Increasing Physical Activity Among Breast Cancer Survivors With Depression
Phase: NA
Conditions: Depression, Physical Activity, Breast Cancer
Sponsor: University of Texas Southwestern Medical Center

Increasing Physical Activity among Breast Cancer Survivors with Depression 
 
    December 29, 2015 
 
 
CONFIDENTIAL 
This material is the property of the UTSW CDRCC. Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015 
i 
Protocol 
 
Increasing Physical Activity among 
Breast Cancer Survivors with 
Depression 
 
IRB#: 122015-072 
Velos#: 20814  
 
 
Principal Investigator(s):  
Chad D. Rethorst, Ph.D. 
UT Southwestern Medical Center - Center for 
Depression Research and Clinical Care (CDRCC) 
 
 
 
 
6363 Forest Park Rd, Dallas, TX 75235 
 
 
 
 
 
Phone: (214) 648-0153 
 
 
 
 
 
Email: Chad.Rethorst@utsouthwestern.edu 
 
Sub-Investigator(s): 
 
Madhukar Trivedi, MD 
Psychiatry 
 
 
 
 
 
Tracy Greer, Ph.D.  
Psychiatry 
 
Biostatistician: 
 
 
Thomas Carmody, Ph.D.  
 
 
 
 
 
UT Southwestern Medical Center 
 
 
 
 
 
6363 Forest Park Rd., Dallas, TX 75235 
 
Initial Version: 
December 29, 2015 
 
Funding Source:  
 
American Cancer Society 
 
 
UT Southwestern Medical Center (UTSW) 
Center for Depression Research and Clinical Care (CDRCC) 
6363 Forest Park Rd., BL 13.100 
Dallas, TX 75235 
 
 

Increasing Physical Activity among Breast Cancer Survivors with Depression 
 
    December 29, 2015 
 
 
CONFIDENTIAL 
This material is the property of the UTSW CDRCC. Do not disclose or use except as authorized in writing by the study sponsor. 
 
Template Updated: 12/2012; 9/2013; 8/2014; 4/2015; 10/2015 
ii 
 
Signature Page 
 
 
The signature below constitutes the approval of this protocol and the attachments, and provides the 
necessary assurances that this trial will be conducted according to all stipulations of the protocol, 
including all statements regarding confidentiality, and according to local legal and regulatory requirements 
and applicable U.S. federal regulations and ICH guidelines. 
 
 
 
Principal Investigator (PI) Name:_____________________________ 
 
 
 
PI Signature: _____________________________ 
 
 
 
Date:____________________ 
 
 
 

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TABLE OF CONTENTS 
1.0 BACKGROUND .............................................................................................................. 1 
2.0 STUDY OBJECTIVES ..................................................................................................... 2 
3.0 STUDY DESIGN .............................................................................................................. 3 
3.1 Overview of Study Design ..................................................................................................... 3 
3.2 Duration of Study and Study Timeline ................................................................................. 3 
4.0 STUDY POPULATION .................................................................................................... 4 
4.1 Inclusion Criteria .................................................................................................................... 4 
4.2 Exclusion Criteria .................................................................................................................. 4 
4.3 Participant Recruitment and Retention ............................................................................... 4 
5.0 STUDY PROCEDURES .................................................................................................. 5 
5.1 Informed Consent .................................................................................................................. 5 
5.2 Screening ................................................................................................................................ 5 
5.3 Baseline .................................................................................................................................. 5 
5.4 Treatment and Study Intervention ........................................................................................ 5 
5.5 Participant Discontinuation .................................................................................................. 5 
5.6 Participant Remuneration ..................................................................................................... 6 
6.0 STUDY ASSESSMENTS ................................................................................................ 7 
6.1 
Time and Event Table (Events Summary) ........................................................................... 7 
6.2 
Types of Assessments ......................................................................................................... 7 
6.2.1 
Eligibility Screening Measures ........................................................................................ 7 
6.2.2 
Diagnostic and Screening Measures .............................................................................. 7 
6.2.3 
Study Assessments ......................................................................................................... 8 
6.2.4 
Physiological Measures .................................................................................................. 9 
6.2.5 
Safety Assessments ...................................................................................................... 10 
7.0 STUDY TREATMENTS ................................................................................................. 11 
7.1 Physical Activity Intervention ............................................................................................. 11 
7.2 Staff Training ........................................................................................................................ 11 
8.0 STATISTICAL ANALYSES ........................................................................................... 12 
8.1 Primary Analyses ................................................................................................................. 12 
9.0 REPORTING AND MONITORING ................................................................................ 13 
9.1 Statement of Compliance .................................................................................................... 13 
9.2 Regulatory Files ................................................................................................................... 13 
9.3 Informed Consent ................................................................................................................ 13 
9.4 Health Insurance Portability and Accountability Act (HIPAA) ......................................... 14 
9.5 Release of Information ........................................................................................................ 14 
9.6 Study Documentation .......................................................................................................... 14 
9.7 Records Retention and Requirements ............................................................................... 14 
9.8 Safety Monitoring ................................................................................................................. 14 
9.8.1 
Data and Safety Monitoring ........................................................................................... 14 
9.8.2 
Protocol Violations Reporting and Management ........................................................... 14 

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9.8.3 
Subject Confidentiality/Privacy ...................................................................................... 15 
9.8.4 
Adverse Events (AEs) and Serious Adverse Events (SAEs) ........................................ 15 
9.8.5 
Definitions of Adverse Event and Serious Adverse Event ............................................ 15 
9.8.6 
Non-Reportable Adverse Event and Serious Adverse Events ...................................... 15 
10.0 DATA MANAGEMENT AND PROCEDURES ............................................................ 17 
10.1 Data Collection Forms ......................................................................................................... 17 
10.2 Data Acquisition and Entry ................................................................................................. 17 
11.0 HUMAN SUBJECTS PROTECTION ........................................................................... 18 
 
 

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LIST OF ABBREVIATIONS 
AE 
 
Adverse Event 
BMI 
 
Body Mass Index 
CDRCC 
Center for Depression Research and Clinical Care 
ERC  
Ethics Review Committee 
GCP  
Good Clinical Practice 
IRB 
 
Institutional Review Board 
MDD  
Major Depressive Disorder 
MOST  
Multi-Phase Optimization Strategy 
MVPA  
Moderate-to-Vigorous Physical Activity 
SAE  
Serious Adverse Event 

