Investigating Various Adaptive-Training Exercise Programs for Improving Cardiorespiratory Fitness After Breast Cancer Treatment (ACTIVATE)
Phase: NA
Conditions: Breast Cancer, Invasive Breast Carcinoma
Sponsor: University of Washington

UNIVERSITY OF WASHINGTON SCHOOL OF NURSING 
CLINICAL PROTOCOL  
 
 
Current version: 2.7 9/18/2023 
 
Title of Protocol: 
Investigating Various Adaptive-Training Exercise Programs for Improving Cardiorespiratory Fitness 
After Breast Cancer Treatment (ACTIVATE) 
 
 
Study Team: 
Name 
Professional Title 
Phone Number 
Kerryn Reding, PhD, 
MPH, RN 
Assistant Member, FHCRC,  
Associate Professor, UW SoN 
(206) 221-1571 
Richard Cheng, MD, MS 
Associate Professor, UW SoM 
 
Rachel Yung, MD 
Assistant Professor, FHCRC 
Assistant Professor, UW SoM 
(206) 606-7703 
Consultants: 
Yonatan Buber, MD 
Associate Professor, UW SoM 
(206) 598-4300 
Teri Albee-Olson, DPT 
Exercise Physiologist 
(206) 598-3567 
Research Staff: 
Warren Szewczyk, BA 
Study Coordinator  
(206) 482-5808 
 
 
 

 
 
1 
Table of Contents 
ABBREVIATIONS .................................................................................................................................................... 2 
1.0 
INTRODUCTION ............................................................................................................................................ 3 
2.0 
BACKGROUND .............................................................................................................................................. 3 
2.1 Cardiorespiratory fitness decline in breast cancer survivors .............................................................. 3 
2.2 Intervention ................................................................................................................................................. 3 
2.3 Experience and Preliminary Work ........................................................................................................... 4 
2.4 Risks/Benefits ............................................................................................................................................. 4 
3.0 
STUDY AIMS ................................................................................................................................................. 5 
4.0 
STUDY DESIGN ............................................................................................................................................ 6 
4.1 Description of Study .................................................................................................................................. 6 
4.2 Endpoints .................................................................................................................................................... 6 
4.2.1 Primary Endpoint ................................................................................................................................. 6 
4.2.2 Secondary Endpoint ............................................................................................................................ 6 
4.3 Study Procedures ...................................................................................................................................... 9 
4.3.1 Recruitment ........................................................................................................................................ 10 
4.3.2 Screening ........................................................................................................................................... 10 
4.3.3 Informed Consent Procedures ........................................................................................................ 10 
4.3.4 Randomization ................................................................................................................................... 11 
4.3.4 Data Collection ................................................................................................................................... 11 
4.3.5 Schedule of Evaluations ................................................................................................................... 13 
5.0 
PARTICIPANT SELECTION ....................................................................................................................... 13 
5.1 Inclusion Criteria ...................................................................................................................................... 13 
5.2 Exclusion Criteria ..................................................................................................................................... 13 
5.3 Ethnic/Gender Distribution ..................................................................................................................... 14 
6.0 
INTERVENTION PLAN ................................................................................................................................ 14 
6.1 Treatment Intervention Arm ................................................................................................................... 14 
6.1.1 Aerobic exercise training ................................................................................................................. 15 
6.1.2 Resistance exercise training ............................................................................................................ 15 
6.1.3 Combined aerobic and resistance exercise training .................................................................... 15 
6.2 Waitlist Control Arm ................................................................................................................................. 15 
7.0 
GUIDELINES FOR ADVERSE EVENT REPORTING ............................................................................... 16 
7.1 Adverse Event Reporting/Institutional Policy ....................................................................................... 16 
7.1.1 Adverse Event Grading ..................................................................................................................... 17 
8.0 
DATA AND SAFETY MONITORING ......................................................................................................... 17 
9.0 
DATA MANAGEMENT/CONFIDENTIALITY ............................................................................................. 17 
10.0 STATISTICAL CONSIDERATIONS ........................................................................................................... 18 
 
 
 

 
 
2 
ABBREVIATIONS 
 
FHCRC 
Fred Hutchison Cancer Research Center 
UW  
University of Washington 
SoN  
School of Nursing 
SoM  
School of Medicine 
SCCA 
Seattle Cancer Care Alliance 
IRB 
Institutional Review Board 
CRF  
Cardioresipratory Fitness  
QoL  
Quality of Life 
CVD  
Cardiovascular disease 
VO2  
Volume Oxygen  
CPET  
Cardiopulmonary Exercise Testing 
MRI  
Magnetic Resonance Imaging 
AE  
Aerobic Exercise OR Adverse Event 
RE  
Resistance Exercise  
IMF  
Intermuscular Fat 
6MWT  
Six Minute Walk Test 
6MWD  
Six Minute Walk Distance 
DSM  
Data & Safety Monitoring 
SAE  
Serious Adverse Event  
 
 
 
 

 
 
3 
1.0    INTRODUCTION 
 
 
This document is a clinical research protocol. The described study will be conducted in compliance with 
the IRB approved protocol, associated Federal regulations, and all applicable IRB requirements. This 
study is being performed in order to examine the feasibility of administering an individually tailored 
exercise intervention among breast cancer survivors. Specifically, we will conduct a pilot study of a 2-
arm exercise intervention among breast cancer survivors with reduced cardiorespiratory fitness.  
 
