staff will contact these 
interested candidates directly and will provide an overview of the study and 
its enrollment requirements and will conduct an initial phone screen.
11.8  
How will permission to participate (i.e., informed consent) be obtained from 
CONSENT METHODS: 
* 
each potential participant. If there will be multiple groups and different plans for consenting each, 
  
check all that apply. See the orange Help bubble to the right for more detailed guidance.  
 
Participants will (check all that apply): (REQUIRED)
Sign a paper consent form at the end of the consent discussion (signed consent)
Sign an electronic consent form using DocuSign (signed consent)
Provide online consent through an app, a website, or a survey tool such as Qualtrics or 
REDCap (waiver of signed consent)
Be told about the study and be given a handout/information sheet and be asked if they agree 
to participate (verbal consent - waiver of signed consent)
Complete the study activities and turn in materials, as in the case of a completed survey that 
is placed in a drop box or mailed to the study team (implied consent - waiver of signed 
consent)
Not be able to provide consent and will have a family member consent for them, as in the 
case of a critically ill or unconscious patient (surrogate consent)
Not be able to provide consent (emergency waiver of consent - allowed for minimal risk 
research or greater than minimal risk research with an approved community consultation plan)
Not know about the study, as in the case of chart reviews or observations of public behavior 
(waiver of consent)
Other method (describe below)
Attach your consent form, information sheet, or electronic consent 
text in the Informed Consent Documents section of the Initial 
Review Submission Packet Form.
11.9  
Describe the process for obtaining informed consent, including details such as 
CONSENT PROCESS: 
* 
who will have the consent discussion and when participants will be asked to sign the consent form in 
relation to finding out about the study: (REQUIRED)   We encourage researchers to review our 
.
guidance on obtaining and documenting informed consent
If there are multiple groups being consented differently, provide details about the consent 
process for each group.
If you are relying on 
, provide details about how that will happen.
verbal or implied consent
For studies using online recruitment and consent or consent via mail, provide details here.
Interested individuals, responding to recruitment efforts, can call the Stress and Health Research 
Program study recruiter for more information. Study personnel will then provide information 
about the study over the telephone or via mail.
 
Before potential participants complete the eligibility phone screen, they will be given the option to 
have their information stored in our database so they may be contacted by program staff 
regarding other studies they may be eligible for. Verbal consent will be obtained for the telephone 
screening interview and for optional storage of screening data for future use. Consent will be 
documented via the attached Verbal Consent for Screening.
 
The potential participant will be asked a series of eligibility questions.  If eligible, the potential 
participant will be invited for a remote appointment with a trained staff member from the Stress 
and Health Research Program. 

 
This appointment will entail meeting with trained research personnel who will describe the study 
in detail, review the consent form, and address any questions/concerns. The potential participant 
will be given ample time and opportunity to ask any questions before written or electronic 
informed consent for study participation is obtained.  Electronic consent will be collected 
using VA DocuSign.
 
 
 It is important that the people obtaining consent are qualified to do so. 
*
Briefly describe the training and experience these individuals have in 
obtaining informed consent: (REQUIRED)
All personnel who obtain informed consent will have at least a Bachelor's degree in Psychology or 
a related field and will have previous experience in human subjects research and/or work with 
individials who have PTSD. They will all complete CITI training (for UCSF and VA) and any 
applicable VA-mandated trainings. Personnel will be familiar with the study protocol, including all 
procedures, risks and benefits, study timeline and data security and storage. They will be trained 
on how to assess participants for their understanding of the study and will be prepared to answer 
the most frequently occurring questions from the previous trial at this site. Staff who are new to 
consenting for this study will be observed until it is determined they are competent to complete 
the task.
11.10  
Indicate how the study team will assess and enhance the subjects' 
CONSENT COMPREHENSION: 
* 
understanding of study procedures, risks, and benefits prior to signing the consent form (check all 
that apply): (REQUIRED)   Tip: Review the Consent Comprehension - Learning Notes in the Help 
bubble at the right for specific questions that can be asked to assess comprehension, consider 
using the UCSF Decision-Making Capacity Assesment Tool, and review our guidance on obtaining 
written or verbal informed consent for more detail on how to conduct the assessment.
The study team will engage the potential participant in a dialogue, using open-ended 
questions about the nature of the study or the experimental treatment, the risks and benefits 
of participating, and the voluntary nature of participation
Potential participants will be asked or shown a series of questions to assess their 
understanding of the study purpose, procedures, risks and benefits, as well as the voluntary 
nature of participation (especially appropriate when the consent process happens online or 
through a mobile health app)
Other method (describe below):
Provide details of the other approaches that will be used, if using another 
method to assess comprehension:
Every possible effort will be made to provide the subject with all required information about the 
study in a language and format that is easily comprehensible. The consent form is written at an 
eighth grade reading level with everyday vocabulary and simple sentence structure. A trained 
research staff member will be present (remotely) to explain the study and obtain consent and 
thus will be available to address any questions or concerns from the subject. A copy of the 
consent form will be given to the subject to take home and have for reference. In addition, there 
is a section in the consent form where we have provided contact information for the subject in 
case they have questions about the study.
11.11  
Does this study rely on some deception or misinformation about what the 
* DECEPTION: 
researchers are observing to get valid data? (REQUIRED)
  Yes  
  No
11.13  
Select the regulatory category under which 
* WAIVER OF DOCUMENTATION OF SIGNED CONSENT: 
the IRB may waive the requirement to obtain 
consent for this study:
signed 
The only record linking the subject and the research would be the consent document and the 
principal risk would be potential harm resulting from a breach of confidentiality. Each subject 
will be asked whether they want documentation linking them with the research. 46.117(c) 
(1)  

The research presents no more than minimal risk of harm to subjects and involves no 
procedures for which written consent is normally required outside of the research context. 
46.117(c) (2)  
11.14  
What is the estimated time commitment for participants (per visit and in total):
TIME: 
Total spent in pre- and post-intervention assessments (
): 
fully remote only
11 - 13 hours 
Total spent in pre- and post-intervention assessments (fully remote with optional in-
): 
person visits
14 -16 hours
Total spent in IE or IMR/PTSD Recovery classes: 36 hours
Screening and Eligibility Assessments:
·      Clinician Administered Diagnostic Interview & Questionnaires (approximately 3 hours)
·      Medical Screen/Clearance (approximately 30 minutes)
·     
 Blood draw and urine screen (approximately 30 minutes)
OPTIONAL
 
Baseline Assessments:
·      Self-Report Questionnaires (approximately 1 hour)
·      Neurocognitive Testing (approximately 30 minutes)
·      
 FMD assessment (approximately 1 hour)
OPTIONAL
 
Telehealth Home Visits:
·      Study staff may conduct one or more virtual home visits (approximately 30 minutes - 
1 hour per visit).
 
Integrative Exercise Sessions:
·      12 week course; 3 sessions per week; 1 hour per session
 
Illness Management and Recovery/PTSD Recovery Sessions:
·      12 week course; 3 sessions per week; 1 hour per session
 
4 and 8-week Self-Report Assessments:
·      Self-Report Questionnaires (approximately 30 minutes)
 
Post 12-week assessments: 
·      Clinician Administered Diagnostic Interview & Questionnaires (approximately 1-2 hours)
·      Self-Report Questionnaires (approximately 1 hour)
·      Neurocognitive Testing (approximately 30 minutes)
·      
 Blood Draw (approximately 30 minutes)
OPTIONAL
·      
 FMD assessment (approximately 1 hour)
OPTIONAL 
 
6-month assessments: 
·      Clinician Administered Diagnostic Interview & Questionnaires (approximately 1-2 hours)
·      Self-Report Questionnaires (approximately 1 hour)
·      Neurocognitive Testing (approximately 30 minutes)
 
 
IMPORTANT TIP: Ensure this information is consistent with the 
information provided in the consent form.
11.15  
Is there a standard of care (SOC) or usual care that would be offered 
ALTERNATIVES: 
to prospective participants at UCSF (or the study site) if they did not participate in this research 
study:
  Yes  
  No
11.16  
Is the study drug or treatment available off-study:
OFF-STUDY TREATMENT: 

Yes 
No  
Not applicable 
11.17  
Describe other alternatives to study participation, if any, that are available 
OTHER ALTERNATIVES: 
to prospective subjects:
Subjects may choose to not take part in this study, or they may choose to take part in another 
research study.
Participants enrolled in this study will have the option to take part in 
study #1413833, "Neurobehavioral Correlates of Pain in Post-Traumatic Stress Disorder 
(PTSD)." In order to coordinate scheduling of study visits and sharing of all data across studies, it 
will be necessary to share PHI such as name, date of birth, and social security number. The 
HIPAA authorization for this study will clearly state that by enrolling in this study, the participant 
is agreeing to sharing of data between the two studies if the participant chooses to take part in 
study #1413833.
12.0
 Waiver of Consent/Authorization for Recruitment 
Purposes
This section is required when medical records may be reviewed to 
determine eligibility for recruitment.
12.1  
Study personnel need to access 
* PRACTICABILITY OF OBTAINING CONSENT PRIOR TO ACCESS: 
protected health information (PHI) during the recruitment process and it is not practicable to obtain 
informed consent until potential subjects have been identified: (REQUIRED)
Yes 
If 
, a waiver of consent/authorization is NOT needed.
no
12.2  
 
A waiver for screening of health records to identify potential subjects poses no 
* RISK TO PRIVACY: 
more than minimal risk to privacy for participants:
Yes 
If 
, a waiver of authorization can NOT be granted.
no
12.3  
Screening health records prior to obtaining consent will not adversely affect 
* RIGHTS/WELFARE: 
subjects' rights and welfare:
Yes 
If 
, a waiver of authorization can NOT be granted.
no
12.4  
Check all the identifiers that will be collected prior to obtaining informed consent:
* IDENTIFIERS: 
Names
Dates
Postal addresses
Phone numbers
Fax numbers
Email addresses

Social Security Numbers*
Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
None
Note: HIPAA rules require that you collect the minimum necessary.
12.5  
 
Describe any health information that will be collected prior to obtaining 
* HEALTH INFORMATION: 
informed consent:
Some participants may be recruited via their participation in other research 
studies within the Stress and Health Research Program, per their consent to 
be contacted for additional studies or through their inclusion in the Stress 
and Health recruitment database through the Program-Wide Prescreen 
(Protocol 12-09158).  In these cases, the research data already collected 
may be reviewed to determine eligibility.
Additionally, the names, service dates, and contact information of some 
participants may be obtained using broad-based diagnostic codes used in 
Veteran health records.  We will contact patients after they have had an 
opportunity to mail in an opt-out postcard (after two weeks). 
Some study participants who respond to advertisements and outreach will be 
screened with the telephone screening attached to this application. Verbal 
consent for screening will be obtained and documented before screening is 
performed.
Note: HIPAA requires that you collect the minimum necessary.
12.6  
Describe your plan to destroy any identifiable data 
* DATA RETENTION/DESTRUCTION PLAN: 
collected to determine eligibility for recruitment. This should be done at the earliest opportunity. If 
you plan to retain identifiable recruitment data, provide the justification for doing so:
The information will be retained, as per current VA and federal 
policy, until disposition instructions are approved by the National 
Archives and Records Administration and are published in VHA's 
Records Control Schedule
13.0
 Risks and Benefits

13.1  
Check if your study involves any of these specific research-related risks 
RESEARCH-RELATED RISKS: 
to participants that may need to be disclosed in the consent form:
Physical discomforts or pain
Risks to employment, or social or legal standing
Risk that the study team may observe possible evidence of child abuse, elder abuse, or a 
threat to self or others that they are required to report
For reportable information, include details of the reporting plan below. (See 
the Help link for Mandated Reporter child and elder abuse resources.)
For any boxes checked above, describe how you will minimize these risks 
* 
and discomforts, e.g., adding or increasing the frequency 
of monitoring, additional screening to identify and exclude people with 
diminished kidney or liver function, or modification of procedures such as 
changing imaging studies to avoid giving contrast agent to people who are 
more likely to suffer side effects from it, etc.: (REQUIRED)
Integrative Exercise:  As with any program involving new exercises, participants may experience 
injuries including muscle strain or soreness.  We have developed the Integrative Exercise therapy 
in consultation with experts worldwide who have extensive knowledge with a variety of 
alternative, integrative medicine exercises to ensure that the program is safe and likely to be 
efective. In the unlikely event that an emergency injury should arise during a session, our skilled 
recreational therapists will assess the situation and call 911, if necessary.
 
Clinical Interviews: Participants are informed via the consent form that we are mandated 
reporters of abuse and threat to self/others. This is especially relevant during the clinical 
interview procedure. All interviewers are trained and supervised by a licensed clinical 
psychologist. Interviewers are trained in assessment of suicide risk; homicide risk; and suspected 
abuse of children, and of elder and dependent adults.Training also covers mandated reporting 
requirements and procedures. Interviewers review with all participants mandated reporting and 
the resultant limits to confidentiality immediately before administering clinical interviews.
13.2  
Describe any anticipated risks and discomforts not listed above: 
RISKS: 
* 
(REQUIRED)
Potential Risks and Protection Against Risks:
 
Clinical Assessment & Questionnaires: The interview and questionnaires may be distressing to 
some subjects.  Subjects will be told that they are free to decline to answer any questions or to 
stop the interviews at any time.  Skilled clinicians who can deal effectively and sensitively with 
uncomfortable emotional or physical responses to the procedures conduct the interviews and 
examinations.  Subjects can choose to not answer any questions posed to them, and subjects 
who are experiencing psychiatric distress or a diagnosed disorder will be referred for appropriate 
treatment.
 
Neurocognitive Testing: The cognitive testing may be slightly frustrating or produce fatigue and 
boredom. Subjects can choose to take a break, skip a question, and/or ask the study staff if they 
have any questions.
 
Optional Blood Draw: The risks of drawing blood include temporary discomfort from the needle 
stick, bruising, discomfort, and rarely, infection. Only a qualified nurse or phlebotomist will draw 
blood following standard procedures.  In the event that subjects have an adverse reaction to any 
of the medical procedures, the lab’s central location near the hospital emergency department 
allows us easy access to emergency response teams.
 
Optional Brachial artery flow-mediated dilation (FMD assessment):  The risks associated with 
ultrasound measurement of brachial artery flow- mediated dilation include discomfort in the arm 
during and immediately post occlusion of the brachial artery with the inflatable cuff.  To minimize 
any risks, medical personnel with extensive experience obtaining various types of vascular 
measurement from patients will be handling all aspects of the procedure. Participants are also 
free to discontinue the exam if they wish.
 
Randomization: Subjects have a 50/50 chance of being randomized to the Integrative Exercise 
vs. IMR/PTSD Recovery Group, which may result in being assigned a treatment that is less 

desirable to the individual.  Subjects will be clearly informed of this possibility during the consent 
process. Participants assigned to IMR/PTSD Recovery will be offered free exercise classes after 
they complete the 12-week assessments.
 