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STUDY SUMMARY 
Title 
Increasing Physical Activity among Breast Cancer Survivors with 
Depression 
Short Title 
Physical Activity in Breast Cancer Survivors with Depression 
Protocol Number 
122015-072 
Phase 
N/A 
Methodology 
Pilot study of a physical activity intervention among breast cancer 
survivors with depression 
Study Duration 
25 weeks 
Study Center(s) 
Single-center, UT Southwestern Center for Depression Research and 
Clinical Care 
Objectives 
Evaluate the feasibility of implementing a multi-component physical 
activity intervention in breast cancer survivors with significant depressive 
symptoms. 
Number of Subjects 
50 
Diagnosis 
and 
Main 
Inclusion Criteria 
Eligible breast cancer survivors between 3 months and 5 years post-
treatment. 
1) Positive depression screen (PHQ-9 score > 8) or current 
antidepressant treatment 
2) Report <150 minutes of weekly moderate-to-vigorous physical activity 
(MVPA) on the GPAQ 
3) Physically able to engage in physical activity 
4) Written and verbal fluency in English. 
Statistical Methodology 
A total of 50 patients will be enrolled in this pilot study. The primary 
objective of this study is to determine the feasibility of implementing a 
multi-component physical activity intervention among breast cancer 
survivors with depression. A preliminary analysis of changes in physical 
activity and depressive symptoms will be conducted following the 
physical activity intervention. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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1.0 
BACKGROUND 
The over 2.9 million breast cancer survivors in the United States face significant post-
treatment health burdens. Five-year recurrence rates for Stage I-III breast cancer survivors 
range from 7-13%1 and a subset of breast cancer survivors (e.g., BRCA1/2 mutation carriers) 
may also have increased risks for other cancers.2 Breast cancer survivors have significant 
medical comorbidities, symptom burdens, and late effects that decrease quality of life and affect 
prognosis.3 Substantial gaps remain in our understanding of how to improve prognosis for this 
rapidly growing population. Depression and physical inactivity are inter-related, but modifiable, 
risk factors associated with prognosis among breast cancer survivors. The proposed pilot 
project will assess the implementation of evidence-based strategies for increasing physical 
activity among breast cancer survivors. Successful completion of project aims will result in 
crucial pilot data to support future grant applications to identify optimal strategies for 
increasing physical activity in breast cancer survivors. 
 
Depression and Cancer Prognosis. Depression is a common comorbidity in breast cancer 
survivors and an important factor associated with poor prognosis. Individual studies 
estimate the prevalence of Major Depressive Disorder (MDD) in breast cancer survivors to 
range from 10-30%.4 When including dysthymia and minor depression, the rates of mood 
disorders in breast cancer survivors are estimated to be as high as 50%.5,6 More importantly, 
depressive symptoms are linked to higher rates of mortality among breast cancer 
survivors. A recent meta-analysis integrated 76 prospective studies, including those in which 
depression was assessed prior to cancer diagnosis and those that assessed depression after 
diagnosis. Results indicated an 18% increase in mortality for breast cancer patients with 
depression.7 Conversely alleviation of depressive symptoms in breast cancer patients is 
associated with longer survival,8 suggesting the importance of evidence-based interventions 
targeting depression. 
 
Physical Activity and Cancer Prognosis. Evidence links physical activity and survival in 
following breast cancer but the role of inflammatory biomarkers in this relationship has 
not been adequately examined.9 The largest longitudinal studies10-14 report consistent 
decreased risk of breast cancer mortality (ranging from 39% to 51%) among physically active 
breast cancer survivors. These studies also find physical activity associated with a reduced risk 
of all-cause mortality, ranging from 27% to 56%. 
 
Physical Activity and Depression. Numerous trials, including our own work described in 
Section (3.3.2), have assessed the efficacy of aerobic exercise as a treatment for 
depression. Meta-analyses summarizing these studies have reported effect sizes ranging from 
0.83 to 1.39 which are comparable to effects of antidepressant medications.15 The effects of 
exercise on depression specifically among cancer survivors have also been widely examined. A 
recent meta-analysis16 identified 15 RCTs that have examined the effect of exercise on 
depressive symptoms in cancer survivors. This meta-analysis estimated an effect size (Cohen’s 
d) of 0.22, suggesting a small-to-moderate effect of exercise on depressive symptoms in cancer 
survivors.  
 
 

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2.0 
STUDY OBJECTIVES 
2.1 
Although multiple strategies for increasing physical activity have proven 
efficacious, little is known about the optimal intervention strategies for 
breast cancer survivors or how those interventions can be effectively 
implemented in real-world settings. The proposed pilot project will 
assess the implementation of evidence based strategies for increasing 
physical activity among breast cancer survivors. Results from this pilot 
project will support future grant applications. These future studies will 
utilize multi-phase optimization strategy (MOST) to identify the optimal 
combination of intervention strategies to increase physical activity 
among breast cancer survivors. 
Aim 1. Evaluate the feasibility of screening and subject recruitment through targeted 
mailings to breast cancer survivors using the UT Southwestern cancer registries.  
Aim 1A. Assess the percentage of contacted survivors completing online questionnaires.  
Aim 1B. Assess the percentage of respondents meeting eligibility criteria (< 150 minutes of 
physical activity per week and > 8 on the PHQ-9). 
Aim 1C. Assess the percentage of eligible respondents enrolled in the physical activity 
intervention. 
Aim 2. Evaluate the feasibility of implementing a multi-component physical activity 
intervention in breast cancer survivors with significant depressive symptoms. 
Aim 2A. Physical activity program compliance. 
 
Aim 2A.a. Assess the percentage of physical activity classes attended 
 
Aim 2A.b. Assess the percentage of days of use of the self-monitoring device 
Aim 2B. Participant-reported program satisfaction 
Aim 3. Conduct preliminary analysis of changes in physical activity and depressive 
symptoms following the physical activity intervention. 
Hypothesis 1. Participants in the physical activity program will demonstrate increases in physical 
activity at three and six months 
Hypothesis 2. Participants in the active living program will demonstrate decreases in depressive 
symptoms at three and six months post-baseline. 
Cancer Relevance: This project simultaneously targets two factors (depression and inactivity) 
related to poor outcomes in breast cancer survivors and provide important information on how to 
effectively address these risk factors in a real-world setting. 
 
 

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3.0 
STUDY DESIGN 
3.1 
Overview of Study Design 
The research project is a pilot study to assess the effects of a multi-component intervention in 
increasing physical activity among breast cancer survivors with depression. Breast cancer 
survivors listed in the UT Southwestern Simmons Cancer Center cancer registry will be 
contacted via mail and invited to complete a brief online questionnaire. Those indicating 
insufficient levels of physical activity and increased depressive symptoms will be invited to 
participate. The 12-week physical activity intervention will consist of three evidence-based 
strategies: print-based materials, active living classes, and activity self-monitoring. 
 