 
2.0    BACKGROUND 
 
 
2.1 Cardiorespiratory fitness decline in breast cancer survivors   
 
Cancer survivors experience substantial reductions in cardiorespiratory fitness. Improved cancer 
treatment has led to 3.8 million breast cancer survivors in the U.S. today.1 However, this improvement is 
offset by an increase in cancer therapy-related morbidity and mortality.2–4 In particular, up to one-third 
of chemotherapy-treated breast cancer patients, particularly those receiving anthracycline 
chemotherapy,  experience substantial reductions in cardiorespiratory fitness (CRF) – defined by 
functional limitations (e.g., becoming out of breath when walking across a room).2–5 Unfortunately, many 
of these women do not regain their fitness after treatment cessation. A recent study demonstrated that 
even treatment historically thought to be well-tolerated is associated with long-term marked impairment 
of cardiorespiratory fitness.6 
 
This substantial loss of fitness leads to a lower quality of life (QoL) and reduces a survivor’s ability to 
maintain activities of daily living.2,5,7,8 Reduced cardiorespiratory fitness also increases the risk of late-
occurring cardiovascular disease (CVD),6 and in cancer survivors strongly predicts CVD mortality.9 
Thus, an increased burden of CVD in these patients adds another layer of complexity and challenges to 
this already vulnerable cohort. Overall reduced cardiorespiratory fitness is associated with a 3-fold 
increased risk of death.6  
 
Cardiac and skeletal muscle composition affect CRF. The factors that increase the risk of reduced 
cardiorespiratory fitness in chemotherapy-treated survivors are multifaceted and extend beyond 
cardiac-specific factors.10,11 Cardiorespiratory fitness is reflective of multiple organ systems, and as such 
is a useful metric to estimate total body health.9 Unfortunately, it is well-documented that cancer 
treatment can lead to dysfunction of many organ systems, including skeletal muscles and cardiac 
muscles. The changes to cardiac muscles and skeletal muscle composition – known as the 
cardiovascular-skeletal muscle axis – are known to play a critical role in cardiorespiratory fitness.3,12,13 A 
2018 White Paper concluded that interventions to improve cardiorespiratory fitness in cancer survivors 
should focus on damage that occurred along this axis.12 Thus, interventions may need to incorporate 
aerobic and resistance training, depending on whether treatment-induced changes occurred to both 
the cardiovascular system and skeletal muscles. 
 
2.2 Intervention 
 
Individualized interventions targeting CRF in breast cancer are needed.  Past research has 
demonstrated the need for individually-adaptive interventions to ameliorate CRF reductions in cancer 

 
 
4 
survivors. A meta-analysis showed significant heterogeneity in the effects of exercise interventions on 
fitness.  While across the total cohort, exercise interventions led to significant improvements among 
cancer survivors, approximately one-third of participants receiving an aerobic exercise intervention saw 
no improvements and one-quarter continued to lose fitness, which suggests a need for examining 
avenues beyond aerobic training for improving CRF.14 This is particularly important for patients who 
demonstrated progressive fitness loss that continued to worsen even after completing exercise 
treatment.14 
 
There is a need to develop individually-tailored interventions, particularly for the subcohort that 
demonstrate reductions in cardiorespiratory post-cancer treatment. This is aligned with a recent 
American Heart Association position paper stating that research is needed to determine the types of 
exercise intervention that are effective at improving fitness in cancer survivors.15As there is no proven 
strategy to improve fitness in breast cancer survivors, providers lack an evidence base to offer an 
‘exercise prescription’ to patients, the lack of which contributes to lower physical activity in breast 
cancer survivors.15 
 
We can glean information on the contributors to reductions in cardiorespiratory fitness from the Fick 
equation which states that exercise capacity is a product of cardiac output and the AVO2 difference,16 a 
measure of oxygen differential between the arterial and venous system which reflects peripheral 
factors, including the ability of the skeletal muscle to oxygenate. Thus, non-cardiac factors, such as 
skeletal muscle dysfunction, could potentially contribute to reduced cardiorespiratory fitness in breast 
cancer survivors. This is supported by literature indicating in particular that increased intermuscular fat 
negatively impacts the skeletal muscle’s ability to oxygenate17 as well as increased intermuscular fat 
was the predominant factor in breast cancer survivors with reduced cardiorespiratory function.18 
 
As it is yet unclear whether cancer survivors would benefit most from aerobic or strength training, this 
study will be the first step toward designing an intervention to test whether one exercise modality has 
superiority over another among cancer survivors. Thus, an adaptive intervention is an ideal design to 
determine which type of intervention is optimal. We propose to employ an intervention in which 
participants who are not responding to an exercise modality are re-assigned to a combined modality, 
thus tailoring the exercise intervention to respond to the needs of participants.  
 