Integrative Exercise:  As with any program involving new exercises, participants may experience 
injuries including muscle strain or soreness.  We have developed the Integrative Exercise therapy 
in consultation with experts worldwide who have extensive knowledge with a variety of 
alternative, integrative medicine exercises to ensure that the program is safe and likely to be 
efective. In the unlikely event that an emergency injury should arise during a session, our skilled 
exercise instructors will assess the situation and call 911, if necessary. Our exercise instructors 
will consistently monitor participants via 2-way video-streaming and will be able to call 911 in the 
case of emergency injury. 
 
During the course of treatment fatigue and/or sleepiness, and/or memory and concentration 
difficulties may occur (although these symptoms are usually limited to the first 1-2 weeks of 
treatment). If side effects occur that are not controllable or that are too bothersome, subjects are 
free to discontinue treatment and withdraw from the study.  In the event that a subject 
experiences persistent side effects, and does not volunteer to withdraw from the study, the PI and
/or our DSMB will review his or her case. This review may be followed by the recommendation 
that the subject be withdrawn from the study.
 
Illness Management and Recovery/PTSD Recovery Classes: There are no physical risks from 
participating in the classes. Some of the topics covered in the classes may be emotionally 
upsetting to participants. Illness Management and Recovery/PTSD Recovery has been developed 
for use with diverse veteran populations and is shown to be safe. The classes will be conducted by 
trained mental health professionals. It is very likely that any feelings of upset or distress will be 
temporary. However, if side effects occur that are not controllable or are too bothersome, 
participants are free to take a break from class or discontinue treatment and withdraw from the 
study.
 
Confidentiality: Participation in research will mean a loss of privacy.  The study records will be 
kept as confidential as is possible under the law. No individual identities will be used in any 
reports or publications resulting from the study.  All subjects will be assigned a unique participant 
identification number that will only be known to the PI and coordinator.  Study information will be 
coded with this unique number.  All information will be kept in secured files. Only study 
personnel, with the permission of the principal investigator, will have access to the files.
 
13.3  
MINIMIZING RISKS: Describe the steps you have taken to minimize the risks/discomforts to 
subjects. Examples include:
designing the study to make use of procedures involving less risk when appropriate
minimizing study procedures by taking advantage of clinical procedures conducted on the 
study participants
mitigating risks by planning special monitoring or conducting supportive interventions for the 
study
having a plan for evaluation and possible referral of subjects who report suicidal ideation
The following resources are in place to ensure the protection of the rights and welfare of 
participants:
 
·      
– The study team consists of a sufficient number of staff 
Trained and Qualified Personnel 
members to effectively carry out the study protocol and ensure that the needs of participants are 
met. All staff members have been trained in the areas of Human Subjects Protection, Privacy, and 
Good Clinical Practices.  The Principal Investigator, Co-Investigators, and other key study 
personnel have extensive experience in clinical research and have worked with several CHR 
protocols.
 
·      
– Sufficient funding has been provided to effectively execute the study protocol. 
Funding 
Funding is sufficient to allow the Investigators to devote enough time to the project to ensure 
adequate study design, procedures, and safety monitoring.
 
·      
 – Subjects are free to decline to answer any question or to 
Confidentiality and Privacy
complete any portion of the interview or, to stop the interviews at any time.  Subjects' names are 
not recorded on test materials; identification numbers are used instead.   Subject number 
identification codes are kept in a secure, locked area.  All data are coded and stored in locked file 

cabinets in secure locked storage areas.  Any electronic data is password protected and stored on 
secure encrypted server and will have no identifying information.
 
·       
– Screening procedures, treatment classes, and post-
Proximity of Healthcare Resources 
treament assessments will take place remotely.  Medical and mental health professionals are 
available by phone and videoconferencing to address subject concerns if they arise. As well, 
participants are given contact information for the study doctor and study coordinator and are 
encouraged to reach out with any questions or concerns.
13.5  
BENEFITS: 
* 
(REQUIRED) Note: These are the benefits that the IRB will consider during their review. 
They are not necessarily appropriate to include in the consent form.
Possible immediate and/or direct benefits to participants and society at 
large (check all that apply):
Positive health outcome (e.g. improvement of condition, relief of pain, increased mobility, 
etc.)
Closer follow-up than standard care may lead to improved outcomes or patient engagement
Health and lifestyle changes may occur as a result of participation
Knowledge may be gained about their health and health conditions
Feeling of contribution to knowledge in the health or social sciences field
The research presents a reasonable opportunity to further the understanding, prevention, or 
alleviation of a serious problem affecting the health or welfare of children
Other benefit (describe below)
None
13.6  
Explain why the risks to subjects are reasonable in relation to anticipated 
RISK TO BENEFIT RATIO: 
benefits, if any, to the participant or society:
All risks are minimal and will be attended to by qualified medical and mental health professionals. 
All subjects benefit to the extent that every participant (including those originally placed in the 
IMR/PTSD Recovery group) will have the chance to participate in Integrative Exercise 
classes.  Integrative Exercise may be found helpful in the sample, providing a new treatment 
option to this population.
13.7  
Do you have a Data and Safety Monitoring Plan (DSMP) for this 
DATA AND SAFETY MONITORING: 
* 
study (
): (Click the Help link for guidance 
A DSMP is 
 for Greater than Minimal Risk research
required
 
on risk determination) (REQUIRED)
 Yes  
 No
This is not required for minimal risk research but the UCSF IRB strongly recommends 
one to ensure the data collected are adequate to meet the research aims:
14.0
 
Data and Safety Monitoring Plan
14.1  
DATA AND SAFETY MONITORING PLAN (DSMP): 
* 
(REQUIRED) Provide a summary of the DSMP:
All greater than minimal risk studies are required to provide a plan. 
Lack of an adequate plan is one of the most common reasons why 
IRB approval is delayed.
 
Instructions:

Describe the plan for monitoring data quality and participant safety. Key 
areas that should be included in the plan are:
An explanation of the plan to monitor data collection, study progress, 
and safety
A description of who will perform the monitoring and at what 
frequency (e.g., the PI only, a contract research organization, a Data 
and Safety Monitoring Board or Data Monitoring Committee, etc.)
The type of data and events that will be reviewed (e.g., adverse 
events, breaches of confidentiality, unanticipated problems involving 
risk to participants or others, unblinded efficacy data, etc.)
Procedures and timeline for communicating monitoring results to the 
UCSF IRB, the study sponsor, and other appropriate entities
As appropriate:
A plan for conducting and reporting interim analysis
Clearly defined stopping rules
Clearly defined rules for withdrawing participants from study 
interventions
This study will use a Data Safety Monitoring Board, which will meet quarterly and will be available 
to have additional ad hoc meetings to review any serious adverse events. This protocol and all 
associated consent forms and questionnaires will be approved and monitored by our University of 
California, San Francisco Committee on Humans Subjects Research (CHR). As such, all adverse 
events that are reported to study staff during classes or study visits will be reported to the UCSF 
CHR. Per the CHR policy, serious adverse events must be reported immediately and all others are 
reported annually.
In the event that a subject experiences a serious adverse event, and does not volunteer to 
withdraw from the study, their case will be reviewed by the PI and/or our DSMB. This review may 
be followed by the recommendation that the subject be withdrawn from the study.
 
Other provisions for subject safety:
During the trial, subjects are seen three times a week. All study staff are trained to report 
adverse events or any concerns about a subject’s wellbeing to the Study Coordinator and 
Principal Investigator. Thus, any untoward event that might occur will be detected almost 
immediately.
To ensure that patients have access to more immediate attention, they are provided with 
a cell phone number for the Study Coordinator, which will give them nearly immediate 
access to assistance over the course of the study.
14.2  
DATA AND SAFETY MONITORING BOARD (DSMB): 
* 
(REQUIRED) Will a Data and Safety Monitoring 
Board (DSMB) be established:
Yes 
No 
14.3  
Provide details about the DSMB, including meeting frequency, and the affiliations 
DSMB DETAILS: 
and qualifications of members:   
If 
Attach the DSMB charter to the Other Study Documents section. 
the DSMB has not yet been established, submit details and the charter to us as soon as they become 
available.
The DSMB has been formed and consists of three medical UCSF/SFVAMC medical professionals: 
Drs. William Wolfe, Ellen Herbst, and Brian Mohlenhoff. Dr. William Wolfe is an Associate 
Professor of Psychiatry at UCSF and the Medical Director of the PTSD program at the SFVAMC. Dr. 
Ellen Herbst is an Associate Professor of Psychiatry at UCSF and a Psychiatrist at the SFVAMC. Dr. 
Brian Mohlenhoff is an Assistant Professor of Psychiatry at UCSF and the Director of 
Pharmacotherapy for the PSTD program at the SFVAMC.
 

The DSMB meets quarterly and is available to have additional ad hoc meetings to review any 
serious adverse events. 
15.0
 Confidentiality, Privacy, and Data Security
15.1  
Indicate how subject privacy will be protected:
PROTECTING PRIVACY: 
Conduct conversations about the research in a private room
Ask the subject how they wish to be communicated with – what phone numbers can be 
called, can messages be left, can they receive mail about the study at home, etc.
Take special measures to ensure that data collected about sensitive issues do not get added 
to their medical records or shared with others without the subject’s permission
Other methods (describe below)
15.2  
Do any of the instruments ask about illegal or stigmatized behavior:
SENSITIVE DATA: 
 Yes  
 No
IMPORTANT NOTE: Indicate in the consent form what kinds of 
sensitive information will be collected.
15.3  
Could a breach of 
SIGNIFICANT CONSEQUENCES OF A LOSS OF PRIVACY OR CONFIDENTIALITY: 
privacy or confidentiality result in any significant consequences to participants, such as criminal or 
civil liability, loss of state or federal benefits, or be damaging to the participant's financial standing, 
employability, or reputation:
  Yes  
  No
15.4  
Explain any extra steps that will be taken to assure 
EXTRA CONFIDENTIALITY MEASURES: 
confidentiality and protect identifiable information from improper use and disclosure, if any:
The study records will be kept as confidential as is possible under the law. Although VA hospital 
personnel will not have access to study materials, a medical record will be created because of 
participation in this study.  The following information will be included in the medical record: 
documentation that the subject has been medically cleared to exercise, the results of the exercise 
treadmill test, and the results of the standard lab tests.  Therefore, other doctors may become 
aware of the individual’s study participation.  Hospital regulations require that all health care 
providers treat information in medical records confidentially.  At the time of consent, subjects will 
be asked to sign forms to authorize the release of their personal health information for research 
purposes. Participants in the PTSD Recovery Classes will have each class scheduled as an 
appointment in their VA medical record (CPRS). A progress note for each class attended will be 
added to the medical record. These are the same procedures that would be followed if the 
veteran was enrolled in any group or class as a VA patient not in a research study.
 
If information from this study is published or presented at scientific meetings, the participant’s 
name and other personal information will not be used.
 
All study information, such as the interviews and questionnaires, will be coded with a code 
number unique to the study. Only study personnel, with the permission of the principal 
investigator, will have access to the key with the name and ID codes.
 
Audio recordings – Clinical Interview: The audio recordings may make a participant somewhat 
more uncomfortable than he or she would be without the taping. The recordings will be labeled 
with a unique code number and will be used only by research personnel in order to calibrate the 
clinicians’ ratings on the standardized interview format.  The audio recordings will be retained in a 
secure location (the digital recordings will be encrypted and passcode protected and stored and 
accessed via the secure VA server).  Subjects will be informed that their screening clinical 
interviews will be audio recorded for the purpose of allowing the research team to ensure 

consistency across all clinical interviews. They will be informed that the recordings will be 
maintained under secure conditions at all times and identified only by the unique Subject ID 
number.
 
Organizations that may look at and/or copy subjects' medical records for research, quality 
assurance, and data analysis include the UCSF IRB (a group of people who review research to 
protect participants’ rights) and the Department of Veterans Affairs Regulatory Personnel (the 
group which protects research participants’ rights at the VA).
 
Additionally, recruiters will access a pool of shared participants utilizing a password-protected 
database at the SFVA.   Individuals in this database have been asked brief screening questions 
from a Program Wide Prescreen, which is described in depth in approved Protocol 12-09158, or 
from a specific study. Recruiters will contact individuals from this database who can decide if they 
want to answer the study specific screen.  Informed consent will be obtained by research staff 
prior to beginning any procedures.
 
To assure confidentiality and protect identifiers from improper use and disclosure, if any, 
screening data will be stored in firewall and password-protected computers within the SFVAMC, 
and only accessed by program staff.  It is not practical to code data at the recruitment stage, as 
personal identifiers are required to contact participants for participation in related CHR-approved 
studies.
15.5  
Do you anticipate that this study may collect information that State or Federal 
 REPORTABILITY: 
*
law requires to be reported to other officials, such as elder abuse, child abuse, or threat to self or 
others: (REQUIRED)
 Yes  
 No
The confidentiality and privacy section of the consent form should 
include this as a possible risk of participation. 
 
Describe the types of reportable information the research team may 
* 
encounter and provide the details of the reporting plan: (REQUIRED)
Exceptions to the protection of a participant’s confidentiality would occur if it were learned 
through the initial interview that the participant was a danger to him/herself or to others, that a 
child had been abused or neglected, or that an elder or dependent had been abused. Should this 
happen, the appropriate authorities would be notified, as required by law.
15.6  
Will this study obtain a Certificate of Confidentiality:
CERTIFICATE OF CONFIDENTIALITY: 
 
  Yes  
  No
15.7  
Will there be any sharing of 
 research test results 
SHARING OF RESEARCH RESULTS: 
EXPERIMENTAL
with subjects or their care providers:
 Yes  
 No
Note: This is unusual and not recommended, particularly in cases 
where the tests are carried out in a non-CLIA certified laboratory, 
the results are of unproven clinical significance, or where there are 
not known preventative strategies and/or treatments. If these are 
the most likely scenarios for your study, you should check 'No.'  
 