3.2 
Duration of Study and Study Timeline 
Recruitment of participants will begin in February 2016. We aim to recruit a cohort of 10 
subjects in per month through June 2016 for a total of 50 subjects.  
 

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4.0 
STUDY POPULATION 
4.1 
Inclusion Criteria 
1) positive depression screen (PHQ-9 score > 8) or current antidepressant treatment 
2) report <150 minutes of weekly moderate-to-vigorous physical activity (MVPA) on the 
GPAQ 
3) physically able to engage in physical activity 
4) written and verbal fluency in English. 
4.2 
Exclusion Criteria 
1) medical condition contraindicating physical activity participation 
2) cognitively unable to give informed consent 
3) non-English speaking. 
4.3 
Participant Recruitment and Retention 
Based on previously published work utilizing contact of breast cancer survivors from the cancer 
registry system,17 we anticipate that approximately one-third (33%) of the contacted survivors 
(n=150) will return the questionnaire and agree to future contact to learn more about further 
physical activity interventions. Based on indications of physical activity frequency from the 
screening questionnaire, we will invite those who meet eligibility criteria (estimated to be at least 
33% of respondents [n=50], based on national prevalence of sedentary behavior and 
depression among breast cancer survivors) to attend an initial in-person screening and baseline 
assessment session. 

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5.0 
STUDY PROCEDURES 
5.1 
Informed Consent 
Interested persons identified as potential participants will be given an explanation of the study 
and will undergo a brief pre-screening with trained study personnel. Interested and preliminarily 
eligible participants will begin the informed consent process. Study personnel will explain the 
details of the study to the potential participant and then give him or her time to read through the 
informed consent document. Study personnel will then go through the document with the 
potential participant and answer any questions he or she may have. Potential participants who 
choose to provide informed consent and sign the informed consent form will then proceed to the 
screening assessment.  
5.2 
Screening 
Breast cancer survivors listed in the UT Southwestern Simmons Cancer Center cancer registry 
will be contacted through an informational letter via mail inviting them to participate in the 
current study. The letter will include information about the current study and directions to 
complete an online eligibility screening questionnaire. Potential participants will be screened for 
eligibility based on all inclusion and exclusion criteria, detailed in sections 4.1 and 4.2. All 
participants who are screened will complete the Demographics Form.  
5.3 
Baseline 
Potential subjects will meet with a trained project interventionist to be assessed for safety of 
engaging in physical activity, following recommendations identified in the ACSM guidelines.18 
The Physical Activity Readiness Questionnaire (PAR-Q)19 is a self-report questionnaire 
designed to assess safety of engaging in physical activity. In addition, lymphedema and pain will 
be assessed at baseline and throughout the program to ensure participant safety. Subjects will 
also be instructed to contact their physician to ensure their safety engaging in physical activity. 
 
Study assessments (described in section 6.0) will be conducted at the baseline assessment 
visit. Participants will complete the PAR-Q to identify potential medical contraindications. 
Participants indicating potential contraindications to exercise will be instructed to discuss 
participation with their physician before engaging in physical activity. 
 
Blood samples will be collected at the baseline assessment visit. 
5.4 
Treatment and Study Intervention 
Participants will be enrolled in the physical activity intervention described in sections 7.0 
Assessments will be conducted based on the schedule outlined in section 6.0. Qualified, 
trained, and certified personnel will conduct clinician-rated assessments (all assessments which 
are not self-report). During the trial, the outcome assessments will be obtained at Weeks 1, 13, 
and 25. Participants will be asked to wear an accelerometer during Weeks 1, 13 and 25. If the 
participant is not able to come to the site and (s)he agrees, some assessments and/or visits 
may be conducted by phone, by mail, or at appropriate off-site locations, and/or on participants’ 
or other off-site computers via the secure study website(s) if access to a computer with internet 
service is available. Detailed descriptions of the assessments are provided in section 6.0. 
5.5 
Participant Discontinuation 
In order to ensure safety, female participants who become pregnant during the study will be 
required to discontinue participation in the intervention. Participants may be asked to stop study 
intervention if any situation arises that, in the investigator’s judgment, poses a safety risk. 

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Participants who must stop the study intervention will still be asked to complete assessment 
visits as scheduled. 
 
5.6 
Participant Remuneration 
Participants will receive monetary remuneration for their participation in the trial to compensate 
for their time, travel arrangements, and the burden of participation. Essential to the study is 
appropriate support for participants’ time and effort contributing to the study. Reimbursement for 
attending data collection visits will be made based on the following schedule: 
• 
Reimbursements will be made for participants who complete the initial survey. 
• 
Reimbursements will also be made for the assessment visits (Baseline and Weeks 13 
and 25). 
25 participants who complete the eligibility screening assessments (described in section 6.2.1) 
will be chosen randomly to receive a $100 gift card. 
Participants will be paid for each eligible visit using a UT Southwestern Greenphire ClinCard, 
which can be used as a credit or debit card. Participants will also receive instructions on how 
use the card.  In order receive study payments, the participant’s name, address, date of birth 
and Social Security Number (SSN) will be collected by the research staff.  All information will be 
stored in a secure fashion and will be deleted from the UT Southwestern Greenphire ClinCard 
system once the study has been completed. 
 
 

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6.0 
STUDY ASSESSMENTS 
6.1 
Time and Event Table (Summary of Assessments) 
  
Screening 
Baseline 
Week 13 
Week 25 
Demographics 
x 
 
 
 
Locator Form 
x 
  
  
 
Prior and Concomitant Medications 
x 
  
  
 
PAR-Q 
x 
 
 
 
PHQ-9 
x 
 
 
 
GPAQ 
x 
 
 
 
QIDS-SR 
 
x 
x 
x 
SF-36 
 
x 
x 
x 
PSQI 
 
x 
x 
x 
BFI 
 
x 
x 
x 
FACT-B 
 
x 
x 
x 
Brief COPE 
 
x 
x 
x 
SHAPS 
 
x 
x 
x 
STAI 
 
x 
x 
x 
Relationship status 
 
x 
 
 
Couples Satisfaction Index (CSI) 
 
x 
 
 
MGH-ATRQ 
 
x 
 
 
PASC-Q 
 
x 
x 
x 
PASE-Q 
 
x 
x 
x 
Blood draw 
 
x 
x 
x 
Accelerometer (activity and sleep) 
 
x 
x 
x 
 
6.2 
Types of Assessments 
6.2.1  Eligibility Screening Measures 
Demographics Form. The demographics form will be administered to all participants at the 
baseline visit. The form consists of basic demographic information (e.g., gender, race/ethnicity, 
etc.). 
Patient Health Questionnaire-9 (PHQ-9). The PHQ-920 is a 9-item scale designed to measure 
depressive symptoms. We will use the PHQ-9 to identify patients with elevations in depressive 
symptoms. Patients scoring 8 or higher on the PHQ-9 will be eligible for participation in the 
study. Large meta-analyses support the utility of the PHQ-9 in identifying MDD and assessing 
depressive symptom severity.21,22  
General Physical Activity Questionnaire (GPAQ). The GPAQ23 is a 16-item scale designed to 
assess physical activity across three domains (work, transportation, and recreation). We will use 
the GPAQ to identify patients that do not currently meet physical activity recommendations of 
150 minutes of weekly moderate-intensity physical activity. 
6.2.2  Diagnostic and Screening Measures 
Locator Form. The Locator Form will be used to obtain contact information for each participant. 
The Locator Form will be filled out at the screening visit and then routinely updated on a monthly 