2.3 Experience and Preliminary Work  
 
Our interdisciplinary research team has previously implemented a lifestyle intervention in a pilot study 
of women at high risk of breast cancer, some of whom who were breast cancer survivors, that involved 
a similar focus on exercise intervention and utilized a similar recruitment plan to identify and enroll 
participants.19,20 In addition, our research team has expertise in assessment of functional exercise 
capacity (e.g., 6-minute walk distance, cardiopulmonary exercise testing) and of body fat depots, 
particularly IMF and depots of abdominal adiposity using magnetic resonance imaging (MRI).21,22  
 
2.4 Risks/Benefits 
 
Anticipated risks. No serious risks are anticipated with this study. Cardiopulmonary exercise testing 
(CPET) may cause some fatigue and physical discomfort. Psychological discomfort, such as anxiety or 
apprehension, may arise for participants related to undergoing MRI and CPET. These are not seen as 
significant risks with levels of discomfort beyond those that they might experience during situations 

 
 
5 
outside of the study. Participants will be informed that they can stop participating in the study at any 
time. 
 
Risks associated with the intervention are minimal, even for individuals with reduced cardiorespiratory 
fitness. However, adverse events may occur with exercise: 
 
Exercise training. The major risks of participating in this monitored program include muscle 
fatigue, muscle soreness, and possible joint or skeletal injury. These risks are reduced by 
enrolling women without contraindications to exercise modifications, proper warm-up/cool down 
periods, conservative exercise prescriptions and progression, and monitoring by experienced 
staff (including exercise physiology specialists). If experienced, exercise-related injuries are 
expected to be of minimal discomfort and short duration and not significantly different than what 
someone might experience in everyday physical activities.   
 
The study will maintain ongoing compliance with all University of Washington guidelines surrounding 
COVID-19 mitigation for in-person clinical research.   
 
All adverse events, regardless of attribution to study procedures, will be collected and recorded. 
Subjects will be asked in an open-ended way about the presence of any adverse events. The PI will 
comply with all requirements of the IRB for the reporting of safety data and adverse/serious adverse 
events. For more information, see the study Data & Safety Monitoring (DSM; Appendix A) 
 
Storing all data with only a code attached will help ensure confidentiality. However, there is a potential 
risk of breach of confidentiality related to collection of sensitive information and participant identifiers. 
Following procedures outlined in Section 9.0 will minimize possible breaches of confidentiality and 
obtaining informed consent will limit invasion of privacy.  
 
MRI risk management. Participants in our study will not receive gadolinium-based contrast agents for 
the MRI scans.  
 
Anticipated direct benefits to participants. Participants in the intervention group may benefit from a free, 
semi-supervised exercise program. All physiologic measures are performed and analyzed for research 
purposes only; we do not plan to share findings with participants.  
 
Individual participants’ findings. Generally, individual findings will not be shared with the participant. We 
do not anticipate the MRI will produce any timely, clinically actionable results. If a life-threatening 
condition is identified through the CPET, this result will be shared with the participant.  
 
 
3.0   STUDY AIMS 
 
 
1. Determine the feasibility of an individually-adaptive exercise intervention among breast cancer 
survivors with reduced cardiorespiratory fitness through examination of recruitment rate, 
enrollment rate, loss to follow-up, intervention adherence, and relative dose intensity (ratio of 
total completed to total planned cumulative dose) 
 

 
 
6 
2. Examine the endpoint of (a) safety; and explore the endpoints of (b) cardiorespiratory fitness; (c) 
functional capacity; (d) physiologic changes; and (e) patient reported outcomes (PRO) in the 
intervention vs control arms. 
 
 
3. Examine the endpoint of (a) safety; and explore the endpoints of (b) cardiorespiratory fitness; (c) 
functional capacity; (d) physiologic changes; and (e) patient reported outcomes (PRO) in the AE 
vs RE vs AE+RE intervention arms.  
 
 
4.0   STUDY DESIGN 
 
4.1 Description of Study 
 
This is a pilot study of a 2-arm randomized trial with a 2:1 initial allocation to exercise intervention or 
waitlist control (see Appendix B for study schema). The intervention group will then be randomly 
assigned (1:1) to receive either a 12-week aerobic exercise (AE) intervention or a 12-week resistance 
exercise (RE) intervention.  
 