If you have an incidental finding of clear clinical significance, call 
the HRPP QIU at 415-476-1814 for a consult. 
Explain under what circumstances research results may be shared:

Results of the blood will not be shared with study participants.The only exception would 
be if the results were abnormal and required clinical follow-up; we will then contact the 
participant and/or primary care physician. This information will be communicated to the 
medical professional only with the permission of the participant, indicated by signing the 
informed consent and HIPAA release.
Any abnormal results will be communicated to the subject's own physician, regardless 
of their veteran status. It will then be the responsibility of the subject's physician to 
interpret the results and follow-up as needed.
Participants enrolled in this study will have the option to take part in 
study #1413833, "Neurobehavioral Correlates of Pain in Post-Traumatic Stress Disorder 
(PTSD)." In order to coordinate scheduling of study visits and sharing of all data across studies, it 
will be necessary to share PHI such as name, date of birth, and social security number. The 
HIPAA authorization for this study will clearly state that by enrolling in this study, the participant 
is agreeing to sharing of all study data between the two studies if the participant chooses to take 
part in study #1413833.
15.9  
Study data will be: 
* HIPAA APPLICABILITY: 
(REQUIRED)
Derived from a medical record (e.g. APeX, OnCore, etc. Identify source below)
Added to the hospital or clinical medical record
Created or collected as part of health care
Used to make health care decisions
Obtained from the subject, including interviews, questionnaires
Obtained ONLY from a foreign country or countries
Obtained ONLY from records open to the public
Obtained from existing research records
None of the above
Derived from the Integrated Data Repository (IDR) or The Health Record Data Service 
(THREDS) at SFGH
In addition to signing a consent form, each subject will have to sign 
 
the UCSF Research Subject Authorization Form (HIPAA Form). 
Upload the HIPAA Authorization Form in the Other Study 
Documents section of the Initial Review Submission Packet Form. 
Failure to have patients sign the HIPAA Authorization is one of the 
 Please call 
most common findings from QIU Routine Site Visits.
the IRB office at 415-476-1814 if you have questions about HIPAA 
research requirements.  
If derived from a medical record, identify source:
CPRS
15.10  
Check all identifiers that will be collected and included in the research records, 
IDENTIFIERS: 
* 
even temporarily: (REQUIRED)
Names
Dates
Postal addresses (if only requesting/receiving zip codes check Yes to the Zip Code question 
below instead of checking this box)
Phone numbers
Fax numbers
Email addresses
Social Security Numbers*

Medical record numbers
Health plan numbers
Account numbers
License or certificate numbers
Vehicle ID numbers
Device identifiers or serial numbers
Web URLs
IP address numbers
Biometric identifiers
Facial photos or other identifiable images
Any other unique identifier
None
* Required for studies conducted at the VAMC
Could study records include 
 photos or images (even 'unidentifiable' 
* 
ANY
ones): (REQUIRED)
  Yes  
  No
* Please provide a justification for including the Social Security Number 
(SSN) in your data set. Best practices dictate that you store the SSN 
separately from the full data set in a password protected file. (REQUIRED)
SSN is required for processing study payment. It will be stored with the study consent and other 
documents containing PHI. It will not be stored with any coded data. 
15.12  
 
Will health information or other clinical data be accessed from UCSF Health, 
* PATIENT RECORDS: 
Benioff Children's Hospital Oakland, or Zuckerberg San Francisco General (ZSFG): (REQUIRED)
  Yes  
  No
15.15  
Does the research require access to any of 
HIPAA - PERMISSION TO ACCESS SENSITIVE DATA: 
* 
the following types of health information from the medical record: (check all that apply) 
(REQUIRED)
Drug or alcohol abuse, diagnosis or treatment
HIV/AIDS testing information
Genetic testing information
Mental health diagnosis or treatment
None of the above
Important note: Ensure that participants initial the corresponding 
line(s) in Section C of the HIPAA authorization form during the 
consent process.
15.19  
(check all that apply): 
* DATA COLLECTION AND STORAGE: 
(REQUIRED)
Collection methods:
Electronic case report form systems (eCRFs), such as OnCore or sponsor-provided clinical trial 
management portal
UCSF ITS approved Web-based online survey tools: Qualtrics or RedCap
Other web-based online surveys or computer-assisted interview tool
Mobile applications (mobile or tablet-based)
Text Messaging

Wearable devices
Audio/video recordings
Photographs
Paper-based (surveys, logs, diaries, etc.)
Other:
What online survey or computer assisted interview tool will you use: 
* 
(REQUIRED)
Qualtrics (Recommended)
RedCAP (Recommended)
Survey Monkey (NOT recommended and may require UCSF ITS Security review)
Other
What's the name of the survey tool and who is it owned by
* 
: (REQUIRED)
Millisecond Inquisit Web for remote neurocognitive testing
If the survey tool is not provided by the study sponsor, and the 
, 
survey tool stores data on a server, vendor, cloud, or 3rd party
contact 
 to determine if you need to complete 
datasecurity@ucsf.edu
a security assessment.
Data will be collected/stored in systems owned by (check all that apply): 
* 
(REQUIRED)
Study sponsor
UCSF data center (including OnCore, RedCap, Qualtrics, and MyResearch)
UCSF encrypted server, workstation, or laptop residing outside of UCSF data center
Personal devices, such as laptops or tablets that are not owned or managed by UCSF
SF VAMC
Zuckerberg San Francisco General Hospital
Benioff Children's Hospital Oakland
Langley Porter Psychiatric Institution
Other UCSF affiliate clinic or location (specify below)
Cloud vendor such as Amazon Web Services (AWS), Salesforce, etc. (specify below)
Other academic institution
3rd party vendor (business entity)
Other (explain below)
Please consult with the VA's Clinical Research Office at 415-221-
4810 x 2-6425 about the VA's requirements for data storage and 
security.
Provide more details about where study data will be stored: 
* 
(REQUIRED)
Neurocognitive data collected using Millisecond Inquisit Web will upload to our Millisecond 
account, where we can login to access and download data. Millisecond Inquisit will save data in a 
highly reliable redundant store with copies maintained on multiple servers in different facilities. 
Please see below for Millisecond's Security Statement, found here: https://www.millisecond.
com/products/securitystatement.aspx
 
"Millisecond is dedicated to protecting all customer data using industry best standards. This 
Security Statement is intended to provide a transparent look at our security infrastructure and 
practices to help assure that your data are sufficiently protected.
Millisecond’s highest priority is the protection and reliability of customer data. Our servers are 
protected by high-end firewall systems, and scans are performed regularly to ensure that any 

vulnerabilities are quickly found and patched. All services have quick failover points and 
redundant hardware, with complete backups performed nightly. Data are stored redundantly 
across data centers for resiliency and availability during disasters.
Millisecond provides each customer a unique username and enforces strong passwords that must 
be entered each time a customer logs on. The user remains authenticated only for the duration of 
the session and is automatically logged off after 30 minutes of inactivity. This system ensures 
that customer data can only be accessed by authenticated and authorized users. Millisecond uses 
AWS Cognito to manage authentication and does not store user passwords locally. For additional 
account security, Millisecond customers can enable multi-factor authentication with a one-time 
password sent via SMS.
Customer data are processed and stored in world-class data center facilities in Oregon, USA and 
Ireland, EU. Data are not moved around to other locations. The data centers are housed in 
nondescript facilities. Physical access is strictly controlled both at the perimeter and at building 
ingress points by professional security staff utilizing video surveillance, intrusion detection 
systems, and other electronic means. Authorized staff must pass two-factor authentication a 
minimum of two times to access data center floors. All visitors and contractors are required to 
present identification and are signed in and continually escorted by authorized staff.
Facilities are equipped with fire detection and suppression equipment, multiple backup power 
systems, and climate and temperature control. Servers are decommissioned and disposed using 
processes that prevent unauthorized access to data.
The servers reside behind high-availability firewalls and are monitored using state of the art 
systems for detection and prevention of various threats including denial of service, man in the 
middle, IP spoofing, port scanning, and packet sniffing. Automated network security audits using 
the industry standard SSAE-16 method are conducted to the standards and requirements of the 
SANS/FBI security test, the U.S. Department of Homeland Security's published recommendations 
and the Payment Card Industry Data Security Standard.
Millisecond encrypts all data in transit by enforcing the latest versions of Transport Layer Security 
(TLS) encryption (also known as HTTPS). Millisecond encrypts all data at rest using the industry 
standard AES-256 cypher.
Millisecond deploys the general requirements set forth by many Federal Acts, including the FISMA 
Act of 2002. We meet or exceed the minimum requirements as outlined in FIPS Publication 200. 
We also comply with FERPA for protecting student privacy.
Since our subscribers control their users and their data, it is important for the users to practice 
sound security practices by using strong account passwords and restricting access to their 
accounts to authorized persons. For added protection, Millisecond supports multi-factor 
authentication for logging into user accounts.
Regarding HIPAA, HITECH, and specific data types: Millisecond provides general research 
software and other services where all data are processed equally, without regard to how a 
customer might classify their data. As such, Millisecond cannot declare or represent any data 
entered into its services. Any processing of specific data types are purely incidental, and not 
required to use the services.
HITECH (Health Information Technology for Economic and Clinical Health Act) updated HIPAA 
rules to ensure that data are properly protected and best security practices followed. Millisecond 
safeguards all customer data, and uses secure data centers to ensure the highest protection as 
per HITECH requirements."
 
 
15.21  
During the lifecycle of data collection, transmission, and storage, will identifiable 
DATA SHARING: 
* 
 
information be shared with or be accessible to anyone outside of UCSF: (REQUIRED)
 Yes  
 No
* Who will have access to the data: (REQUIRED)
Collaborators listed in the study application
NIH or other shared data repository
Sponsors

FDA
Other 3rd party (such as vendors/contractors)
IMPORTANT: The IRB now recommends that all consent forms 
include a provision for sharing of de-identified/coded data to permit 
re-use of data for secondary research purposes. This doesn't apply 
if you've been granted a waiver of consent for this study.
Provide the details of whom the data will be shared with and what types 
* 
of information and identifiers will be shared: (REQUIRED)
The YMCA will receive the names and contact information of all individuals who receive a 6-month 
YMCA membership as a result of their study completion.  No other study data or individual health 
information will be shared with the YMCA. Participants will consent to this release of their name 
via the consent form and HIPAA authorization.
 
Participants enrolled in this study will have the option to take part in 
study #1413833, "Neurobehavioral Correlates of Pain in Post-Traumatic Stress Disorder 
(PTSD)." In order to coordinate scheduling of study visits and sharing of all data across studies, it 
will be necessary to share PHI such as name, date of birth, and social security number. The 
HIPAA authorization for this study will clearly state that by enrolling in this study, the participant 
is agreeing to sharing of all study data between the two studies if the participant chooses to take 
part in study #1413833.
15.22  
 
: How will data be securely shared with the 3rd party: 
* DATA SHARING METHODS
(REQUIRED)
Collaborators will access data in MyResearch
Collaborators will access data in REDCap
Collaborators will be sponsored as an affiliate and be treated as an UCSF user (includes using 
UCSF Box)
UCSF Secure Email will be used to share data
Collaborator’s or Sponsor’s system will be used (specify below)
Other method (describe below)
Please provide details about how the data will be shared:
The YMCA will receive the names and contact information of all individuals who receive a 6-month 
YMCA membership as a result of their study completion.  No other study data or individual health 
information will be shared with the YMCA. Participants will consent to this release of their name 
via the consent form and HIPAA authorization.
16.0
 Financial Considerations
16.1  
Will subjects be paid for participation, reimbursed for time or expenses, or receive any 
* PAYMENT: 
other kind of compensation: (REQUIRED)
 Yes  
 No
16.2  
Subjects payment or compensation method (check all that apply):
PAYMENT METHODS: 
Payments will be (check all that apply):
Cash
Check
Gift card
Debit card
UCSF Research Subject Payment Card
Reimbursement for parking and other expenses

Other:
Specify 
 payment/compensation method:
other
Direct deposit.
16.3  
Describe the schedule and amounts of payments, including the total subjects 
PAYMENT SCHEDULE: 
can receive for completing the study:
If there are multiple visits over time, explain how payments will be prorated for partial 
completion
If deviating from recommendations in Subject Payment Guidelines, include specific 
justification below
In return for their time and effort, subjects will be compensated for taking part in this study 
according to the schedules described below:
 
Total possible compensation (in addition to receiving free IMR/PTSD Recovery Classes and/or 
Integrative Exercise):
Fully Remote Only: Up to $310, plus 6-month YMCA membership
Fully Remote with Optional In-Person Assessments: Up to $400, plus free breakfast 
post-FMD procedures, and 6-month YMCA membership
 
Screening/Eligibility Assessments:
Clinician Administered Diagnostic Interview & Questionnaires = $55
Pre-treatment Assessments:
Medical Screen/Clearance = $15
Self-Report Questionnaires & Neurocognitive testing = $25
4 week Self-Report Questionnaires = $25
 
8 week Self-Report Questionnaires = $25
 
Post 12-week Assessments:
Clinician Administered Diagnostic Interview & Questionnaires = $25
Self-Report Questionnaires & Neurocognitive Testing = $25
** A 6-month free YMCA gym membership will be provided 
 (at the completion of all 
after the trial
Post 12-week Assessments) as an additional completion bonus for completing all assessments, 
questionnaires, and study procedures, and to promote exercise continuity/commitment to healthy 
living. If there is no YMCA available within 25 miles of participants homes, we will either send 
them additional payment, equivalent to the cost of a YMCA membership, so that they may choose 
a fitness facility nearby or use the funds to purchase the participant additional at-home exercise 
equipment or online fitness classes. Because of limitations imposed by the COVID-19 pandemic (e.
g., YMCA closures), we may provide direct deposit payments for the amount of a 6-month YMCA 
membership to eligible Veterans.
 
6 Month Follow-Up Assessments:
Clinician Administered Diagnostic Interview & Questionnaires/Neurocognitive Tests = $55
Completion Bonus = $60
Optional in-person pre- and post-treatment assessments:
Pre-treatment blood draw = $15
Pre-treatment FMD = $30 (in addition to free breakfast on the day of your appointment)
Post-treatment blood draw = $15
Post-treatment FMD = $30 (in addition to free breakfast on the day of your appointment
16.4  
Will subjects or their insurance be charged for any study activities:
COSTS TO SUBJECTS: 
  Yes  
  No

17.0
 Other Approvals and Registrations
17.4  
Indicate if this study involves other regulated materials and requires approval 
OTHER APPROVALS: 
and/or authorization from the following regulatory committees:
Institutional Biological Safety Committee (IBC)
Specify BUA #:
NEYT-16-1
Institutional Animal Care and Use Committee (IACUC)
Specify IACUC #:
Controlled Substances
18.0
 Qualifications of Key Study Personnel and Affiliated 
Personnel
 
NEW: January 2019 - Affiliated personnel who do not 
need access to iRIS no longer need to get a UCSF ID. 
Instead, add them below in the Affiliated Personnel 
table below. 
18.1  
 
Qualifications of Key Study Personnel:
Instructions:
 
For UCSF Key Study Personnel (KSP)* listed in 
 select the KSP 
Section 3.0,
from the drop down list and add a description of their study responsibilities, 
qualifications and training. In study responsibilities, identify every individual 
who will be involved in the consent process. Under qualifications, please 
include:
Academic Title
Institutional Affiliation (UCSF, SFGH, VAMC, etc.)
Department
Certifications
NOTE: This information is required and your application will be 
 
considered incomplete without it. If this study involves invasive or 
risky procedures, or procedures requiring special training or 
certification, please identify who will be conducting these 
procedures and provide details about their qualifications and 
training. Click the orange question mark for more information and 
examples. 
 