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basis thereafter (excluding the final visit). In addition, a Locator Form may be 
completed/updated any time the participant reports a change in contact information. 
Prior and Concomitant Medications. The Prior and Concomitant Medications form assesses 
prescribed medications taken by the participant. The Prior and Concomitant Medications form 
will be administered at the screening visit and then monthly thereafter, if the participant 
endorses a change in medication status. 
Physical Activity Readiness Questionnaire-Revised (PAR-Q). The PAR-Q19 asks 7 health-
related questions to determine whether a person needs to consult with their physician prior to 
engaging in an exercise program. The PAR-Q will be administered at the screening visit. 
 
6.2.3 Study Assessments 
Measurements of Physical Activity: 
Actigraph GT3X+ accelerometer. – The Actigraph will provide a valid and reliable objective 
assessment of physical activity.24 Subjects will be asked to wear the device for a 7-day 
period at each assessment time point (baseline and weeks 13 and 25). Subjects will be 
instructed to wear the device on their non-dominant arm and to remove the device only 
when it may become submerged in water (bathing, swimming, etc.). Following, the 7-day 
period, subjects will return the accelerometers using a postage-paid envelope. 
Measurement of Psychosocial and Physical Outcomes: 
Quick Inventory of Depressive Symptomatology – Self-Rated (QIDS-SR16). The QIDS-SR16 
25-27 is a 16-item questionnaire to assess severity of depression-specific symptoms. The 
QIDS-SR16 has high reliability (Cronbach’s alpha of 0.83), good concurrent validity 
(correlations between the QIDS-SR16 and the 17-item Hamilton Rating Scale for Depression 
is 0.81)25.  
Short Form 36 Health Survey (SF-36). The SF-3628 is a 36-item survey of patient-reported 
general health and quality of life across eight domains of well-being (physical functioning, 
social functioning, vitality, pain, general health, physical role functioning, emotional role 
functioning, and mental health). 
Pittsburgh Sleep Quality Index (PSQI). The PSQI29 is a 19-item scale designed to assess 
sleep quality and disturbances. Scores range from 0 to 21 with higher scores representing 
worse sleep quality. The PSQI has demonstrated reliability (Cronbach’s alpha of 0.80) in the 
assessment of self-reported sleep quality and validity when compared to sleep diaries and 
polysomnography.30  
Brief Fatigue Inventory (BFI). The BFI31 is a 9-item scale designed to assess fatigue. The 
BFI demonstrates good reliability (Cronbach’s alpha of 0.96) and validity (correlation of 0.86 
with the POMS fatigue subscale).  
Functional Assessment of Cancer Therapy – Breast (FACT-B) – The FACT-B32 is a 44-item 
scale designed to measure multidimensional quality of life in breast cancer patients. The 
FACT-B has demonstrated reliability (Cronbach’s alpha of 0.90) and concurrent validity 
(0.87 correlation with the Functional Living Index-Cancer and 0.86 correlation with the 
Functional Assessment of Cancer Therapy-General). 
Brief COPE. The Brief Cope33 is a 28-item scale designed to assess a wide range of coping 
responses. The Brief COPE has been used in studies of cancer patients and demonstrates 
good reliability and validity. 

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Snaith-Hamilton Pleasure Scale (SHAPS). The SHAPS34 is a 14-item scale that measures 
anhedonia, the inability to experience pleasure. The SHAPS has adequate construct validity, 
satisfactory test-retest reliability (ICC=0.70) and high internal consistency has also been 
reported (Cronbach’s alpha of 0.94).  
State Trait Anxiety Inventory (STAI). The STAI35 is a 40-item scale that measures state and 
trait anxiety.  
Anthropomorphic assessments. Height will be assessed at baseline. Weight and waist 
circumference will be measured at each assessment time point. Height and weight 
measurements will be used to calculate Body Mass Index (BMI).  
Metabolic indices. Blood samples will be collected by a trained phlebotomist to allow for 
evaluation of markers of metabolic health, including blood glucose, triglycerides, and lipids. 
Antidepressant Medication Use. The Massachusetts General Hospital Antidepressant 
Treatment History Questionnaire (MGH-ATRQ) will be assess the current use 
antidepressant medication. 
Relationship Status. A single-item question will ask participants to indicate their current 
relationship status from one of 7 categories (single, never married; cohabiting with partner; 
married, living together; married, not living together; separated; divorced; widowed). The 
Couples Satisfaction Index (CSI)36 is a 16-item form that captures relationship quality among 
participants who endorsed currently being in a romantic relationship. The CSI is a well-
validated and reliable measure that draws from other previously established relationship 
satisfaction measures. 
 
At the end of the program we will conduct a self-report questionnaire aimed at evaluation 
participants’ satisfaction with the program. This questionnaire will include Likert-scale questions 
about: 1) satisfaction with the program; 2) program engagement/adherence; 3) program 
enjoyment; 4) perception of program effectiveness; 5) willingness to recommend program to 
others; 6) barriers to program participation; 7) intent to maintain physical activity; and 8) 
attitudes toward physical activity. This assessment will allow for further refinement of the 
intervention to ensure its sustainability and broad dissemination. 
Psychological Mediators/Moderators of Physical Activity Behavior Change: 
Physical Activity Stages of Change Questionnaire. The 4-item scale assesses the current 
stage within the Transtheoretical Model framework (Pre-contemplation, Contemplation, 
Preparation, Action, Maintenance). These stages are highly correlated with change in 
physical activity over time.37 
Physical Activity Self-Efficacy Questionnaire. The 3-item scale assesses self-efficacy for 
physical activity. Activity-specific self-efficacy is highly correlated with activity change and 
psychosocial outcomes.37 
6.2.4 Physiological Measures 
Physiological Measures. Physiological measures include height, weight, body mass index (BMI) 
and waist circumference.  Height will be obtained once at baseline and the other measures will 
be obtained at each assessment visit.  
6.2.5 Safety Assessments 
Assessments involved in determining participants’ ability to safely participate in the protocol 
(maximal exercise testing, laboratory tests, and physical exam) are described under Diagnostic 

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and Screening Measures. Additionally, reportable AEs and all SAEs will require completion of 
an AE Form (and SAE form as applicable) to document and track reportable AEs. 