At 12 weeks, the intervention group will be assessed for intervention response, defined as a ≥5% 
increase in 6-minute walk distance (6MWD) over baseline. Non-responders to either AE or RE will 
receive 12 weeks of combined AE+RE. Intervention responders will continue the exercise intervention 
in their current assignment, either AE or RE alone, for the additional 12 weeks.  
 
This study will employ a waitlist control. After 24 weeks, the waitlist control group will receive a digital 
copy of sessions provided to the intervention arm. The control and intervention arms’ schedule of 
evaluations will be identical across all 24 weeks of the trial.  
 
4.2 Endpoints 
 
4.2.1 Primary Endpoint 
 
Intervention Feasibility: Intervention feasibility will be determined with all-cause intervention 
discontinuation rate, which is the proportion of all intervention participants who permanently stop the 
intervention prior to Week 24 for any reason. 
 
4.2.2 Secondary Endpoint 
 
The secondary outcomes include:  
 
Intervention Safety  
 
Safety: Intervention safety will be determined by reviewing and quantifying the number of adverse 
events (mild, moderate, or severe), serious adverse events, and by reviewing the type and severity of 
adverse events attributed to study procedures among each study group. See Section 8.0 for adverse 
event definitions and protocols.   
 
Study Feasibility & Acceptability 

 
 
7 
 
Study feasibility: Study feasibility will be measured by calculating recruitment rates (proportion of 
enrolled participants to all individuals approached), lost to follow-up (proportion of participants who do 
not complete post-intervention assessments), relative dose intensity (proportion of completed to 
planned sessions), early session terminations (proportion of sessions ended by participant prior to 
completing planned duration), intervention interruptions (missing 3 or more planned sessions 
consecutively), attendance (proportion of attended to planned sessions), and adherence (gathered from 
HR/accelerometry data and self-report of exercise via questionnaires). A benchmark to determine 
feasibility is <40% loss to follow-up. 
 
Intervention acceptability: Acceptability will be measured with qualitative, open-ended to assess 
participant experience in the intervention and gather information for improving the protocol in future 
studies. Of particular attention will be the tolerability of a remote, home-based exercise intervention with 
a semi-supervised format.  
 
Intervention session intensity and adherence: The Rating of Perceived Exertion (RPE) scale asks 
respondents to rate the intensity of exercise on a 6 – 20 scale.23 The measure has been validated for 
estimating both aerobic and resistance exercise exertion levels,24 providing a standard measure across 
intervention modalities. Participants will record RPE after each session in order to track session intensity 
and completion (adherence).  
 
Functional Capacity 
 
Submaximal exercise capacity: Submaximal exercise capacity, also considered functional capacity, will 
be determined with the six minute walk test (6MWT),26 which measures the distance a person can walk 
in six minutes (6MWD). A widely used measure of submaximal exercise capacity, the 6MWT will be 
administered at all study timepoints to evaluate intervention response. 
 
Strength: One Repetition Maximum (1-RM) or the maximum amount of force that can be generated in 
one maximum effort movement, will be used to assess participant strength at each time point. A chest 
press machine and leg press machine will be utilized to separately estimate upper body strength and 
lower body strength for each participant. The 1-RM test will be administered by a trained exercise 
physiologist.  
 
4.2.3 Other/Exploratory Endpoints 
 
Cardiorespiratory Fitness 
Maximal exercise capacity: This study’s primary outcome is cardiorespiratory fitness (CRF). This is 
operationalized as maximal exercise capacity, which is ascertained by measuring peak oxygen 
consumption (VO2 peak) during CPET. All CPETs will be administered by a trained exercise physiologist 
using the Modified Bruce protocol, an appropriate testing paradigm for people with reduced physical 
functioning. This procedure will estimate the VO2 (absolute and relative to bodyweight), VCO2, 
VE/VCO2, BP, HR. Total exercise time as well as workload and peak exercise will be collected as well. 
Ventilatory and work efficiency/economy will be calculated. Ventilatory threshold will be determined 
from VO2 – VCO2 plot (V-Slope). 
 

 
 
8 
Intervention adherence (accelerometry): Participants will wear 2 devices during the study: (1) a waist-
worn actigraph and (2) a wrist-worn FitBit activity monitor (Charge 4, FitBit, San Francisco, CA). The 
actigraph will be worn for 7-day intervals immediately prior to the baseline and endpoint assessments. 
In addition, participants will be asked to wear the actigraph 24-hours per day during that 7-day interval 
with the exception of when engaged in water activities for the duration of their intervention participation. 
Together, these data will be used to gauge adherence to the exercise intervention. The raw data 
generated from these devices will be reviewed by a trained accelerometer analyst for quality control 
and cleaning. Then the analyst will calculate the amount of time (in min/per day) spent in activities of 
low-, moderate-, and vigorous-activity. Categorization of the level of physical activity will use accepted 
cutpoints from the literature. 25 
Physiologic Changes  
 
Anthropometrics: Prior to the measurement of body weight, participants will be instructed to remove 
heavy clothing and empty pockets of their contents. Weight will be measured to the nearest one-tenth 
kg with a calibrated balance beam or digital scale. Height will be measured while the participant stands 
without shoes using a wall-mounted stadiometer to the nearest one-tenth cm. Hip and waist 
circumference will be measured to the nearest one-tenth cm.  
 