Training Requirements: 

The IRB requires that all Key Study Personnel complete Human Subjects 
Protection Training through 
 prior to approval of a new study, or a 
CITI
modification in which KSP are being added. More information on the CITI 
training requirement can be found on our 
. 
website  
 
* Definition of Key Study Personnel and CITI Training Requirements (Nov, 
 UCSF Key Study Personnel include the Principal Investigator, other investigators 
2015):
and research personnel who are directly involved in conducting research with study 
participants or who are directly involved in using study participants’ identifiable private 
information during the course of the research. Key Personnel also include faculty mentors
/advisors who provide direct oversight to Postdoctoral Fellows, Residents and Clinical 
Fellows serving as PI on the IRB application.
 
KSP Name
Description of Study 
Responsibilities - Briefly 
describe what will each 
person be doing on the study. 
If there are procedures 
requiring special expertise or 
certification, identify who will 
be carrying these out. Also 
identify who will be obtaining 
informed consent.
Qualifications, Licensure, and 
Training
Dr. Neylan, Thomas MD
Dr. Neylan will be the 
Principal Investigator for 
this study. He will 
assume overall scientific 
and administrative 
leadership for the study. 
He will be responsible for 
supervising the study 
team with regards to the 
recruitment,diagnostic 
assessment, and 
enrollment of subjects 
and the coordination of 
all study 
procedures. 
Dr. Neylan will have 
overall responsibility for 
the standardization of 
data collection, 
data quality control, data 
analysis, and 
interpretation. He will 
have overall 
responsibility for subject 
safety, rights, and 
welfare. He will be an 
active participant in the 
preparation of abstracts 
and manuscripts and will 
assure the dissemination 
of study findings in the 
professional and scientific 
communities.
Thomas Neylan, M.D. has 
a joint appointment at 
UCSF and the SFVAMC. 
He is a Professor of 
Psychiatry at UCSF and 
Director of the Stress 
and Health Research 
Program. 
Dr. Neylan has been 
active in the field of sleep 
and PTSD research for 
the past 15 years. During 
that time, he has been 
the Principal Investigator 
or Co-Principal 
Investigator for CHR 
protocols in 
psychopharmacology, 
psychobiology, and 
treatment of PTSD.
Chesney, Margaret A, PhD
As Co-Investigator, Dr. 
Chesney will provide 
senior level guidance, 
particularly regarding 
aspects of the project 
Dr. Chesney is Professor 
of Medicine and former 
Director of the Osher 
Center for Integrative 
Medicine. She was the 
interim director of the 
National Institute for 

related to integrative 
medicine.
Complementary and 
Integrative Medicine at 
the NIH and involved in 
its research.
Cohen, Beth, MD, MA
Co-Investigator
Dr. Cohen is an Assistant 
Professor in the 
Department of Medicine 
at UCSF and physician at 
the SF VA Medical Center
Hlavin, Jennifer
Ms. Hlavin is the Lab 
Manager of the Stress 
and Health Research 
Program. She will be 
supervising the 
coordination of the study.
Jennifer Hlavin, MS in 
Counseling, has 10 years 
of clinical research 
experience at the San 
Francisco VA Medical 
Center. She has been a 
Study Coordinator and 
Lab Manager for the past 
8 years, working with 
diverse groups of 
Veteran and non-Veteran 
research participants.
Dr. Mehling, Wolf MD, MD
As Co-Investigator, Dr. 
Mehling will work with 
Dr. Neylan in the 
development and 
implementation of the 
study, particularly 
regarding aspects of the 
study related to 
integrative medicine.
Dr. Mehling is an Assoc. 
Prof. of Clinical Family 
and Community Medicine 
and on faculty at the 
Osher Center for 
Integrative Medicine. His 
research focuses on body-
oriented complementary 
therapies and mind-body 
interactions.
Metzler, Thomas J
Thomas Metzler, M.S., 
will be the Biostatistician 
for the study. He will be 
responsible for the 
overall quality and 
fidelity of the study data 
collected. After the 
conclusion of the study, 
he will conduct the 
statistical analyses on all 
data gathered and he will 
have an extensive role in 
the preparation of 
manuscripts, slides, and 
poster presentations of 
the data derived in the 
study.
Mr. Metzler has served as 
the primary 
biostatistician for the 
PTSD Research Program 
at the SFVAMC for the 
past 12 years and has 
conducted and analyzed 
psychophysiological 
assessments on multiple 
funded studies. 
Mayzel, Olga
Data Manager
Olga Mayzel has 
extensive experience 
performing data 
management at VA, 
database design, and 
application development 
for several large-scale 
studies. Ms. Mayzel will 
be responsible for 
database development 
and management.

Goldstein, Lizabeth
Research Fellow
Lizabeth Goldstein is a 
MIRECC Fellow at the 
SFVAMC and will be 
involved in data analysis 
and dissemination of 
results.
Boyd, Jennifer E
As Co-Investigator, Dr. 
Boyd will oversee the 
Illness Management and 
Recovery Classes. She 
will supervise the Peer 
Specialist, a Recreation 
Therapist and psychology 
doctoral students who 
will co-facilitate the IMR 
classes.
Dr. Boyd is the Associate 
Chief for Psychosocial 
Recovery Services, and 
oversees the 
Psychosocial 
Rehabilitation and 
Recovery Center (PRRC), 
the Recreation Therapy 
program, and the Peer 
Specialist program. The 
PRRC will provide 
research participants and 
will host the IMR classes.
Shumaker, Erik
Will consult with the 
Investigator and the 
Research Psychologist on 
clinical assessment of 
PTSD.
Dr. Shumaker is a 
Clinical Psychologist at 
the San Francisco VA 
Medical Center.
Bertenthal, Daniel S
Will serve as consulting 
data manager and 
biostatistician.
Dan Bertenthal received 
his B.A. in Sociology of 
Culture and B.S. in 
Microbiology from the 
University of California, 
San Diego. He continued 
at the University of 
California, Berkeley 
School of Public Health, 
where he developed 
quantitative skills while 
completing an MPH in 
Epidemiology & 
Biostatistics. He has 
worked with health 
services researchers at 
the San Francisco VA 
Medical Center since 
2001.
Cheng, David
Technician, Flow 
Mediated Dilation 
Measures
David Cheng currently 
works in the CRC located 
at the San Francisco VA. 
He has extensive 
experience obtaining 
various types of vascular 
measurements from 
patients.
Victor Antonetti will serve 
as a group exercise 
instructor for this study. 
Victor has over 17 years 
experience as a personal 
trainer/group fitness 

Antonetti, Victor
Senior Exercise Instructor
instructor. In addition, he 
is a NASM Certified 
Personal Trainer, a NASM 
Corrective Exercise 
Specialist, and a Certified 
Yoga instructor.
Williams, Chanda
Exercise Instructor
Chanda Williams will 
serve as a group exercise 
instructor for this study.
Gasper, Warren J
Other Investigator
Dr. Warren Gasper is 
Assistant Professor of 
Clinical Surgery, Division 
of Vascular and 
Endovascular Surgery at 
UCSF. He is Acting Chief 
of Vascular Surgery at 
the San Francisco VA 
Medical Center, and is 
the Director of the 
Vascular Integrated 
Physiology and 
Experimental 
Therapeutics (ViperX) 
Lab at the SFVAMC.
Phan, Jordan Dominique
Study Recruiter
Richards, Anne
Other Investigator
Dr. Richards is Associate 
Clinical Professor at the 
University of California, 
San Francisco and Staff 
Psychiatrist at the San 
Francisco VA Medical 
Center. Expertise in the 
treatment of PTSD and 
sleep disorders gained 
through years of 
experience treating male 
and female veterans with 
PTSD with medication 
and psychotherapy. In 
2015, transitioned from a 
predominantly clinical 
role at the SFVAMC/UCSF 
to a VA research Career 
Development Award 
focused on 
understanding how sleep 
disturbance contributes 
to the consolidation and 
maintenance of PTSD in 
male and female 
veterans.
Garcia Guerra, Sergio R
Study Coordinator
VA/UCSF personnel with 
experience conducting 
clinical studies of PTSD
/TBI.
UCSF/VA personnel. 

Dr. Strigo, Irina PhD, PhD
Other Investigator
Research Physiologist at 
the SFVAMC and 
Associate Professor of 
Psychiatry at UCSF, is an 
expert in conduction 
human pain research in
veteran and non-veteran 
populations.
Palyo, Sarah A
Other Investigator
VA personnel. Clinical 
Director of the Intensive 
Pain Rehabilitation 
Program.
Muratore, Laura
Study Coordinator
Laura Ann Muratore 
holds a bachelors degree 
in Psychology and a 
minor in Applied 
Psychology from UC 
Santa Barbara and is on 
track to complete her 
Master’s degree in 
Research and 
Experimental Psychology 
from San Jose State 
University (expected 
December 2019). She 
has four years of 
experience in human 
subjects research and 
has completed CITI 
trainings for human 
subjects research.
West, Anna
Dr. West will be 
responsible for the 
oversight of the 
diagnostic psychological 
and neurocognitive 
assessments that will be 
administered to subjects 
throughout the study. 
She will provide clinical 
supervision for the 
mental health clinicians 
who will be administering 
the diagnostic 
psychological and 
neuropsychological 
assessments.
Anna West, Ph.D. 
graduated from California 
School of Professional 
Psychology and has been 
a licensed Marriage and 
Family Therapist since 
2004. Prior to starting 
her PhD, Anna 
successfully operated her 
own private practice. She 
completed her pre-
doctoral residency at APA 
accredited California 
Pacific Medical Center, 
working with an inpatient 
population. Her post-
doctoral residency was at 
APA accredited Kaiser 
Permanente, San Rafael. 
Anna’s clinical interests 
include providing 
evidenced-based 
treatments for psychosis, 
serious mental illness, 
and trauma.
Emily Stenson has a BA 
in psychology from CSU
Chico, and is currently 
enrolled in a masters
program in research and 

Stenson, Emily P
Study Coordinator
experimental psychology 
at San Jose State 
University. She is a 
current study coordinator 
at NCIRE.
Dr. O'Donovan, Aoife PhD, 
PhD
Other Investigator
Dr. Aoife O'Donovan is 
an Associate Professor in 
the department of 
Psychiatry & Weill 
Institute for 
Neurosciences and 
THRIVE Lab Director.
18.2  Affiliated Personnel:
Instructions:
 
This section is for personnel who are not listed in Section 3.0: Grant Key 
 because their names were not found in 
Personnel Access to the Study
the User Directory when 
 the iRIS Database and MyAccess directories 
both
were searched. Add any study personnel who fit 
 of the following criteria 
ALL
in the table below:
They meet the definition of Key Study Personnel (see above), and
They are associated with a UCSF-affiliated institution (e.g., VAMC, 
Gladstone, Institute on Aging, Vitalant, NCIRE, SFDPH, or ZSFG), and
They do 
 have a UCSF ID, 
not
and
They do 
 need access to the study application and other study 
not
materials in iRIS.
 in the 
Note: Attach a CITI Certificate for all persons listed below
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 after completing the 
.
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who to include and who not to include in this section.
 
Do 
 list personnel from outside sites/non-UCSF-affiliated institutions. 
not
Contacts for those sites (i.e. other institution, community-based site, 
foreign country, or Sovereign Native American nation) should be listed in 
the 
 section of the application.
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If there are no personnel on your study that meet the above 
criteria, leave this section blank.
 
Name
Institution
Telephone
E-mail
Role
Induni 
Wickramasinghe 
VA 
415-221-
4810 x26624  
iwickramasinghe@paloaltou.
edu
Project Staff
Adriana Costa 
San Francisco 
VA Medical 
Center 
415-221-
4810 x26624  
acosta@wi.edu
Project Staff
Nomi Kosman-
Wiener 
San Francisco 
VA Medical 
Center 
415-221-
4810 x26624  
nkosman-wiener@wi.edu
Project Staff

Erika Roach 
San Francisco 
VA Medical 
Center 
415-221-
4810 x26624  
erika.ro@berkeley.edu
Project Staff
Elizabeth Roskey 
San Francisco 
VA Medical 
Center 
415-221-
4810 x26624  
eroskey@wi.edu
Project Staff
Lexie Thomas 
San Francisco 
VA Medical 
Center 
415-221-
4810 x26624  
lthomas@wi.edu
Project Staff
Parker Kelley 
University of 
California San 
Francisco 
415 221 4810 
x24959 
parker.kelley@ucsf.edu
Clinical 
Research 
Associate
Please describe the study responsibilities and qualifications of each affiliated 
person listed above:
Dr. Parker Kelley is a data science postdoctoral fellow in PTSD in the Department of Psychiatry 
& Weill Institute for Neurosciences (UC San Francisco). Dr. Kelley will be assisting with data 
analysis. 
Adriana Costa will be administering the diagnostic psychological assessments. She is a fifth-year 
graduate student working towards her Doctorate in Clinical Psychology at the Wright Institute. 
Adriana has trained as a school-based therapist and community mental health counselor in the 
Bay Area. She has also supported incarcerated youth and their families in San Mateo County.
Email: acosta@wi.edu
Naomi Kosman-Wiener will be administering the diagnostic psychological assessments. She is a 
third-year graduate student working towards her Doctorate in Clinical Psychology at the Wright 
Institute. She has worked as a psychology trainee at school settings and community mental 
health clinics in San Francisco and the East Bay and is currently working at a community college 
in the East Bay. Prior to graduate school, Naomi worked as a counselor at a residential program 
in San Francisco for teenagers.
Email: nkosman-wiener@wi.edu
Erika Roach will be administering the diagnostic psychological assessments. She is a second-
year doctoral student in Clinical Science at UC Berkeley and a trainee in the UC Berkeley 
Psychology Clinic. Her research interests include stress, emotion regulation, and developmental 
psychopathology. She received her B.A. in Psychology and Human Biology and her M.A. in 
Psychology from Stanford University.
Email: erika.ro@berkeley.edu
Elizabeth Roskey will be administering the diagnostic psychological assessments. She is a third-
year graduate student working towards her Doctorate in Clinical Psychology at the Wright 
Institute.  She was worked as a therapist at several community mental health clinics in the Bay 
area with specific focus on serving Spanish speakers and individuals with substance use disorders.
Email: eroskey@wi.edu
Lexie Thomas will be administering the diagnostic psychological assessments. She is third-year 
graduate student working towards her Doctorate in Clinical Psychology at the Wright 
Institute.  She has clinical experience treating various populations that faced challenges related to 
complex trauma, the criminal justice system, severe mental illness/serious emotional disturbance, 
and chemical dependency. Currently she works in psychiatric emergency services where she 
performs assessments, brief therapy interventions, and individualize treatment planning to a 
diverse population of patients in acute crises.