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7.0 
STUDY TREATMENTS 
7.1 
Physical Activity Intervention 
Print-based education 
All participants will receive print-based education focused on physical activity. Provision of 
print-based materials can result in significantly increases physical activity as demonstrated in a 
study by Vallance et al.38 in which breast cancer survivors who received the book, Exercise for 
Health: An Exercise for Breast Cancer Survivors, increased their physical activity levels by 70 
minutes per week.38 All subjects in the current project will be given a copy of Exercise for 
Health: An Exercise Guide for Breast Cancer Survivors,38,39 a 56-page book based on the theory 
of planned behavior. The book was developed and evaluated by experts in the field 39 and has 
been proven efficacious in increasing physical activity in breast cancer survivors.38 Topics 
covered within the book include benefits of exercise in breast cancer survivors; 
recommendations on type, duration, frequency and intensity of exercise; goal-setting; and 
advice on overcoming common barriers. 
Self-monitoring 
Subjects will be provided with a commercially available activity monitor (i.e., Fitbit). The 
project interventionist will instruct subjects on proper use of the device and options for viewing 
the data collected by the device. Subjects will be instructed to wear the device daily. Those with 
access to smartphones or computers will be instructed to upload data on a regular basis for 
continuous self-monitoring. These devices are compatible with both Android and Apple phones 
or can be synced with any computer with internet access. Individuals without access to a 
compatible device will be given paper logs and instructed to record their activity counts provided 
by the activity monitor on a daily basis.  
Active Living counseling 
The Active Living counseling program will consists of 12 weekly group educational sessions, 
facilitated by project interventionists. Interventionists will be trained in delivery of the ALED 
program. These sessions will involve discussion of topics related to increasing physical activity, 
including: identifying and overcoming barriers, setting goals, social support, and time 
management.  
Facility Access 
Subjects will have access to the exercise lab in the UT Southwestern Depression Center 
consisting of equipment for aerobic exercise (treadmills, stationary bikes, etc.). Subjects can 
schedule times to access the facility. The facility will be staffed by the Exercise Interventionist or 
PI at all times. 
 
7.2 
Staff Training 
The study staff will be trained and certified as specified in the Manual of Procedures and Study 
Tools Manual. Training will cover protocol-specific training as needed (e.g., assessments, study 
interventions, fidelity to the protocol and safety procedures, data management and collection, 
research procedures including understanding reliability and validity, and problem solving), as 
well as any IRB-required trainings  

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8.0 
STATISTICAL ANALYSES 
8.1 
Primary Analyses 
Based on recommendations of Leon et al.,40 the Aims 1 and 2 will examine the feasibility of 
implementing a physical activity intervention for breast cancer survivors. The feasibility of the 
study will be assessed by the following criteria: 
1) Screening - the number of subjects screened through the web-based questionnaire and 
the percentage of those screened who meet program eligibility requirements  
2) Recruitment - the percentage of screened subjects that are ultimately enrolled 
3) Intervention Compliance – defined as percentage of weekly exercise does completed by 
participants randomized to the exercise condition 
4) Retention – defined as percentage of assessments completed 
 
Consistent with Aim 3, we will conduct a data analysis examining the effects of the intervention 
on physical activity and depressive symptoms. A mixed-effects repeated measures model will 
be used to analyze the primary outcome measures (minutes of MVPA and QIDS-C scores). The 
independent variables in the model will be time (weeks 1, 13, and 25)(within-subjects factor). 
The model will allow for random slopes and intercepts while all other factors will be fixed effects. 
The baseline value of the dependent variable will be included as a covariate as will the other 
potential covariates if needed [age, race, gender, history of depression]. The need for higher 
order times terms or the transformation log (time+1) to obtain a better fitting model will be 
considered. The goodness of fit of the final model will be investigated. The analysis will use all 
available data from all randomized patients with at least one post-baseline visit (i.e., modified 
“intent to treat” sample) and all tests will be two-sided with alpha of .05 used for significance. 
The hypothesis will be tested by the significance of the time effect main effect. The analysis will 
be done using SAS Proc Mixed. Statistical analysis will be completed by Thomas Carmody, 
PhD within the Center for Depression Research and Clinical Care.  

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13 
 
9.0 
REPORTING AND MONITORING 
9.1 
Statement of Compliance 
This trial will be conducted in compliance with the appropriate protocol, appropriate ICH 
guidelines (including current Good Clinical Practice [GCP]), the principles of the Declaration of 
Helsinki, and all other applicable regulatory requirements. The study team must obtain written 
approval of the study protocol, consent form, other supporting documents, and any advertising 
for participant recruitment from the UT Southwestern institutional review board (IRB) in order to 
participate in the study. Prior to study initiation, the protocol and the informed consent 
documents will be reviewed and approved by an appropriate Ethics Review Committee (ERC) 
or IRB. Any amendments to the protocol or consent materials must be approved before they are 
implemented. Annual progress reports and Serious Adverse Event (SAE) reports will be 
submitted to each IRB, according to its usual procedures. 
9.2 
Regulatory Files 
The regulatory files should contain all required regulatory documents, study-specific documents, 
and all important communications. Regulatory files will be reviewed at each participating site for 
regulatory document compliance prior to study initiation, throughout the study, as well as at the 
study closure. 
9.3 
Informed Consent 
The informed consent form is a means of providing information regarding the trial to a 
prospective participant and allows for an informed decision about participation in the study. The 
informed consent will be approved by their IRB(s). Every study participant is required to sign a 
valid, IRB-approved current version of the study informed consent form prior to the initiation of 
any study related procedures. The original signed informed consent for every participant will be 
stored in a locked, secure location that is in compliance with their IRB and institutional. Every 
study participant must be offered a copy of the signed consent form. Participants may contact 
site personnel with any questions after signing Informed Consent. 
Prior to signing the informed consent form, research staff who are knowledgeable about the 
study will explain the study to the potential participant and provide the participant with a copy of 
the consent to read. If the participant is interested in participating in the study, a researcher who 
is authorized to obtain informed consent will review each section of the informed consent form in 
detail, answer any of the participant’s questions, and determine if the participant comprehends 
the information provided by administering the comprehension tool. The participant will consent 
by signing and dating the consent document. The person obtaining consent will also sign and 
date the consent document. The consent must be properly executed and complete to be valid. It 
is strongly recommended that another research staff member review the consent after it is 
signed to ensure that the consent is properly executed and complete. All persons obtaining 
consent must have completed appropriate training. 
The informed consent form must be updated or revised whenever important new safety 
information is available, or whenever the protocol is amended in a way that may affect a 
participants’ participation in the trial. A copy of the informed consent will be given to a 
prospective participant to review during the consent process and to keep for reference. The 
participant will be informed that their participation is voluntary and they may withdraw from the 
study at any time, for any reason without penalty. 
Study participation is voluntary and there are no benefits lost if an individual declines 
participation. Individuals who refuse to participate or who withdraw from the study will be treated 