Intermuscular fat (IMF): The ratio of thigh IMF to skeletal muscle (SM) will be ascertained via MRI by 
trained MRI technologists (see Appendix C for the MRI protocol). Participants will undergo a screening 
process with the MRI technologist to ensure that eligibility criteria for MRI scans are met. Participants 
will then change into a hospital gown and enter the MRI scanner. In this longitudinal assessment of IMF, 
the MRI technologist will be instructed to match participant scan positions across time by matching the 
current scan position with the participant’s previous scan position, recorded at the timepoint prior. MRI 
analysts will quantitate total and compartment amounts of muscle and adipose tissue using cross-
sectional areas of thigh skeletal muscle (SM) and IMF using commercially available software. Thigh IMF 
area will be calculated as the number of fat pixels within the thigh musculature multiplied by the pixel 
surface area. The analyst will be blinded to MRI visit number, participant’s prior/future MRI results, 
intervention group, and participant characteristics. This technique for determining muscle composition 
has been validated against cadaver specimens. 
 
Abdominal depots of fat: Subcutaneous (SQ) fat and visceral adipose tissue (VAT) will be assessed via 
abdominal MRI (see MRI Protocol in Appendix C). For analysis, fat depots will be separated into 
abdominal SQ fat and VAT which will be further segmented into intraperitoneal (IP) and retroperitoneal 
(RP) fat using commercially available software. SQ fat will be defined as the fat outside the muscular 
abdominal wall; IP fat as fat within the mesentery and omentum bounded anteriorly and laterally by the 
abdominal wall and posteriorly by a curved line drawn between the kidneys; RP fat as the remaining fat. 
Adipose tissues will be segmented and colored from other tissues based on pixel intensity and known 
divisions of tissue planes. The MRI analyst, blinded to participant characteristics, will correct any 
misidentified fat or non-fat regions using manual tools provided within the software. To calculate each of 
the compartmental fat deposits, the number of subpixels within each fat compartment (SQ, VAT, IP, and 
RP) will be multiplied by the individual pixel dimensions within the image and by the slice thickness to 
determine the area of fat (in cm2) for each compartment.  
 
Patient Reported Outcomes  
 
Quality of Life  
 

 
 
9 
Quality of life will be assessed with the Short Form Health Survey-36 (SF-12), a widely used self-report 
measure of quality of life and health status.27 Comprised of 12 multiple choice questions, the SF-12 
queries general perceptions a participant has about their health, as well as limitations to physical 
activity, physical health problems, mental health problems, pain, and energy/fatigue. The SF-12 is used 
across health research domains, and in breast cancer has been utilized as a longitudinal monitor of 
quality of life.28–30 
 
Physical activity: The Stanford 7 Day Physical Activity Recall (PAR) interview31 will be used to estimate 
participant engagement in physical activity for the 7 days prior to each clinic visit. The PAR assesses 
the amount of moderate to vigorous PA performed by participants in the preceding week, as well as the 
amount of time completing both strength and flexibility exercises and hours of sleep each night. The 
PAR interview has been widely validated and previously used to assess PA outcomes in a home-based 
exercise intervention for breast cancer survivors.32    
 
Sedentary behaviors: Time spent engaging  in sedentary behaviors will be measured with the self-
administered  Sedentary Behaviors Questionnaire (SBQ).33,34 The SBQ measures the minutes spent 
participating in 9 different sedentary behaviors per “typical” weekday and weekend day.  
 
Perceptions of Physical Activity: Participant perceptions of their readiness for physical activity and 
barriers to successful PA will be captured with an internally developed scale created by combining 
questions assessing Capability, Opportunity, and Motivation (COM-B) for physical activity35 and 
questions assessing perceived barriers to PA that have previously been used in adult cancer 
survivors.36 
 
Perceived well-being: Participants’ perception of their current well-being will be assessed with the 28-
item 5-point Likert scale Functional Assessment of Cancer Therapy (FACT)-General.37 The FACT-G 
contains 4 subscales measuring physical, social, emotional, and functional well-being and has been 
validated for reliably measuring well-being in cancer patients.38,39 
 
Insomnia: Participant sleep will be assessed with the Insomnia Severity Index (ISI).40 The ISI is a 7-item, 
5-point Likert scale self-report scale measuring the nature, severity, and effects of insomnia over the 
previous month. Items are summed to a total score where greater than 7 indicates clinically significant 
insomnia.  
 