Email: lthomas@wi.edu
Induni Wickramasinghe will be administering the diagnostic psychological assessments. She 
received her Master of Science in Psychology from Palo Alto University in 2021 and is currently 
working towards her doctorate. She has trained at the Palto Alto VA Telemental Health Clinic and 
with the San Francisco VA PTSD Clinical Team.
Email: iwickramasinghe@paloaltou.edu
19.0
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survey

 
RESEARCH PLAN 
 
Background and Significance:  
Given that aerobic exercise has been found to improve brain health and neurogenesis10, cognitive function11, 
mood12, sleep13, and cardiovascular health14, there is a strong rationale to determine if exercise may be an 
effective rehabilitative intervention for Veterans with combat related PTSD. Our group has also demonstrated 
that individuals with PTSD have lower rates of exercise compared to others without PTSD of the same age and 
sex15, suggesting they may particularly benefit from a focus on exercise. Despite the high acceptance of 
exercise therapy for PTSD found in one study16, and the considerable advantage of a treatment lacking stigma, 
to date there are no reported controlled trials for exercise in any population with PTSD.  
 
Summary of Relevant Clinical Trials: At present, there is limited published data on the effects of exercise in 
Veterans with PTSD. There have been several pilot studies published suggesting that exercise reduces PTSD 
and associated mood and anxiety symptoms in children17, adolescents18, and civilian adults19, 20. These studies 
have been limited by lack of control conditions and small sample sizes. Nevertheless, the pilot work does 
indicate acceptability, feasibility, and promise of efficacy. 
 
Exercise for Depression and Anxiety: Multiple controlled trials have demonstrated that exercise is effective 
for the treatment of depression both as an augmentation or stand-alone intervention21. The American 
Psychiatric Association has endorsed exercise as a primary treatment for major depression. A recent 
Cochrane review of exercise for depression showed that exercise had comparable efficacy to first line 
antidepressant treatment22. Similarly, meta-analyses of controlled trials of exercise for anxiety have shown that 
active treatment has potent effects in reducing symptoms in both clinical and non-clinical samples 23. Although 
the mechanism underlying these results remains uncertain, it has been suggested that improvements in self-
efficacy or mastery may be responsible for mood changes, or that long-term psychological benefits accrue 
from the blunting of psychological responses to stress following individual bouts of exercise, and that these 
effects accumulate over time independently of fitness changes24. A recent Cochrane review of exercise for 
anxiety and depression in children and young adults concluded that it makes little difference whether the 
exercises were of high or low intensity25.  
 
Exercise and Sleep: Exercise is endorsed by the American Sleep Disorders Association. Driver and Taylor 
published a narrative review of exercise and sleep studies and concluded from self-report studies that 
moderate and regular physical activity has therapeutic and sleep promoting benefits26. The most beneficial 
effect seems to come from improved fitness with aerobic endurance training and acute exercise that lasts for 
more than an hour, whereas exhaustive exercise of high-intensity and long duration is disruptive to sleep, 
decreasing REM sleep and increasing wakefulness. The authors reported that exercise increased slow-wave 
sleep, reduced REM sleep and delayed REM latency in already fit subjects. In clinical populations, self-report 
data indicates that regular exercise is a useful modality in treating disorders of initiating and maintaining sleep, 
as well as complaints of poor sleep quality26. 
 
Sleep: A Common Element in PTSD, psychomotor functioning, and brain health: Sleep disturbances are 
highly prevalent in PTSD: As many as 90% of people with PTSD report nightmares and insomnia, and even 
when nightmares are excluded, sleep disturbance is the most frequently reported symptom of PTSD27. The 
National Comorbidity Survey estimates that the lifetime prevalence of PTSD in the United States population is 
7.8%28. Overall, insomnia is sufficiently frequent, and experienced by PTSD patients as sufficiently severe to 
warrant medical intervention- so much so that over 50% of PTSD patients on psychopharmacologic 
medications are prescribed trazodone or sedative hypnotics29. Further, residual sleep disturbance is highly 
prevalent in PTSD patients who have received PTSD specific treatment30. 
 
PTSD and Cardiovascular Health: Patients with PTSD are at increased risk of developing cardiovascular 
disease (CVD), leading to decreased quality of life, impaired function, and early mortality31-36. Traditional CVD 
risk factors, including smoking, hypertension, diabetes, dyslipidemia, and obesity do not explain the increased 
risk, suggesting treatment of these will not be sufficient to prevent PTSD-associated CVD34, 37. Several studies 
have now established the association between PTSD and CVD using objective cardiovascular testing. A study 
of Vietnam-era Veteran twin pairs found patients with PTSD had increased incidence of CVD events and 
decreased myocardial perfusion on cardiac Positron Emission Tomography scans37. Patients with PTSD also 
have higher levels of coronary artery calcium, a marker of atherosclerosis38. Dr. Beth Cohen, an internist and 
Co-Investigator on this proposal has demonstrated an association of PTSD with CVD using functional exercise 

 
treadmill testing and stress echocardiography39. Given the convincing evidence that exercise has strong effects 
in protecting against the development of CVD (reviewed in40), the results from this trial have broad implications 
for the health and well-being of returning warfighters. 
 
The Stress and Health Program is broadly focused on understanding the relationship between stress and 
physical health and developing and testing novel treatments to improve the health of Veterans impacted by 
combat trauma. Dr. Cohen leads a research program focused on the association of PTSD to Cardiovascular 
Disease (CVD). Dr. Christopher Owens, a vascular surgeon and Co-Investigator, is focused on mechanisms 
and treatment of peripheral vascular disease. We propose to measure both exercise capacity on treadmill 
testing and endothelial function in our subjects pre- and post-treatment to test: a) if improved exercise capacity 
predicts and is necessary for treatment response; and b) if endothelial function, a potent risk factor for 
cardiovascular disease and understudied in PTSD, is modifiable by exercise in a Veteran population with 
PTSD. Dysfunction of the endothelium and blood vessels cause increased thrombosis and impairments in 
blood flow that underlie atherosclerotic plaque formation and accelerated progression of CVD41. Several non-
invasive physiologic measurements of vascular function are available, and these measures predict risk of 
future CVD events42, 43. Brachial artery flow mediated vasodilation (FMD) is the most widely accepted measure 
of endothelial function. Flow is occluded with a blood pressure cuff, and upon deflation of the cuff, in healthy 
endothelium, nitric oxide will be released in response to the increased blood flow and cause vasodilation. FMD 
is impaired early in the development of atherosclerosis, and lower FMD has predicted incident CVD events in 
several large cohort studies42, 44.  
 
Why Integrative Exercise? Aerobic exercises are a part of daily life of all military personnel during their 
service time. Exercise is familiar to Veterans and attractive to younger Veterans as a self-image boosting and 
mood stabilizing physical practice. In the past decade, while physical activity and aerobic exercise are still 
emphasized, mindfulness based practices have increasingly been adopted in military settings45 and controlled 
trials of Mindfulness-Based Stress Reduction (MBSR) are currently underway with support from both DoD and 
VA. While a recently published controlled pilot study of MBSR in Veterans with PTSD found no reliable effects 
of MBSR on PTSD or depression on intention-to-treat analyses, completer analyses (>/= 4 classes attended) 
showed medium to large between-group effect sizes for the effect of MBSR on decreasing depression and 
increasing mental health-related quality of life46. Further, more Veterans randomized to MBSR had clinically 
meaningful reductions in PTSD symptoms at 4 month follow-up compared to treatment as usual46. The 
investigators in this important pilot study raised the question as to whether the mindfulness should be modified 
or tailored for Veterans, particularly with a focus on staying present with a non-judging attitude46. Another 
recently published VA-study compared MBSR to present-centered group therapy (N = 116)47.  At 2-month 
follow-up participants in the MBSR group had improved PTSD Checklist mean scores (range, 17-85; reduction 
of ≥10 considered minimal clinically important difference) from 63.6 to 54.4 vs 58.8 to 56.0 in the active control 
group, respectively (P < .001). Although participants in the mindfulness-based stress reduction group were 
more likely to show clinically significant improvement in self-reported PTSD symptom severity (48.9% vs 28.1% 
with control; (difference, 20.9%; 95% CI, 2.2%-39.5%; P = .03), they were no more likely to have loss of PTSD 
diagnosis (53.3% vs 47.3%, respectively. The authors concluded that MBSR, compared with present-centered 
group therapy, resulted in a greater decrease in PTSD symptom severity. However, the magnitude of the 
average improvement suggests a modest effect. A systematic review published at the same time examined the 
effectiveness of psychotherapies for PTSD in military and veteran populations and included 5 RCTs of 
Cognitive Processing Therapy (CPT) and 4 RCTs of prolonged exposure48. Forty-nine percent to 70% of 
participants receiving CPT and prolonged exposure attained clinically meaningful symptom improvement. 
However, approximately two-thirds of patients receiving CPT or prolonged exposure retained their PTSD 
diagnosis after treatment. The authors concluded that there is a need for improvement in existing PTSD 
treatments and for development and testing of novel treatments. There is a large descriptive literature 
suggesting that breath training might have benefit for PTSD and stress-related medical conditions49. Might a 
program that integrated mindful breathing with other exercises, including both aerobics and strength training, 
be a good fit for Veterans? This is the approach taken in the Carl R. Darnall Army Medical Center’s Warrior 
Combat Stress Reset Program in Fort Hood. This program includes movement exercises, self-regulation 
practices and yoga, with its emphasis on breathing. In the Warrior Combat Stress Reset Program, the 
emphasis was on helping to calm Veterans’ mind, body, and spirit after returning from war.  
 
In the current study, a program of exercise was created to take advantage of the large body of 
evidence demonstrating that aerobic exercise effectively improves many outcomes relevant to 

 
Posttraumatic Stress (PTSD), the pilot studies indicating acceptability, feasibility and promise of 
efficacy for the effects of exercise on PTSD symptoms, while incorporating elements of mindfulness, 
including core tenets, such as non-judging attitude and mindful breathing.  
 
Preliminary Studies 
In our pilot study, we enrolled a total of 46 (9 women) veteran participants. Twenty-one subjects were assigned 
to exercise and 25 to the wait list. Note, randomization was conducted from block randomization lists from 4 
strata defined by gender and age. We had a total of 9 dropouts: 5 from the Integrative Exercise (IE) group and 
4 from the Wait List (WL) group. All 5 subjects from the IE group and 2 from the WL group dropped out in the 
first week after randomization and were lost to follow-up. One of the subjects who dropped from WL 
immediately following randomization indicated they elected to enroll in a fitness program outside of the 
research setting. We have 38 total completers (21 WL and 16 IE).  
The clinical and demographic characteristics of our subjects in the pilot trial are presented in Table 1. 
 
 
IE 
(n = 21) 
WL 
(n =25) 
Test statistic 
All participants 
Age, mean (SD), years 
47.42 (15.94) 
46.97 (14.25) 
t(44) = .01 
47.18 (14.88) 
Gender, no. (%) 
 
 
x2(1) = .01 
 
Male 
17 (80.95) 
20 (80.00) 
 
37 (80.43) 
Female 
4 (19.05) 
5 (20.00) 
 
9 (19.57) 
Race, no. (%) 
 
 
x2(6) = 5.36 
 
Caucasian 
12 (57.14) 
12 (48.00) 
 
24 (52.187) 
Black/African 
American 
4 (19.05) 
8 (32.00) 
 
12 (26.09) 
Asian 
1 (4.76) 
2 (8.00) 
 
3 (6.52) 
American Indian or 
Alaska Native 
0 (0.00) 
1 (4.00) 
 
1 (2.17) 
Native Hawaiian or 
Other Pacific Islander 
0 (0.00) 
1 (4.00) 
 
1 (2.17) 
More Than One Race 
3 (14.29) 
1 (4.00) 
 
4 (8.70) 
Other 
1 (4.76) 
0 (0.00) 
 
1 (2.17) 
Hispanic 
 
6 (28.57) 
4 (16.67) 
x2(1) = .91 
10 (22.22) 
Education duration, 
mean (SD), years 
16.10 (3.70) 
15.40 (2.29) 
t(44) = .78 
15.72 (3.00) 
Baseline CAPS, mean 
(SD) 
64.25 (20.54) 
59.12 (14.11) 
t(43) = .99 
61.40 (17.25) 
Effects of Integrative Exercise on Aerobic Capacity, PTSD symptoms, and WHOQOL Physical and 
Psychological Domains: Figure 1 shows the change in World Health Organization Quality of Life (WHOQOL) 
Psychological and Physical Domains, mean metabolic equivalent (METS) on exercise treadmill testing, and  
scores on the Clinician Administered PTSD Scale (CAPS50) for Exercise vs. Wait List completers at baseline 
and end of study. Error bars represent standard errors of the means.1) The WHOQOL-BREF51, 52 instrument 
comprises 26 items, which measure the following broad domains: physical health, psychological health, social 
relationships, and environment. The WHOQOL-BREF is a shorter version of the original instrument and more 
convenient for use in large research studies or clinical trials. The Psychological Domain, our primary outcome, 
is derived from 6 items which index body image, negative & positive feelings, self-esteem, spirituality, and 
cognition. Each item has 5 response options with higher scores denoting higher psychological health. The 
mean score of items within each domain is used to calculate the domain score. Mean scores are then 
multiplied by 4 in order to make domain scores comparable with the scores used in the larger WHOQOL-100 
scale52. The group difference in change from baseline to 12 weeks, estimated from the mixed model fit to all 
time points, was 1.39 points greater improvement in Psychological Domain scores in the IE condition 
compared to Wait List, Cohen’s d= 0.54, 95% C.I. = (.17, .91), p = .005.The relative improvement in the 
WHOQOL Physical Domain was 0.70 points, or d = .28, 95% C.I. = (-.21, .78), p = .25. Cohen’s d is calculated 
Table 1 

 
r = -.48
-80
-60
-40
-20
0
Change in CAPS Score
-4
-2
0
2
4
Change in METS
Wait List
Exercise
Relationship between METS and PTSD Symptom Improvement
0
.5
1
1.5
2
2.5
Wait List
Exercise
WHOQOL Psychological Domain
-1
-.5
0
.5
1
1.5
Wait List
Exercise
WHOQOL Physical Domain
-2
-1
0
1
2
Wait List
Exercise
METS
-40
-30
-20
-10
0
Wait List
Exercise
CAPS
here as the group difference in baseline-adjusted post-treatment scores divided by the standard deviation of 
baseline scores.  
 
Aerobic fitness was assessed 
by measuring exercise capacity 
using a symptom-limited 
graded exercise treadmill test 
according to a standard Bruce 
protocol at baseline and end of 
treatment or wait list. (More 
details presented in Research 
Design and Methods.) 
Participants were asked to walk 
on a treadmill beginning at a 
workload of 20-30 watts and 
increasing by 20-30 watts 
every 3 minutes until reaching 
dyspnea, symptom-limited 
fatigue, chest discomfort, or 
electrocardiographic changes 
suggestive of ischemia33, 53. 
Metabolic equivalents (METS) 
were measured throughout and 
maximum exercise capacity 
was calculated as the total 
number of METS achieved. IE subjects demonstrated that the exercise intervention produced a significant 
increase in exercise capacity. The WL subjects also showed a reduction in exercise capacity during the 12-
week waiting period which demonstrates that subjects did not initiate an exercise program on their own. The 
group by time interaction from a mixed model analysis was highly significant (z= 5.2, p < 0.001), Cohen’s d = 
3.9. This data also demonstrate objectively that our team was successful in engaging subjects in a program of 
fitness that produced a measurable impact on cardiovascular health. 
 