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14 
 
without prejudice. Study sites will be responsible for maintaining signed consent forms as 
source documents for quality assurance review and regulatory compliance. 
Participants will be offered copies of the signed informed consent form, and the originals will be 
stored in a secure location at each study site. Contract and local monitors will inspect the 
informed consent forms periodically to ensure that correct signatures and dates were obtained 
on valid informed consent forms prior to any study interventions. 
9.4 
Health Insurance Portability and Accountability Act (HIPAA) 
Study sites may be required by their institutions to obtain authorization from participants for use 
of protected health information. Sites will be responsible for communicating with their IRBs or 
Privacy Boards and obtaining the appropriate approvals or waivers to be in regulatory 
compliance. 
9.5 
Release of Information 
Study participants will be asked to sign a release of information form that will give study staff 
permission to seek and acquire their treatment records. This release of information is voluntary. 
There will be no benefits lost if study participants refuse to release information. They may 
continue to participate in the study. 
9.6 
Study Documentation 
Study documentation includes all case report forms, data correction forms, workbooks, source 
documents, monitoring logs and appointment schedules, sponsor-investigator correspondence, 
and signed protocol and amendments, Ethics Review Committee or Institutional Review 
Committee correspondence and approved consent form and signed participant consent forms. 
Source documents include all recordings of observations or notations of clinical activities and all 
reports and records necessary for the evaluation and reconstruction of the clinical research 
study. Whenever possible, the original recording of an observation should be retained as the 
source document; however, a photocopy is acceptable provided that it is a clear, legible, and 
exact duplication of the original document. 
9.7 
Records Retention and Requirements 
All research records for all subjects will be stored by the investigator in a secure location to be 
accessed only by authorized research personnel. Study records will be stored in accordance 
with local IRB, State, and Federal Regulations but, in any case, will be kept for a minimum of  
7 following study completion. 
9.8 
Safety Monitoring 
9.8.1 Data and Safety Monitoring 
Drs. Rethorst and Trivedi will meet weekly to examine accumulating data to assure protection of 
participants’ safety while the study’s scientific goals are being met. These meetings will 
determine whether there is support for continuation of the trial, or evidence that study 
procedures should be changed, or if the trial should be halted, for reasons relating to the safety 
of the study participants, the efficacy of the treatment under study, or inadequate trial 
performance (e.g., poor recruitment). 
9.8.2 Protocol Violations Reporting and Management 
A protocol departure is any departure from procedures and requirements outlined in the 
protocol. Protocol departures may occur on two levels, deviation versus violation. The difference 
between a protocol deviation and violation has to do with the seriousness of the event and the 
corrective action required. A protocol deviation is considered an action (or inaction) that by itself 

Increasing Physical Activity among Breast Cancer Survivors with Depression 
    
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15 
 
is not likely to affect the scientific soundness of the investigation or seriously affect the safety, 
rights, or welfare of a study participant.  Protocol violations are departures that may compromise 
the participant safety, participant rights, inclusion/exclusion criteria or study data and could be 
cause for corrective actions if not rectified or prevented from re-occurrence. Protocol violations 
will be monitored for (1) significance, (2) frequency, and (3) impact on the study objectives, to 
ensure the integrity of the trial. The PI or designee will make the decision about whether a 
departure from the protocol will be designated as a protocol deviation or a protocol violation. All 
protocol violations and deviations will be reported to the IRB as required.  
9.8.3 Subject Confidentiality/Privacy 
Participant records will be held confidential by the use of study codes for identifying participants 
on CRFs, secure and separate storage of any documents that have participant identifiers, and 
secure computing procedures for entering and transferring electronic data. 
All research information obtained on participants is confidential, and disclosure to any third 
parties without specific authorization is strictly prohibited. To maintain subject privacy, all study 
forms and reports will be identified by a coded study identification number only. No subject 
identifying information will be included in any presentations or publications resulting from the 
study. 
Study records may be inspected by the sponsor and its authorized representatives, other 
government agencies such as the U.S. Department of Health and Human Services (DHHS) 
Office for Human Research Protections (OHRP), authorized Node Staff, or the local IRB for 
quality assurance purposes. 
9.8.4 Adverse Events (AEs) and Serious Adverse Events (SAEs) 
The Primary Investigator (PI) may appoint a Study Clinician (MD, PhD, or PI) for this study, who 
will review or provide consultation for each Serious Adverse Event (SAE) as needed. These 
reviews will include an assessment of the possible relatedness of the event to the study 
intervention or other study procedures. The Study Clinician will also provide advice for decisions 
to exclude, refer, or withdraw participants as required. The study staff will be trained to monitor 
for and report Adverse Events and Serious Adverse Events. 
9.8.5 Definitions of Adverse Event and Serious Adverse Event 
Standard definitions for Adverse Events and Serious Adverse Events, their identification, 
characterization regarding severity and relationship to the study intervention and processing are 
described in Appendix 1. 
9.8.6 Non-Reportable Adverse Event and Serious Adverse Events 
Adverse Events 
For the purpose of this study, the following AEs will not require reporting in the data system and 
will not be captured: 
• 
Grade 1 (mild) unrelated event. 
• 
Grade 2 (moderate) unrelated event. 
This would typically include physical events such as headache, cold, etc that was considered 
unrelated to study participation by the PI. 
Serious Adverse Events 
For the purpose of this study, the following SAEs will not be recorded in the data system but will 
be documented: 

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• 
Admission to a hospital/surgery center for preplanned/elective surgeries (captured in 
the Visit Summary/Progress Note). 
• 
Admission to a hospital for scheduled labor and delivery (captured in the Visit 
Checklist/Progress Note). 
Local documentation and reporting guidelines should also be followed based on IRB 
requirements. 

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10.0 
DATA MANAGEMENT AND PROCEDURES 
10.1 
Data Collection Forms 
The data collection process consists of data entry into the CRFs according to the instructions 
provided and project specific training. The investigator is responsible for maintaining accurate, 
complete and up-to-date records, and for ensuring the completion of the CRFs for each 
research participant. Selected CRFs may also require the investigator’s written signature. CRFs 
will be monitored for completeness, accuracy, and attention to detail throughout the study. 
10.2 
Data Acquisition and Entry 
Data entry into an electronic database shall be performed by authorized individuals. Data will be 
double entered to ensure accuracy. 