Mood disturbances: Symptoms of anxiety and depression will be assessed with the 4-item, 5-point 
Likert scale Patient Health Questionnaire (PHQ-4). The PHQ-4 is a brief and validated screener for 
clinically significant insomnia and depression, and has been used to predict long term physical activity 
levels in breast cancer survivors.  
 
Fatigue: The Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue scale is a 13-item scale 
originally developed for and widely used to assess cancer-related fatigue.41,42 The FACIT-Fatigue scale 
measures severity (e.g.., “I feel fatigued”; “I feel weak all over”) and impact of fatigue (e.g., “I need help 
doing my usual activities”; “I have to limit my social activity because I am tired”) over the past week, 
with responses scored on a 5-point scale, from 0 “not at all” to 4 “very much.” The FACIT-Fatigue scale 
has excellent psychometric properties and a focus on physical aspects of fatigue. 
 
4.3 Study Procedures 
 

 
 
10 
4.3.1 Recruitment 
 
This project will recruit 30 study participants through a multi-pronged approach:  
 
Seattle Cancer Care Alliance (SCCA) clinics: At SCCA, we will work with the breast oncology clinic 
research team to obtain a list of potentially eligible research participants that will include patient name, 
phone number, and mailing address. This eligibility will be based on age and approximate end date of 
chemotherapy or Herceptin therapy. Potentially eligible participants identified through SCCA will 
receive a mailed letter endorsed by their oncologist inviting them to call the study coordinator for more 
information and/or screening. The study team may follow up proactively with a phone call no less than 
two weeks after sending the letter. 
 
Breast cancer support groups in the community: Study information will be provided to breast cancer 
support groups in the community by sharing study flyers (paper, electronic, or Web versions) with the 
organizers of these groups and by giving presentations at in-person group events, as permitted by 
organizers.  
 
Re-contacting previous breast cancer research participants: The pool of previous breast cancer 
research participants will be generated from past projects under the purview of the study’s principal 
investigators or shared from affiliate investigators. Previous participants or candidates will be contacted 
via phone, email, or mailed letter, depending on what information is available to the study PIs.  
 
The UW ITHS Leaf tool: The University of Washington’s Leaf system will be used to generate an 
identifiable cohort of potentially eligible patients in the UW Medicine system. The study will query the 
database for patients who meet key eligibility criteria and who have recently visited the UW Medicine 
system for treatment. Candidates generated from this list will be sent a letter that describes the study 
and invites them to contact the study team should they be interested in participation. The study team 
may follow up proactively with a phone call no less than two weeks after sending the letter.    
 
4.3.2 Screening 
 
The study coordinator will use the screening script and questionnaire to complete screening (in-person 
or over-the-phone) of participant eligibility, according to eligibility criteria detailed in section 5.0. 
Inclusion criterion 4 (reduced CRF) will be estimated with an algorithm based on BMI, resting HR, and 
self-reported physical activity.43  Eligible candidates will be given information on the consent process 
and sent a copy of the consent form for review prior to their baseline visit. Consent will occur at the 
baseline visit.  
 
 
 
4.3.3 Informed Consent Procedures  
 
Candidates will be guided through the written informed consent process. All eligible candidates will be 
provided the same informed consent. The consent forms will contain the details for all study 
procedures, including both intervention and waitlist control arms, and for the storage and protection of 
de-identified data. Participants will be provided with a copy for their records. The consent process will 
clearly state what type of information will be collected and that all data provided by participants will be 
confidential. Participants will be assured that all records will be kept confidential in research files 

 
 
11 
located in a locked office and entered into a password-protected computer located behind a secure and 
maintained firewall. Candidates will be sent a copy of the consent form prior to their baseline visit for 
review. They will be encouraged to ask questions prior to or at the beginning of their baseline visit. 
Consent will be obtained before data collection procedures at the participant’s baseline visit.  
 
Consent forms will be reviewed for completeness and stored in a locked file cabinet in a locked office, 
away from any material with personal or sensitive study data. Participants will be reassured that they 
can withdraw from the study at any time.  
 
Comprehension: Misunderstandings will be addressed in real-time through the teach-back method: 
During the informed consent process potential participants will be asked to summarize the primary 
study objective and procedures.  
 
Ongoing process: Enrolled participants will have regular communication with study team. The study 
team will attempt to address any participant concerns over the study that arise in order to strengthen 
compliance and retention. Ultimately, participants will be reminded that they are volunteering and may 
withdraw from the study at any time. 
 