PTSD symptom severity was measured with the CAPS which provides both a dimensional and categorical 
measure of PTSD. The CAPS measures frequency and intensity of PTSD-related symptoms. Possible scores 
range from 0 to 136. The CAPS interview was conducted in all subjects at baseline and after the 12-week 
treatment or monitor-only period. All of the instruments were conducted by an evaluator who was blind to 
treatment assignment. Subjects were instructed prior to each assessment to not disclose their treatment 
assignment to the evaluator. Figure 1 shows the mean change in CAPS total scores for Exercise vs. Wait List 
groups at baseline and end of study. The differential improvement in CAPS score in the IE vs. the WL group 
was 15.9 points, Cohen’s d = 
1.13, z = 2.37, p = .018. Overall 
our pilot data demonstrate 
favorable promise for the effects 
of Integrative Exercise on 
improving the total CAPS score. 
Figure 2 shows the correlation 
between change in mean 
Metabolic equivalent (METS) and 
CAPS score in the combined 
sample of IE vs WL completers. 
Note the predominantly negative 
values for METs in the wait list 
group.  
 
Preliminary data on 
measurement of endothelial 
function: Previous research has shown peripheral blood biomarkers of endothelial dysfunction increase and 
Figure 2 
Figure 1 

 
flow mediated dilation (FMD) decreases after acute psychological stressors54-56. Studies also suggest chronic 
psychological stress from PTSD may impair vascular function, but they have been limited in their sample size 
and scope of vascular function measures. In a study of 28 medically healthy patients with and without PTSD, 
those with PTSD had significantly higher levels of peripheral biomarkers of endothelial dysfunction, and levels 
were correlated with severity of PTSD symptoms57. A separate study conducted in 100 police officers found 
higher levels of PTSD symptoms were associated with a nearly twofold decrease in FMD after adjustment for 
demographics and health behaviors.58 We studied FMD in 214 subjects at the San Francisco VAMC. Brachial 
artery FMD was evaluated after inflation of a blood pressure cuff to suprasystolic pressures for 5 minutes as 
described in the Measures Section. Veterans with PTSD (N= 67) relative to Veterans without PTSD (N= 147) 
had a significantly lower brachial artery FMD (5.8 ± 3.4% vs 7.5 ± 3.7%; p=0.003) adjusting for demographics, 
comorbidities, and treatment characteristics. This difference has significant predictive potential for the risk of 
CV events. In fact, in recent meta-analysis, it has been estimated that a 1% decrease in FMD is predictive of a 
10% absolute increase in future CV events and mortality59, 60.  
We obtained FMD data in a sub-sample of our pilot treatment study before and after IE (N= 6) or WL (N= 9). 
The results are presented in Table 2 below: 
Group 
Baseline 
End of Trial 
Effect Size (d) 
p 
Wait List (N=9) 
8.3% (s.e. = 1.1) 
7.8 (s.e. = 1.1) 
-.18 
.73 
Integrative Exercise (N=6) 
9.6% (s.e. = 2.0) 
13.7 (s.e. = 2.0) 
.87 
.09 
Although not statistically significant given the small sample size, these preliminary data provide additional 
support for the hypothesis that FMD, a potent risk factor for cardiovascular disease, is modifiable with 
integrative exercise in a population with PTSD. 
Feasibility and Acceptability in the subjects who completed Integrative Exercise. Note that all 5 of the 
dropouts assigned to IE left the study immediately after randomization. None of the subjects who initiated 
treatment dropped out. IE completers (N = 16) reported high satisfaction with the intervention. On the 
Feasibility and Acceptability Questionnaire (see Table 3 below), the most highly rated areas were perceiving 
benefit from this treatment, learning new skills and techniques, experiencing the treatment as adaptable to 
personal capabilities, and finding the instructors and intervention to be engaging. All completers said they 
would recommend this treatment to a friend. Though participants indicated slightly less satisfaction with the 
length of treatment, only 4 participants reported they thought the treatment was not “just the right length.” 
 
Table 3. Feasibility and Acceptability Questionnaire - 16 IE completers 
Item 
Mean (SD) 
Median 
(Min-Max) 
Overall treatment impressions 
 
 
I feel like I benefitted from this treatment 
4.81 (0.40) 
5 (4-5) 
This treatment taught me new skills and techniques 
4.75 (0.45) 
5 (4-5) 
I would recommend this treatment to a friend who was 
dealing with similar issues 
4.69 (0.48) 
5 (4-5) 
I was able to tolerate this treatment well 
4.44 (0.89) 
5 (2-5) 
Content of intervention 
 
 
The instructors suggested modifications to match my 
fitness level/physical limitations to exercise 
4.75 (0.45) 
5 (4-5) 
The instructors were engaging and made class fun 
4.75 (0.45) 
5 (4-5) 
The breathing techniques covered in class were just 
right 
4.25 (0.58) 
4 (3-5) 
We spent the right amount of time on each exercise 
4.31 (0.70) 
4 (3-5) 
The exercises covered in class were just right 
4.19 (0.91) 
4 (2-5) 
I wish other exercises had been included 
3.38 (1.15) 
3 (1-5) 
Length of intervention 
 
 
The 60 minute workouts were too long* 
4.13 (0.62)* 
4 (3-5) 
This treatment did not seem like too big of a burden 
4.00 (0.89) 
4 (2-5) 
I wish the treatment had more sessions 
3.44 (1.41) 
3.5 (1-5) 
The 36 session treatment (3 times per week for 12 
weeks) was just the right length 
3.31 (1.35) 
3 (1-5) 

 
Note: Response options ranged from 1 (strongly disagree) to 5 (strongly agree).  
*This item was reverse coded; the results indicate that most participants did not think the 60 minute workouts 
were too long. 
 
Summary: There are strong converging lines of evidence that exercise can have positive effects on multiple 
functional domains relevant to PTSD: psychological and physical heath, sleep, and cardiovascular health. We 
have developed a novel protocol integrating the best elements of aerobics, strength training, and mindfulness-
based breath training. We currently have a dedicated study team in place and with our success at recruitment 
and engagement, we are poised to complete a new definitive efficacy trial with an active control condition that 
will have sufficient power to properly evaluate whether an exercise intervention improves quality of life and 
broad measures of psychological and physical health in combat Veterans with PTSD. Because of the strengths 
of our team in PTSD-related comorbidities and clinical trials, we are in a unique position to test if exercise has 
positive effects on quality of life, psychological health, sleep, and cardiovascular fitness. It is our position that 
positive results in all of 
these domains would 
greatly enhance the 
attractiveness of this 
intervention to returning 
warfighters with PTSD and 
attract more Veterans into 
treatment. Further, the 
empiric data obtained from 
this project will help inform 
policy regarding 
therapeutics that serve the 
rehabilitation mission of 
RR&D. 
 
Research Design and 
Methods:  (Figure 3) 
Overview: Subjects with 
full PTSD will be recruited 
to participate in a parallel-
groups trial. 104 subjects 
will be randomly assigned 
to one of two groups: one 
receiving treatment (12-
week course of Integrative 
Exercise [IE]; Appendix 2), 
the other assigned to a 12-
week Illness Management 
and Recovery (IMR) 
condition (Appendix 3). A 
stratified randomization 
strategy will be deployed to 
help ensure that the 2 
conditions do not differ for 
subjects who are or are not 
engaged in current 
treatment for PTSD. 
Integrative Exercise will be 
delivered using manualized 
procedures described 
below. The therapists will 
review session-specific 
adherence checklists for 
Figure 3 

 
both conditions (see Appendices 2 & 3) at the conclusion of each session. Drs. Mehling and Boyd, who have 
extensive experience with delivering IE and IMR respectively, will rate recorded sessions and independently 
rate adherence. Participants will complete baseline assessments and an exercise treadmill and flow-mediated 
dilation (FMD) test prior to randomization. Integrative Exercise treatment involves a combination of aerobic and 
strength training exercises as well as concentration training based on mindful breathing techniques. Subjects 
will exercise 3 times weekly, with each total workout being approximately 60 minutes in length. After the 12-
week intervention, participants will repeat the clinical assessment, exercise treadmill and FMD test. Measures 
of subjective sleep quality, PTSD symptoms, mood states – particularly depression, and quality of life (QOL), 
will be obtained in all subjects (Integrative Exercise and IMR) at baseline, weeks 4 & 8, and again following the 
end of 12 weeks.  Subjects randomized to Integrative Exercise will be asked to rate their satisfaction with the 
intervention (i.e., acceptability and feasibility and comparison with other PTSD treatments that participants may 
have experienced in the past) at the end of 12 weeks and will have repeat clinical assessments at 6 months to 
examine durability of treatment gains. 
 
Major Design Issue: The Control Condition 
This remains our most challenging design decision given that our pilot study was conducted with a waitlist 
control condition. We have chosen IMR for several reasons. One, it is predominantly a health education 
oriented format and it allows us to match attention by study personnel across the two conditions. Further, it has 
been disseminated widely in the VA and is a mandated component of Psychosocial Rehabilitation and 
Recovery Center (PRRC) programs across the country. A recent meta-analysis61 showed that dropout rates 
are around 20%, similar to our experience with IE. Finally, the curriculum is modular and is adaptable to 
different populations. (For more details see the Illness Management and Recovery Treatment section.)  
 
Recruitment and Feasibility: Medically healthy men and women with chronic PTSD will be recruited from 
newspaper advertisements, web-based postings, flyers posted in San Francisco and regional community 
based outpatient clinics (CBOCs), and from the clinical PTSD Program at the SFVAMC which in the past 2 
years treated 17,641 Veterans with PTSD. Further, we have acquired, with full IRB and SFVAMC R&D 
approval, a list of names and contact information of 5,200 Veterans in the San Francisco Bay Area from the 
Defense Manpower Data Center. Specifically, these are Veterans who are within a 50-mile radius from the 
SFVAMC and served in active duty between 2001 and March of 2014. This has substantially enabled our 
recruitment in the current pilot study and has allowed us to contact Veterans who are not currently enrolled in 
VA health care. The PTSD research program has successfully enrolled over 480 male and female PTSD and 
control subjects in the past 2 years. Our goal will be to have at least 45% racial/ethnic minorities and at least 
12% women in our sample (See Human Subjects). Recruitment efforts will be enhanced by the Stress and 
Health Strategic Outreach and Recruitment/Retention (SOAR) program, which is supported in part by the 
Sierra Pacific MIRECC and will provide staff support and a host of essential functions and materials key to 
successful recruitment. Subjects who respond to recruitment solicitation will be initially screened by telephone 
and next invited for an assessment interview by study personnel. The screening clinician will obtain written 
informed consent at the time of the first diagnostic interview, prior to beginning the assessment.  
 
Subjects: 104 subjects with PTSD will be randomized with an end goal of having 80 subjects with complete 
data for the entire trial. The 25% attrition rate is a conservative estimate based on our experience with this 
treatment and conducting other treatment studies in similar samples of PTSD subjects. There are at least 4 
factors that account for this: 1) our staff and therapists are trained to be very “patient centered”, 2) many 
patients with PTSD are pleased to have the opportunity to address the problem without relying on medications 
or trauma focused therapy, 3) all patients that participate in our RCTs and are randomized to attention control 
conditions are guaranteed access to the active treatment at study end at no cost, and 4) a bonus remuneration 
payment is provided to subjects that successfully complete the trial. Our current experience is that dropouts 
occur shortly after randomization. This is very similar to the experience of a large, controlled treatment trial for 
PTSD in an exclusively Veteran population led by Barbara Rothbaum at Emory University3. We have strong 
methods of retaining participants who drop out of treatment for follow-up assessments. Our research into 
retention in clinical trials 62 has identified several factors related to retention. Study teams that train their 
research associates and clinical evaluators to respond to participants with empathy, particularly in the face of 
participant complaints, have better retention. Monetary inducements offered at each assessment point have 
been shown to significantly reduce lost-to-follow-up (LTF) rates63 and minimize the risk of differential LTF rates 
across treatments when there are differences in the desirability of treatments. These payments will increase 
compliance with assessments across the study63.  

 
 
Screening for Inclusion: Once subjects have initiated contact, they will be given more information about the 
study, either on the phone or through email or the Web. Prescreening interviews will be done by telephone 
after the subjects have given their verbal consent. They will be informed that some of the questions are about 
trauma and reminded that they can skip any question or stop the interview at any time. An internet-based 
survey will also be available if participants give electronic consent. The participants will have the option of 
calling the research team if they have questions or want further information. These subjects will be mailed or 
emailed a copy of the consent form which describes the next phase of the study. Procedures will not begin until 
written consent has been received. 
 
Evaluation of PTSD Subjects:  
Overview: All participants entering the study will participate in an audiotaped diagnostic interview conducted by 
Dr. Christiane Zenteno. Dr. Zenteno has conducted over 600 such interviews and is an expert in 
standardization and calibration of clinical evaluations. The Stress and Health Research Group conducts a 
weekly recruitment and consensus diagnostic conference, a weekly scientific administrative meeting to track 
the flow of subjects in the various protocols, and a weekly study design and data review conference. 
Discrepancies in the evaluation of subjects will be resolved by a consensus meeting.   
Inclusion/Exclusion Criteria: 
Inclusion Criteria: (1) Male and female Veterans between the ages of 18-69 who are physically able to 
participate in an exercise program; (2) Meet criteria for current full syndrome PTSD of at least 3 months 
duration, as indexed by the Clinician Administered PTSD Scale for DSM-5 (CAPS-5). 
Exclusion Criteria: (1) Lifetime history of any psychiatric disorder with psychotic features, bipolar disorder, or 
mania, or meet criteria for moderate drug or alcohol use disorder within the past year as assessed by the 
Structured Clinical Interview for DSM-5; (2) Prominent suicidal or homicidal ideation; (3) Currently exposed to 
recurrent trauma or have been exposed to a traumatic event within the past 3 months; (4) Pregnant, have a 
clinically significant neurologic disorder, systemic illness affecting CNS function, history of seizure disorder, 
and/or physical disabilities making it impossible to use exercise equipment; (5) Contraindications for the 
exercise treadmill test which includes any acute coronary events (i.e., Myocardial Infarction) in the past 6 
months; (6) Moderate to severe Traumatic Brain Injury (any history of head trauma associated with the onset of 
persistent cognitive complaints, neurological symptoms, or loss of consciousness > 30 minutes). 
We will not exclude PTSD patients who are currently receiving individual or group therapy or patients who are 
currently taking antidepressant or anti-anxiety medication, but will apply the following criteria: patients must 
have been in treatment for at least 2 months, meet symptomatic criteria for inclusion, and not have plans to 
discontinue treatment during the course of the trial. 
Measures: 
Medical Screening: All subjects will meet with a study nurse practitioner at the CTSI Clinical Research Center 
at the San Francisco VA Medical Center. The nurse practitioner will review subjects’ medical and surgical 
history as well as concurrent medications, and perform a physical exam. Vital signs, height, weight, and 
smoking status will be collected. The baseline lab tests for all participants will include a serum chemistry panel, 
liver function tests, thyroid functions, complete blood count, and differential, total cholesterol, HDL-cholesterol, 
LDL-cholesterol, triglycerides, glucose, hemoglobin A1c, and a urine toxicology screen. Depending on the 
subject's medical history, additional tests may be ordered to confirm that the subject is healthy and eligible to 
participate in the study.  Female participants will be asked to provide a urine sample for pregnancy testing. 
Subjects who are pregnant or who have plans to become pregnant will be excluded from the study.  The lab 
work results will be reviewed by Dr. Neylan. If significant abnormal findings are discovered, the subject will be 
referred to their primary care provider for treatment. Subjects will also be asked to complete the Physical 
Activity Readiness Questionnaire (American College of Sports Medicine [ACSM Guidelines]) to be cleared to 
exercise. If needed, each subject will perform a graded exercise test (ASCM Guidelines) to assess functional 
capacity. A portable screening device monitoring airflow, respiratory effort, pulse, and oximetry (ResMed 
ApneaLink Plus) will be used to prescreen for untreated obstructive sleep apnea (OSA) in all subjects. Cutoff 
criteria for apnea will be 10 apnea/hypopnea events per hour in bed. 
 