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11.0 
HUMAN SUBJECTS PROTECTION 
All requirements relating to obtaining institutional review board (IRB) review and approval and 
informed consent will be met. Written informed consent will be obtained from each study 
participant utilizing the local IRB-approved informed consent form. Appropriate research 
personnel will explain all aspects of the study to each participant, answering all questions and 
ensuring that all basic elements of the informed consent process are covered. 
All study personnel will be required to complete Human Subject Protection, Good Clinical 
Practice and HIPAA training (as required) and will be instructed to act under those guidelines at 
all times when working with participants, participants data or protected participant health 
information. 

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Holmes MD, Chen WY, Feskanich D, Kroenke CH, Colditz GA. Physical activity 
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Kroenke K, Spitzer RL, Williams JBW. The PHQ-9. J. Gen. Intern. Med. 
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Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and 
Self-Report (QIDS-SR) in public sector patients with mood disorders: a 
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(QIDS-SR): a psychometric evaluation in patients with chronic major depression. 
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Backhaus J, Junghanns K, Broocks A, Riemann D, Hohagen F. Test-retest 
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Brady MJ, Cella DF, Mo F, et al. Reliability and validity of the functional 
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Carver CS. You want to measure coping but your protocol's too long: Consider 
the brief COPE. Int J Behav Med. 1997;4(1):92-100. 
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Franken IH, Rassin E, Muris P. The assessment of anhedonia in clinical and non-
clinical populations: further validation of the Snaith-Hamilton Pleasure Scale 
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35. 
Spielberger CD. Assessment of state and trait anxiety: Conceptual and 
methodological issues. Southern Psychologist. 1985. 
36. 
Funk J, Rogge R. Testing the ruler with item response theory: increasing 
precision of measurement for relationship satisfaction with the Couples 
Satisfaction Index. Journal of family psychology: JFP: journal of the Division of 
Family Psychology of the American Psychological Association (Division 43). 
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37. 
Marcus BH, Forsyth L. Motivating people to be physically active. Human Kinetics; 
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Vallance JKH, Courneya KS, Plotnikoff RC, Yasui Y, Mackey JR. Randomized 
controlled trial of the effects of print materials and step pedometers on physical 
activity and quality of life in breast cancer survivors. Journal of Clinical Oncology. 
2007;25(17):2352-2359. 
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Vallance JK, Courneya KS, Taylor LM, Plotnikoff RC, Mackey JR. Development 
and evaluation of a theory-based physical activity guidebook for breast cancer 
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40. 
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22 
 
 
 
 
 
 
 
APPENDIX 1 
Adverse Event Reporting Definitions and Procedures 
1.0 
Definitions of Adverse Events and Serious Adverse Events 
1.1 
Adverse Event (AE) 
An adverse event (AE) is defined as any reaction, side effect, or untoward event including any 
new illness, symptom, sign or worsening of a pre-existing condition or abnormality that occurs 
during the course of an individual’s participation in a clinical trial, whether or not the event is 
considered related to the clinical trial intervention. 
Stable chronic conditions, such as arthritis, which are present prior to an individual’s enrollment 
in a clinical trial and that do not worsen during the course of their participation are not 
considered AEs. In order to avoid the reporting of pre-existing conditions as new AEs, and to 
assist with the assessment of a condition that may have worsened in intensity or severity, a 
thorough medical history should be performed during the eligibility assessment phase to record 
any chronic, acute, or intermittent preexisting or current illnesses, diseases, symptoms, or 
laboratory signs. 
An AE case report form (CRF) is used to capture reported AEs (as defined by the protocol) and 
may also be used to record follow-up information for unresolved or ongoing events that were 
reported previously. 
A site study investigator is responsible for reviewing and characterizing each AE that is 
reported, and is expected to follow appropriate reporting procedures. 
Adverse events and their resolution outcome should be elicited from study participants at each 
study related contact.  The site must actively seek information about the AE until it is resolved or 
medically stable or until the participant is lost to follow-up and terminated from the study. 
1.2 
Serious Adverse Event (SAE) 
A serious adverse event (SAE) is an adverse event that is deemed serious by a study 
investigator because it meets one or more of the following criteria (although the event may meet 
more than one of the criteria below, investigator’s should choose only the most serious when 
reporting the event): 
An adverse event is serious if it results in: 
• 
Death: A death that occurs either during the course of the clinical trial or that comes to the 
attention of the investigator during the protocol-defined follow-up period and after the 
completion of therapy, whether or not it is considered treatment-related must be reported. 
• 
Life threatening: Any adverse event that when it occurs places the participant at immediate 
risk of death (i.e., it does not include a reaction that had it occurred in a more serious form, 
might have caused death). 
• 
Admission to the hospital or is responsible for the prolongation of an existing 
hospitalization. 
• 
A persistent or significant disability or incapacity. 
• 
A congenital anomaly or birth defect. 

 
 
 
23 
 
 
 
 
 
 
 
• 
Requiring a medical intervention to prevent one of the above outcomes. 
A SAE case report form is used to capture reported SAEs and may also be used to record 
follow-up information for unresolved or ongoing events that were reported previously. 
A site study investigator at the site is responsible for reviewing and characterizing each SAE 
that is reported, and is expected to follow appropriate reporting procedures, including the 
reporting of the event to their IRB as per local IRB guidelines. 
Serious adverse events will be followed until resolved or considered stable, with reporting to the 
NIDA appointed Safety Monitor through the follow-up period. The site must actively seek 
information about the SAE as appropriate until the SAE is resolved or medically stable or until 
the participant is lost to follow-up and terminated from the study. 
In the event that a FDA MedWatch form is generated and distributed by the NIDA appointed 
Safety Monitor as a result of a related and unexpected event, the site staff will be responsible 
for reporting this to their IRB as per local IRB guidelines and for maintaining this information in 
their regulatory binders. 
1.3 
Pregnancy 
All pregnancies that are reported during the course of the clinical trial will be captured on a Visit 
Checklist/Progress Note and not separately reported as an AE or SAE. Pregnancies will be 
followed through resolution, regardless of the outcome. 
2.0 
Eliciting and Monitoring Adverse Events 
The assessment of Adverse Events will begin once a participant has signed consent and will 
continue through last study visit or the participant’s study termination date, whichever comes 
first. Follow up of an event will continue for up to 30 days past the Adverse Event assessment 
date. Qualified research staff is responsible for consistently and thoroughly eliciting medical 
and/or psychiatric AEs/SAEs from participants during every study assessment visit in order to 
complete the AE/SAE CRFs in a timely manner. This may require consent in the form of a 
release of information (ROI) from the participant in order to request medical records, hospital 
discharge summaries, etc. 
Qualified research staff is responsible for reviewing all clinician progress notes and checklists 
following each participant contact in order to ensure that all AEs/SAEs have been appropriately 
reported. Reported AEs/SAEs will be followed until resolution or stabilization or study end, and 
any serious and related AEs/SAEs will be followed until resolution or stabilization, even beyond 
the end of the study. The study principal investigator is responsible for study oversight, including 
ensuring human research subject protection by designating appropriately qualified, trained 
research staff and medical clinicians to assess, report, and monitor adverse events. 
3.0 
Assessment of Severity and Relatedness 
A study investigator is responsible for reviewing all reported AEs on a weekly basis in order to 
characterize their seriousness, severity, and relatedness to the study intervention. 
3.1 
Severity 