4.3.4 Randomization 
 
Participants will be randomly allocated to the intervention or waitlist control arm using blocked 
randomization (2:1 intervention to control), stratified upon whether the participant has received “AC” 
chemotherapy (doxorubicin and cyclophosphamide combination therapy).10 Intervention participants 
will then be randomized to either aerobic exercise training or resistance strength training, again using 
blocked randomization stratified on AC treatment history. Randomization will be performed in REDCap 
with the REDCap Randomization module.  
 
4.3.4 Data Collection  
 
Clinical and self-report data will be collected at 3 total timepoints: baseline, 12 weeks, 24 weeks. 
 
Self-reported data: Participants will be asked to complete baseline questionnaires ascertaining 
demographic information, health history and current health behaviors. At all timepoints (i.e. baseline, 
12-, and 24-Week) participants will be asked to complete self-reported questionnaires on quality of life, 
physical activity, and fatigue.  
 
Clinic visits: In-person clinic visits will take place at baseline and 24-weeks for all participants. All clinic 
visits will include anthropometric assessment, MRI, supervised 6MWT and CPET. Participants will 
complete a supervised 6MWT. Study procedures will occur at the University of Washington Medical 
Center and the Fred Hutchinson Prevention Center. At intervention completion participants will be 
asked open-ended questions regarding their experience with the study. The responses will be analyzed 
for themes to improve future study designs.  
 
Passive Data Collection: Some data will be remotely collected via wrist- and waist-worn actigraphy 
monitors, worn in the 7 days prior to each clinic visit. Wrist-worn monitors will be worn 24 hours a day 
including sleep, while waist-worn monitor will be removed for sleep. Wrist-worn devices will also be 
utilized during all intervention sessions, as a measure of intervention adherence.  
 
 

 
 
12 
Measure 
Type of measure 
Instrument 
Source 
Sample Characteristics 
 
 
 
Demographics 
Baseline 
Questionnaire 
Participant 
Physical & mental health history 
Baseline 
Questionnaire 
Participant 
Intervention Feasibility 
 
 
 
Intervention Feasibility  
Primary outcome 
Attendance/Retention 
Case Report Form 
Intervention Acceptability 
Secondary outcome 
Questionnaire 
Participant 
Exercise intervention adherence 
Other/Exploratory 
outcome 
Actigraphy Monitor 
Participant 
Exercise intervention adherence 
Secondary outcome 
RPE 
Participant 
Intervention session Intensity 
Secondary outcome 
RPE 
Participant 
Safety 
 
 
 
Safety 
Secondary outcome 
Adverse Events 
Case Report Form  
Cardiorespiratory Fitness 
 
 
 
VO2 (maximal exercise capacity) 
Other/Exploratory 
outcome 
CPET 
Case Report Form 
Functional Capacity 
 
 
 
6MWD (submaximal capacity) 
Other/Exploratory 
outcome 
6MWT 
Case Report Form  
1 Repetition Maximum (strength) 
Exploratory outcome 1-RM 
Case Report Form 
Physiologic Changes 
 
 
 
Anthropometrics 
Other/Exploratory 
outcome 
Physical exam 
Case Report Form 
Thigh IMF:SM 
Other/Exploratory 
outcome 
MRI 
Case Report Form 
Abdominal fat deposition 
 Other/Exploratory 
outcome 
MRI 
Case Report Form 
Patient Reported Outcomes 
 
 
 
Quality of life 
Other/Exploratory 
outcome 
SF-12 
Participant 
Physical activity 
Other/Exploratory 
outcome 
PAR/Actigraphy Monitor 
Participant 
Physical Activity Perceptions 
Other/Exploratory 
Outcome 
PA Perceptions & Barriers 
Participant 
Sedentary behaviors 
Other/Exploratory 
outcome 
SBQ 
Participant  
Perceived well-being 
Other/Exploratory  
outcome 
FACT-G Questionnaire 
Participant  
Insomnia 
Other/Exploratory 
outcome 
ISI 
Participant 
Mood Disturbance 
Other/Exploratory 
outcome 
PHQ-4 
Participant 

 
 
13 
Fatigue 
Other/Exploratory  
outcome 
FACIT-F 
Participant 
 
4.3.5 Schedule of Evaluations 
 
STUDY PROCEDURES 
Baseline 
Week 12 
Week 24 
Intervention Arm 
 
 
 
CPET 
X 
 
X 
MRI 
X 
 
X 
6MWT 
X 
X 
X 
1-RM 
X 
X 
X 
Anthropometrics 
X 
X 
X 
Questionnaires 
X 
X 
X 
Safety (ongoing) 
X 
X 
X 
Accelerometry (ongoing) 
X 
X 
X 
Control Arm 
 
 
 
CPET 
X 
 
X 
MRI 
X 
 
X 
6MWT 
X 
X 
X 
1-RM 
X 
X 
X 
Anthropometrics 
X 
X 
X 
Questionnaires 
X 
X 
X 
Safety (ongoing) 
X 
X 
X 
Accelerometry (ongoing) 
X 
X 
X 
 
 
5.0   PARTICIPANT SELECTION 
 
 
A criterion should be listed as either inclusion or exclusion but not both. 
 