Assessments: 
The following assessments will be utilized in all subjects at baseline and after the 12-week treatment period. 
For subjects randomized to Integrated Exercise, a third set of assessments with the following measures will be 
conducted at the 6-month follow-up period. All of the instruments involving a clinical rater will be conducted by 
an evaluator who will not be conducting the treatment and will be kept blind to treatment assignment. Subjects 

 
will be instructed prior to the assessment at 12 weeks not to disclose their treatment assignment to the 
interviewer.  
1. The World Health Organization Quality of Life (WHOQOL-BREF)51, 52: The WHOQOL-BREF instrument 
comprises 26 items, which measure the following broad domains: physical health, psychological health, 
social relationships, and environment. The WHOQOL-BREF is a shorter version of the original 
WHOQOL-100 instrument and is more convenient for use in large research studies or clinical trials. The 
Psychological Domain, our primary outcome, is derived from 6 items which index body image, negative 
& positive feelings, self-esteem, spirituality, and cognition. Each item has 5 response options with 
higher scores denoting higher psychological health. The mean score of items within each domain is 
used to calculate the domain score. Mean scores are then multiplied by 4 in order to make transformed 
domain scores to a range of 4-20 comparable with the scores used in the WHOQOL-100.  
2. Structured Clinical Interview for DSM-5-Research Version (SCID-5-RV,64). The SCID will be repeated 
after the 12-week treatment period. 
3. Clinician Administered PTSD Scale for DSM-5 (CAPS-5,65). The CAPS-5 is a 30 item scale that 
provides both a dimensional and categorical measure of PTSD. The CAPS-5 will determine lifetime and 
current PTSD. The CAPS-5 items are rated with a single severity score that incorporates both 
frequency and intensity PTSD-related symptoms. In addition to assessing the 20 DSM-5 PTSD 
symptoms, questions target the onset and duration of symptoms, subjective distress, impact of 
symptoms on social and occupational functioning, improvement in symptoms since a previous CAPS 
administration, overall response validity, overall PTSD severity, and specifications for the dissociative 
subtype (depersonalization and derealization)65.   
4. Life Stressor Checklist-Revised (LSC-R): Structured clinical interview for lifetime exposure to stressful 
life events 66. This structured clinical interview for lifetime exposure to stressful life events will be used 
to characterize the type of trauma exposure and age of occurrence(s) of different traumas in all 
subjects. 
5. Addiction Severity Index Lite (ASI-Lite)67: The ASI-Lite Composite Score for Alcohol Use will provide a 
secondary measure of past month alcohol use severity, and the ASI-Lite number of years of alcohol 
use will provide a marker of lifetime alcohol use. The ASI-Lite Composite Score for Drug Use will 
provide a secondary measure of past month non-alcohol substance use severity, and the ASI-Lite 
number of years of drug use will provide a marker of lifetime non-alcohol substance use. The ASI-Lite is 
a valid and reliable standardized research interview to assess the occurrence and severity of alcohol 
and non-alcohol substance abuse. The ASI-Lite includes questions about the frequency, duration, and 
severity of problems over the subject’s lifetime and in the past 30 days. 
6. Smoking status68 is a two-question categorical measure employed by the Centers for Disease Control 
and Prevention National Health Interview Survey, and categorizes individuals into one of three groups: 
(a) "Never smokers", adults 18 or over who have smoked fewer than 100 cigarettes in their lifetime; (b) 
"Former smokers", adults who have smoked at least 100 cigarettes in their lifetime but are not smoking 
at time of interview; and (c) "Current smokers", adults who have smoked at least 100 cigarettes over 
their lifetime and who are still smoking at time of interview. 
7. Number of pack years68 is a two-question continuous measure of smoking that utilizes the number of 
cigarettes per day multiplied by the number of years of smoking to calculate pack years of smoking. 
8. Five Facet Mindfulness Questionnaire (FFMQ)69, 70: The FFMQ is a 39-item questionnaire derived from 
a factor analysis of other mindfulness questionnaires. It assesses five facets of mindfulness: observing, 
describing, acting with awareness, non-judging and non-reactivity to inner experience which represent 
elements of mindfulness as it is currently conceptualized. Items are rated on a Likert scale ranging from 
1 (never or very rarely true) to 5 (very often or always true). The FFMQ has been shown to have good 
internal consistency (alpha coefficient range .72 to .92) in several samples and significant relationships 
in the predicted directions with domains related to mindfulness69, 70. The FFMQ allows a detailed 
assessment of changes as a function of mindfulness and therefore will be used as a secondary 
outcome. 
9. Godin Leisure-Time Exercise Questionnaire71, 72: is a validated brief inventory assessing sedentary, 
work, recreational, and aerobic activity in a typical week. This metric will be used to measure time spent 
in vigorous activity and will serve multiple purposes: a) It will be used to test if randomization effectively 
balances levels of baseline vigorous activity across the two groups; b) It will be used as a manipulation 
check to ensure that subjects randomized to IE engage in more vigorous activity after randomization 
than subjects randomized to IMR; c) It will be used as a secondary predictor of treatment response. 

 
10. The Physical Activity Self-Efficacy scale (PASE)73: The PASE will be used as an exploratory measure 
of  perceived confidence to continue exercising in the face of competing day-to-day conditions. 
Symptoms Scales:  
The following measures will be obtained in all subjects (Integrative Exercise and IMR) at baseline, week 4, 
week 8, and after 12 weeks for the exploratory hypotheses in Aim 1. Subjects randomized to Integrated 
Exercise will also complete these measures at the 6 month follow-up period: 
1. PTSD Checklist for DSM-5 (PCL-5)74. The PCL-5 is a validated self-report rating scale for assessing 
PTSD symptoms. It consists of 20 items that correspond to the DSM-5 symptoms of PTSD. 
2. Symptom Check-List-90-Revised (SCL-90-R) [147]. The SCL-90-R is a standard self-report measure of 
general psychopathology. Scored for nine primary dimensions and three summary indices, the SCL-90-
R manual reports extensive reliability and validity data. 
Sleep and Alertness Assessment Methods:  
1. Pittsburgh Sleep Quality Index (PSQI)75. This self-report measure provides a subjective assessment of 
sleep quality, sleep latency, sleep duration, sleep efficiency, sleep disturbances (including nightmares), 
use of sedative-hypnotics, and daytime energy. This index is now widely used and has been validated 
by polysomnography. The PSQI will be our main measure of sleep quality. 
2. PSQI- PTSD Addendum (PSQI-A)76. The PSQI-A assesses disruptive nocturnal behaviors related to 
PTSD, such as hot flashes, nightmares, and episodes of terror during sleep. The total score ranges 
from 0 (normal) to 21 (severe). The PSQI-A has demonstrated good internal consistency and 
convergent validity. The PSQI-A will be secondary measure of sleep quality that will be used in 
exploratory analyses. 
3. Insomnia Severity Index (ISI): The ISI is a valid and reliable self-report measure77 that is a more 
specific index of perceived insomnia severity, as compared to the widely used PSQI measure which 
captures sleep disturbances of all types. The internal consistency of the ISI was found to be excellent 
(Cronbach’s α= 0.74) and has been validated with both sleep diary and polysomnography77. The ISI will 
be secondary measure of sleep quality that will be used in exploratory analyses. 
Exercise Treadmill Test: Aerobic fitness will be assessed by measuring exercise capacity using a symptom-
limited graded exercise treadmill test according to a standard Bruce protocol. Participants will be asked to walk 
on a treadmill beginning at a workload of 20-30 watts and increasing by 20-30 watts every three minutes until 
reaching dyspnea, symptom-limited fatigue, chest discomfort, or electrocardiographic changes suggestive of 
ischemia33, 53. Heart rate, cuff blood pressure, minimum oxyhemoglobin saturation, and 12-lead 
electrocardiography will be recorded at rest, at each stage of exercise, and after four minutes of recovery. 
Continuous electrocardiographic monitoring of a 12-lead electrocardiogram will be performed throughout 
exercise. Metabolic equivalent (METS) will be measured throughout and maximum exercise capacity will be 
calculated as the total number of METS achieved. Maximum heart rate and time on the treadmill will also be 
measured. The main outcome measure for aerobic fitness will be exercise capacity (i.e., total number of METS 
achieved) during the treadmill test. This variable will be used to test if therapeutic gains associated with 
Integrative Exercise are associated with objective measures of exercise capacity. 
Flow Mediated Dilation: Our main outcome will be flow mediated, brachial artery endothelium dependent 
vasodilation using a protocol endorsed by the International Brachial Artery Reactivity Task Force78. A trained 
vascular technician blinded to treatment status will perform all examinations. A blood pressure cuff will be 
inflated on the upper arm, blood pressure will be measured, and then the cuff will be inflated to suprasystolic 
pressures for 5 minutes. Following release of the cuff, there will be vasodilation and an increase in flow through 
the brachial artery (reactive hyperemia). FMD is calculated as the percentage of brachial artery dilation from 
baseline. Measures of baseline and reactive hyperemia blood velocity, blood flow, and shear stress will also be 
captured. Shear stress is recommended for normalization of FMD and blood flow is examined for quality 
control, with recommendations that blood flow increases at least 400% following release of cuff79, 80. These 
techniques have an interobserver variability of 0.05 ± 0.16% and intraobserver variability of <0.01 ± 0.15%.78  
 
Randomization: After passing all screening procedures and found to be appropriate for the study, the study 
coordinator will randomize 104 subjects to either the 12-week treatment group (Integrative Exercise) or the 
IMR control group in a one-to-one ratio. A stratified randomization strategy will be deployed to help ensure that 
the two conditions do not differ for subjects enrolled in concurrent PTSD treatment. We will accomplish this by 
using two separate block randomization lists for those enrolled or not enrolled in concurrent treatment.  
NOTE: There are a variety of factors that, when uncontrolled, may affect the study outcomes in such a way as 
to obscure or to create artifactual group differences. Accordingly, it is tempting to stratify on a whole host of 

 
factors. Some examples would include age, gender, major depression, insomnia severity, or prior exposure to 
supervised exercise, etc. However, the attempt to control for all of these factors through randomization would 
be impractical and ineffective. Moreover, post-hoc adjustments for unanticipated baseline differences risk 
capitalizing on chance differences and create multiple testing problems. Accordingly, the primary analyses will 
be the unadjusted analyses. Any baseline variables that show large group imbalances despite randomization 
will be examined as covariates in a secondary sensitivity analysis, but will not be included in the primary 
analyses.  Substantial differences in inferences supported by the primary and secondary analyses would 
indicate a potential problem of randomization failure, and would warrant caution in interpreting results of the 
primary analyses , while consistency of inferences strengthen confidence in the primary analysis.   
 
Integrative Exercise Treatment (Overview): All participants will be medically screened before they can 
participate in the study.  This will involve completing a physical activity readiness questionnaire (American 
College of Sports Medicine [ACSM] guidelines). Each subject, after being cleared to participate based on 
ACSM guidelines, will, if needed, perform a graded exercise test to assess functional capacity. The exercise 
program will be 12 weeks in duration, integrating a combination of aerobic and strength training with 
concentration training based on mindful breathing techniques (from yoga and mindfulness approaches 
recommended by Hoge81). Subjects will exercise 3 times weekly, with each total workout being approximately 
60 minutes in length. These sessions will take place at the Embarcadero YMCA in San Francisco. All exercise 
will be supervised and documented by a trained professional in order to validate adherence and allow for 
program replications by others as part of an intervention program for PTSD. Exercises are adapted to 
individual participants’ fitness levels and pre-existing health conditions or injuries. 
 
The exercise program is designed with the following overall characteristics: It can be reproduced indoors as 
well as outdoors; it can be done in a group setting with participants at various fitness levels; it does not require 
a club membership or machines; it is accessible to combat Veterans of all socio-economic and educational 
levels; it is safe to Veterans with injuries; it is sufficiently different from usual fitness center programs to be 
attractive to 20-40 years old, younger Veterans; although it is not advertised as a form of psychotherapy, it will 
support the development of a “tool box” for coping with PTSD; the exercise instructions can be recorded on CD 
or MP3 and used in a private home. Overall, the goals of the exercises are twofold: 1) Increasing strength and 
cardio-vascular fitness, 2) Using the body that has physically returned to the homeland to bring the mind back 
home as well81. 
 
The sequence of exercises includes a variation of movements and loads for strength training and aerobic 
activities performed in a variety of ways, including continuous and interval training, as recommended by the 
American College of Sports Medicine (ACSM)82-85 and using nonlinear periodization84. Props include 
dumbbells, stretch bands, and stepping platforms. (The full protocol is in Appendix 2.) Exercises are 
accompanied by appropriately paced, rhythmic and exciting, or calming music. 
 
Following a moment of welcoming of participants with a brief review of the previous session, every session will 
start and end with 3-5 minutes of mindful breathing. Participants will be introduced to deep abdominal 
breathing, to pay attention to their breathing during the course of the session while working out and to dose the 
intensity of their exercising according to their ability to maintain breathing through his or her nose. Throughout, 
exercise movements will be closely coordinated with breathing phases, e.g. stretches with inhalation and 
weight pushes with exhalation. The mental focus on breathing during all exercises is a key ingredient of this 
integrative program to provide an embodied sense of mental centeredness and concentration. Mindful 
breathing is the cornerstone of mindfulness-based intervention for anxiety and depression86-88. 
 