 
 
 
24 
 
 
 
 
 
 
 
The seriousness of an event is determined by whether or not it meets one or more of the criteria 
for a serious adverse event. The severity of an event refers to the intensity of the event. 
Severity grades are assigned by the study site to indicate the severity of adverse experiences. 
Adverse events severity grade definitions are provided below: 
Grade 1 
Mild 
Transient or mild discomfort (< 48 hours), no or 
minimal medical intervention/therapy required, 
hospitalization not necessary (non-prescription or 
single-use prescription therapy may be employed to 
relieve symptoms, e.g., aspirin for simple 
headache, acetaminophen for post-surgical pain). 
Grade 2 
Moderate 
Mild to moderate limitation in activity some 
assistance may be needed; no or minimal 
intervention/therapy required, hospitalization 
possible. 
Grade 3 
Severe 
Marked limitation in activity, some assistance 
usually required; medical intervention/therapy 
and/or required hospitalization possible. 
Grade 4 
Life-
threatening 
Extreme limitation in activity, significant assistance 
required; significant medical intervention/therapy 
required, hospitalization or hospice care probable. 
Grade 5 
Death 
 
 

 
 
 
25 
 
 
 
 
 
 
 
3.2 
Relatedness 
The relatedness of the event refers to causality of the event to the study intervention. 
Relatedness requires an assessment of temporal relationships, underlying diseases or other 
causative factors and plausibility. 
Relationship to intervention is defined as: 
• 
Definitely related: An adverse event that follows a temporal sequence from administration 
of the test intervention and/or procedure and follows a known response pattern to the test 
intervention and/or procedure; and, when appropriate to the protocol, is confirmed by 
improvement after stopping the test intervention and cannot be reasonably explained by 
known characteristics of the participant’s clinical state or by other therapies. 
• 
Probably related: An adverse event that follows a reasonable temporal sequence from 
administration of the test intervention and/or procedure and follows a known response 
pattern to the test intervention and/or procedure and cannot be reasonably explained by 
the known characteristics of the participant’s clinical state or other therapies. 
• 
Possibly related: An adverse event that follows a reasonable temporal sequence from 
administration of the test intervention and/or procedure and follows a known response 
pattern to the test intervention and/or procedure, but could have been produced by the 
participant’s clinical state or by other therapies. 
• 
Unrelated: An adverse event that does not follow a reasonable temporal sequence after 
administration of the test intervention and/or procedure and is most likely explained by the 
participant’s clinical disease state or by other therapies. 
4.0 
Reporting Procedures of AE/SAEs 
Standard reporting, or the process of reporting an event within 7 days of the site becoming 
aware of the event, is required for all reportable AEs, whether or not they are considered related 
to the clinical trial participation. 
Expedited reporting, or the process of reporting an event within 24 hours of the occurrence of 
the event and/or the site's knowledge of the event, is required for all SAEs, including deaths. 
The SAE case report form and a progress note summary as well as any other relevant 
documentation related to the event should also be submitted with the initial report. If complete 
information about the event is not available at the time of the initial report, the event should still 
be reported with as much information as possible within the 24 hour window. The research staff 
is then responsible for gathering as much additional information as possible, and submitting this 
information within 14 days to the electronic database. If the SAE is not resolved or medically 
stable at this time or if new information becomes available after the SAE form is submitted, 
follow-up SAE information must be submitted as soon as possible, but at most within 14 days 
after the site learns of the information. 
Additional information may need to be gathered in order for the research staff and investigator 
to evaluate the SAE and to complete the AE and SAE case report forms. This information is 
necessary to provide a complete and clear picture of the SAE and of the events preceding and 
following the event and may include obtaining hospital discharge reports, physician records, 
autopsy records or other types of records or information. 

 
 
 
26 
 
 
 
 
 
 
 
Drs. Rethorst and Trivedi will receive and review summary reports of all reportable adverse 
events associated with a clinical trial at least annually. Details regarding adverse events, if 
requested by the, local IRB or regulatory authorities, should be summarized in writing by the 
Principal Investigator and should include the treatment and resolution. 
5.0 
Discontinuation of Participant From a Clinical Trial Related to a Reported AE/SAE 
The principal investigator must apply his/her clinical judgment in order to determine whether or 
not an AE/SAE is of sufficient severity to require that a participant be removed from the study 
intervention. If necessary, the Investigator may suspend any trial treatments and institute the 
necessary medical therapy or refer a participant to appropriate medical care in order to protect a 
participant from any immediate danger. 
Subsequent review of the event(s) by the IRB or the sponsor may also suspend further trial 
treatment at a site. The study sponsor retains the authority to suspend additional enrollment and 
treatments for an individual study site or the entire study as applicable. 
A participant also has the right to voluntarily withdraw from treatment due to what he/she 
perceives as an intolerable adverse event or for any other reason. If voluntary withdrawal is 
requested, the participant should be asked to continue (at least limited) scheduled evaluations, 
complete an end-of-study evaluation and be referred to appropriate care for medical supervision 
until the symptoms of any adverse event resolve or until their condition becomes stable. 

 
 
 
27 
 
 
 
 
 
 
 
 
AE Identified. 
Standard reporting. 
Enter AE into EDC. 
Report to IRB as required 
per IRB. 
Complete AE and SAE forms 
reported in EDC system within 14 
days. EDC system will 
automatically notify Safety 
Monitor and Lead Investigator. 
Local site investigator or 
designee reviews all 
relevant records and 
completes SAE Report 
and documentation. 
Serious? 
AE reviewed by 
designated staff. 
Continue follow-up and 
reporting until event is 
resolved or stabilized. 
Expedited initial reporting 
within 24 hours via EDC. 
Reportable AE. 
NO 
YES 
YES 
Record and report 
per site and IRB 
requirements. 
NO 
Report to IRB as required 
per IRB.