The aerobic and strength program will begin with a warm-up and instructions for postural alignment supporting 
core engagement. Exercises will engage all major muscle groups in a systematic fashion that chains body 
parts together, but vary between sessions, starting with small weights and adding weights and aerobic intensity 
to pre-exhaust levels. Yoga moves and stretches, breathing and mindfulness instructions are woven into the 
program. Exercise sessions will end with a 5-minute cool-down period that returns to guided mindful breathing, 
fostering a physically experienced sense of body-based centeredness and relaxed concentration. For a 
detailed description of the intervention with its general principles, training components, class structure, mindful 
breathing teaching scripts, and physical exercises, we refer to the Manual in Appendix 2. 
 
Illness Management and Recovery Treatment: The control condition will involve 36 hours of health 
education using the Illness and Management and Recovery (IMR) program89 which is mandated by the 

 
Uniform Mental Health Services directive to be a component of PRRCs at each VA medical center. The IMR 
control condition, sometimes referred to as Wellness Management and Recovery, is an educational curriculum 
focused on helping clients more effectively manage their illnesses to pursue their personal recovery goals. 
Originally developed for severe mental illness, it has been empirically tested in diverse patient groups including 
PTSD5, 6. IMR begins with the concept of recovery and education is predicated on a stress-vulnerability model 
of mental illness. The IMR workbook (See Appendix 3) has detailed adherence checklists which filled out by 
research staff at the end of each session. The 11 modules include the following topic areas which have been 
adapted for use in PTSD: recovery, practical facts about PTSD, stress-vulnerability, building social support, 
medications for PTSD, drug and alcohol use, reducing relapse, coping with stress, coping with persistent 
symptoms, getting needs met in the VA healthcare system, and living a healthy lifestyle61, 89. 
Data Quality Control 
Data collection methods: The PI, Study Coordinator, data manager, and biostatistician will oversee data 
entry and management operations. Assessment test results will be entered into a password-protected 
database, which will be stored on a secure VA server. The data manager and the biostatistician will store 
“working” datasets as password-protected files on a SFVAMC secure server. Data will be entered into SQL 
Server tables using MS Access as a front-end or batch load from an external file.  At a point of entry, form 
values are subjected to consistency edit checks (e.g. range and type verification, missing data). Scoring 
algorithms are applied where appropriate. Once data is entered into the database, edit checks are run for 
accuracy.  On a regular basis, data management staff carries out quality edit checks. Data errors are corrected 
and previous / new values are automatically logged into a set of the database Audit tables. The reason for 
change, the date when the change has occurred and the person making the change are also captured by the 
audit trail mechanism and are stored in the database.  A form tracking system is available to determine if all of 
the data forms have been received and entered. In addition to Windows authentication, the system also uses 
role-based model to access study data. It allows Data Management staff to grant users different level of access 
based on their active role in the study. Authorization is used to control access to browsing data as well as 
access to records modification and administrative functionality. Authorization rules are compliant with IRB 
regulations and the VA. 
Data Analysis Plan  
Study groups will be described in terms of baseline characteristics (including demographic and clinical 
measures, and baseline levels of the outcome variables) using appropriate summary statistics. Distributions of 
clinical measures and outcomes will be examined for presence of outliers and need for outcome 
transformations. The primary analyses will be unadjusted intent-to-treat analyses, with all subjects randomized 
included in the analyses. Only the stratification factor, concurrent PTSD treatment status, will be included as a 
covariate in the primary analysis. Other baseline factors that remain unbalanced after randomization and are 
related to the outcomes will be analyzed in a separate sensitivity analysis to assess the robustness of the 
primary analysis. All available time point data from any dropouts will be included in the analyses, using mixed 
models to accommodate the missing data. Residuals will be examined to ensure model assumptions are met. 
If we find violation of distributional assumptions, we will consider (1) transformations of or alternative 
distributions for the outcomes, and (2) bootstrapped 95% CI on the estimated intervention effect. If outliers are 
found, we will determine if data errors were overlooked during cleaning and check their influence via removal. 
The frequency and timing at which outcomes are obtained varies by measure.  Some key measures, including 
the CAPS and the Exercise Treadmill Test, are measured at two time points, pre- and post-treatment, while 
self-report measures such as the WHOQOL, PCL and PSQI are measured at four time points.  All of these 
outcomes will be analyzed with linear mixed models (LMM’s).  Measures with more than two measurement 
occasions make full use of the LMM strategy, whereas LMM’s for pre-post measures reduce to ANCOVA as a 
special case, except for the added flexibility of modeling heterogeneous group variances.  In analyses with 
intermediate time points, a number of modeling choices must be made, including whether to treat the time 
variable as continuous or categorical, the form of the within-subjects correlation matrix, and whether to allow 
for heterogeneity of variance across groups and/or time points.  The best fitting model will be selected 
according to likelihood ratio tests (for nested models) or the Bayesian Information Criterion (BIC; for non-
nested models) before examining any coefficients or test statistics. The LMM is an unbiased intent-to-treat 
analysis under assumptions of Missing At Random (MAR).  Any baseline clinical measures that correlate with 
dropout will be added to the models in a sensitivity analysis.  However, the possibility of informative 
missingness (i.e., missingness related to the missing outcome or other unmeasured variables) cannot be 
tested but also cannot be ruled out.  Therefore, besides our primary LMM analytic strategy, we propose 
another sensitivity analysis for departure from MAR, based on copy reference (CR) imputation90, 91. In this 

 
procedure, post-dropout data in the treatment group are multiply imputed from a model that assumes that 
treatment arm dropouts revert to the control group trajectory at a rate determined by the within-control group 
correlation structure.  In the limiting case of participants who drop out of the treatment arm immediately after 
baseline, their imputed trajectory follows that of the control group.  Dropouts from the control group are 
imputed from the control group only model based on baseline data and any observed time points before 
dropout.  Multiply-imputed data sets are analyzed with the LMMs as proposed, with the estimates combined 
using Rubin’s rules. The effect is to reduce the estimated difference between groups at end of trial, and yields 
a more conservative effect estimate than the LMM without imputation. 
Primary Hypothesis Testing: 
Hypothesis 1a: Subjects randomized to Integrative Exercise will have a greater improvement in quality of life 
as measured by the WHOQOL-BREF psychological domain compared to subjects randomized to IMR. For 
Hypothesis 1a, a linear mixed model will be estimated for the total score of the WHOQOL-BREF psychological 
domain using the Stata mixed procedure. Subjects will be entered as a random effect, while treatment group 
will be entered as a fixed effect. Treatment period (baseline, 4, 8, and 12 weeks) will be modeled both linearly 
and non-linearly (with a quadratic term for time), with the choice of model determined by a likelihood ratio test 
for the addition on the quadratic term. If the model with a linear function of time is retained, we will examine 
whether to include a random (subject-specific) effect for time, with the choice again made via a likelihood ratio 
test. (Four time points are insufficient to model both non-linear and random effects.) The hypothesis will be 
tested by the significance of the group (Integrative Exercise vs. IMR) by treatment period (pre- vs. post-
treatment) interaction, with the baseline-adjusted group difference at Week 12 being the effect size. 
Hypothesis 1b: Subjects randomized to Integrative exercise versus IMR will have greater improvements in 
cardiovascular health as measured by exercise capacity on the treadmill test. For Hypothesis 1b, a linear 
mixed model will be estimated for the total number of METS achieved on the treadmill test using the Stata 
mixed procedure. Subjects will be entered as a random effect, while treatment group and treatment period 
(randomization vs. end of trial Week 12) will be entered as fixed effects. The hypothesis will be tested by the 
significance of the group (Integrative Exercise vs. IMR) by treatment period (pre- vs. post-treatment) 
interaction, with the baseline-adjusted group difference at Week 12 being the effect size. Unlike Hypothesis 1a, 
the outcome is obtained at only two time points. 
Hypothesis 1c: Greater improvements in quality of life will be correlated with greater improvements in exercise 
capacity on treadmill, and changes in exercise capacity will partially mediate the effects of Integrative Exercise 
on quality of life. For hypothesis 1c, a mediation model will be specified as a linear path model using structural 
equation modeling software (Mplus 7.2).  The model specifies a direct effect of treatment on both baseline-
adjusted treadmill METS and baseline-adjusted WHOQOL Psychological Domain scores, with a path from 
METS to WHOQOL.  The mediation path from treatment condition through change in METS to change in 
WHOQOL scores will be tested for significance using bootstrapped standard errors, and the mediation effect 
expressed as a percentage of the total effect that is mediated.  We stress here that our design does not allow 
for an unambiguous causal interpretation of a mediation effect because the outcome and mediator are 
measured at the same time point.  However, a finding of statistical mediation would be consistent with, and 
necessary for, a causal interpretation of the mediation effect.   
 
Exploratory Hypotheses: Subjects randomized to IE versus IMR will have greater improvements in additional 
health outcomes, including mood, subjective sleep quality, and brachial artery flow mediated vasodilation. 
These outcomes will be used to examine the internal consistency of the effects of treatment on the primary 
WHOQOL-BREF outcome. Scores will be computed for each of these outcome variables in the pre-
randomization and post treatment (end of trial week 12) periods.  Separate linear mixed models will be 
estimated for each outcome. Subjects will be entered as a random effect, while treatment group, time (pre- vs. 
post-treatment) will be entered as fixed effects. The hypothesis will be tested by the significance of the group 
(IE vs. IMR) by treatment period (pre- vs. post-treatment) interaction. We also will explore whether symptom 
improvement follows a dose-response relationship to amount of exercise in the IE group. Number of exercise 
sessions completed will be entered as a (possibly nonlinear) moderator variable in a mixed model prediction of 
symptom change over time within the IE group alone. The hypothesis will be tested by the significance of the 
interaction between time and number of completed sessions. 
Hypothesis 2a: Participants randomized to Integrative Exercise will demonstrate greater improvements in 
PTSD symptoms as measured by the CAPS score compared to those in the IMR control group. For Hypothesis 
2a, a linear mixed model will be estimated for the CAPS total score using the Stata mixed procedure. Subjects 
will be entered as a random effect, while treatment group and treatment period (randomization vs. end of trial 

 
Week 12) will be entered as fixed effects. The hypothesis will be tested by the significance of the group 
(Integrative Exercise vs. IMR) by treatment period (pre- vs. post-treatment) interaction, with the adjusted group 
difference at Week 12 being the effect size.  
Multiplicity Correction:  We plan to test primary hypotheses on primary outcomes at the nominal p < .05 
significance level without adjustment.  Significance tests for the secondary hypotheses will be adjusted for 
multiple outcomes using a resampling-based step-down procedure92 to take advantage of the correlational 
structure among the secondary outcomes.  
Exploratory analysis of treatment moderators:  While we wish to avoid formal subgroup analyses because 
of lack of power and lack of pre-specified hypotheses, we nonetheless will explore potential treatment 
moderators (e.g., age, baseline level of vigorous activity) as a hypothesis-generating procedure to inform future 
studies. This will be achieved by examining interactions between subject characteristics and treatment effects. 
The emphasis here will be on estimated effect sizes rather than statistical significance (Kraemer et al. 20062). 
Power Analysis: Our pilot data on WHOQOL-BREF, PTSD symptoms and METS units in response to exercise 
treatment are promising, but we are reluctant to base our power calculations entirely on effect sizes derived from 
pilot data, as these tend to be far too imprecise 93.  Rather we have powered the study to detect clinically 
meaningful effects on our primary variables.  We conducted our power calculations for measures obtained at only 
pre- and post-treatment time points, because these are key outcomes and because the two time point case 
represents a lower bound for power when outcomes are measured more frequently.  We used simulation (2000 
replications each at multiple effect sizes) under the LMM to estimate power. Because our interest is in between-
group differences in treatment outcomes, it is both appropriate and intuitive to express effect sizes in terms of 
standardized group differences at outcome.  These are calculated from LMM-based marginal means and 
variances of post-treatment outcomes adjusted for baseline outcome measures. In the special cases where the 
LMM reduces to classical ANOVA-type models, these effect size estimates are identical to Cohen’s d, and they 
have the same interpretation in more complex models. Our proposed total sample size of 80 completers yields 
power of 80% at alpha = .05 to detect standardized effects (model-estimated differences between the two groups 
at Week 12) of d = .5, assuming within-participant correlations of .7, which is a somewhat conservative 
correlation compared to our pilot data (r = .8) and previous experience in our lab. Using standard deviation 
estimates from similar patient populations studied in our lab, we estimate that an effect size of d = .5 translates to 
a difference in CAPS scores of approximately 8 points, WHOQOL scores of 1.3 points, and METS scores of 2.7 
units, which we believe are clinically meaningful effects and which are somewhat smaller than observed in our 
pilot data.  There are no existing effect size estimates for calculating power for the mediation hypothesis, Hyp. 1c, 
and our pilot data sample is too small to provide reasonable estimates of mediation effects, as these depend on 
the relationship among several coefficients each of which is estimated with considerable error in a small sample.  
However, taking the point estimates of our pilot treatment effects on WHOQOL and CAPS at face value, we will 
have 80% power to detect a mediation effect of approximately 40% of the total effect of treatment on WHOQOL 
and 22% of the total effect on CAPS scores, using the method of Vittinghoff, Senn, and McCullough94.  The 
mediation effects estimated from our pilot data are approximately 18% for both WHOQOL and CAPS, but with 
95% C.I.’s ranging from -25% (i.e., an effect in the wrong direction) to more than 60%, so these estimates 
provide little information.  Still, our proposed sample size will be able to detect a fairly substantial mediation effect 
if it exists, and a smaller effect is not likely to be clinically important.  
 
Intent-to-treat (ITT) analysis:  Under assumptions of missing at random (MAR), the mixed model yields valid ITT 
estimates by including dropouts as missing data points.  In the two-time point case, in which dropouts have 
baseline measures but no post-treatment measures, these observations contribute little to the analysis, and 
including dropouts in addition to the 80 completers has no appreciable effect on either effect estimates or power.  
In analyses with intermediate time point measures, power should be improved slightly by including mid-point 
dropouts in addition to the 80 completers (i.e., additional data, even if incomplete, can only improve power under 
the assumption of MAR).  However, as discussed the Data Analysis Plan, even though the MAR assumption may 
be reasonable, it is not testable, and it is prudent to conduct a sensitivity analysis to the MAR assumption using 
other ITT methods.  The proposed copy reference (CR) imputation method essentially assigns the treatment 
dropouts to a post-dropout trajectory similar to the control group, while still assigning them to the treatment group 
for analysis. It thus reduces estimated effect size in a principled way compared to the MAR analysis.  This does 
not affect power directly, but it does so indirectly by reducing the effect size estimate.  In our simulations, a worst 
case scenario has all of the dropouts occurring immediately after randomization, with no data beyond baseline.  
This would reduce an effect size of .5 to approximately .4, for which we would have power of approximately .64 
rather than .80.