5.1 Inclusion Criteria  
 
1. Age 18 - 75 years, inclusive 
2. Female gender 
3. Prior diagnosis of invasive breast cancer 
4. Completion of chemotherapy or receipt of trastuzumab (Herceptin) therapy within the past 6 – 
60 months (0.5 – 5 years) 
5. Reduced cardiorespiratory functional capacity, defined as below the median estimated CRF  for 
age/sex-matched controls  
 
5.2 Exclusion Criteria  
 
 

 
 
14 
1. Actively receiving radiation treatment 
2. Medical history of heart failure, coronary artery disease or arrhythmia  
3. Contraindications to cardiopulmonary exercise testing (CPET)   
4. Contraindications to magnetic resonance imaging (MRI) (e.g ferromagnetic cerebral aneurysm 
clips or other intraorbital/intracranial metal; pacemakers, defibrillators, functioning 
neurostimulator devices, non-compatible MRI tissue expanders or breast implants, or other 
implanted non-compatible MRI devices), weight over 550 lbs, or symptomatic claustrophobia 
5. Contraindications to exercise, including a history of surgery with sequelae that restrict ability to 
exercise safely or comfortably 
6. Unwilling to complete intervention procedures or outcome measures 
 
5.3 Ethnic/Gender Distribution  
 
TARGETED / PLANNED ENROLLMENT: 30 
Ethnic Category 
 
Sex / Gender 
 
Females 
Males 
Total 
Hispanic or Latino 
2 
0 
2 
Not Hispanic or Latino 
28 
0 
28 
Ethnic Category Total of All Subjects* 
30 
0 
30 
 
Racial Categories 
 
 
American Indian / Alaska Native 
0 
0 
0 
Asian 
0 
0 
0 
Native Hawaiian or Other Pacific 
0 
0 
0 
Black or African American 
6 
0 
6 
White 
24 
0 
24 
Racial Categories: Total of All Subjects* 30 
0 
30 
 
 
6.0    INTERVENTION PLAN 
 
 
6.1 Treatment Intervention Arm  
 
Participants in the intervention group will be randomized to receive either AE or RE training. The 
intervention will comprise of a combination of supervised and unsupervised sessions. Supervised 
sessions will be led remotely via videoconferencing by a trained fitness instructor, while unsupervised 
sessions will involve following along with recorded videos. Training protocols will be adapted from the 
American College of Sports Medicine’s (ACSM) guidelines44,45 and designed to progress in intensity, 
depending on patient tolerance.  
 

 
 
15 
All intervention sessions will include 5 minutes of warm up and 5 minutes of cool down. Warm up and 
cool down will consist of light aerobics and stretching for both groups. Sessions will occur 3 times a 
week, with 1 supervised and 2 unsupervised. In the first 3 weeks of resistance training, sessions will 
occur 2 times per week (1 supervised), to account for increased muscle soreness when starting a 
resistance training regimen.  
 
Exercise intensity will be measured using the Rating of Perceived Exertion (RPE) scale,23 which collects 
respondent’s perception of exertion level on a scale from 6-20. Moderate exercise will be considered a 
12-13 on this scale, while 14-16 will constitute vigorous exercise.  
 
Participants will rate their perceived exertion after each exercise session, and RPE feedback will be 
utilized to adjust intensity levels for participants’ upcoming sessions.  
 
6.1.1 Aerobic exercise training 
 
Aerobic exercise sessions will entail various standard calisthenics, including such as marching in place, 
side steps, and jumping jacks. Participants will complete exercises in sets, performing a sequence of 
exercises for a certain number of seconds each (e.g. 30-60 seconds per exercise) before a rest of 60-
240 seconds. The total time of each session will be at least 30 minutes and both the duration and 
intensity of the sessions will increase during the intervention, as outlined in Appendix D. 
 
Intensity will be varied by adjusting the type of exercise, the number of seconds per exercise and/or the 
amount of rest time between sets. The intensity will progress, as tolerated, for the first 6 weeks of the 
intervention, starting at moderate intensity and building to sustained vigorous intensity (see Appendix 
D). The estimation of intensity will be based off a participant’s heart rate (HR) at peak VO2 from the 
CPET at baseline. Trained staff will help participants to determine this target HR. 
 
6.1.2 Resistance exercise training 
 
Resistance exercise training will comprise of weight bearing functional tasks (e.g. sit-to-stand) and 
weighted exercises, with each session targeting upper and lower body large muscle groups. 
Participants will complete 5 exercises in sets of 1 or 2, performing a sequence of exercises for a certain 
number of repetitions (“reps”) each (e.g. 8-12 reps per exercise) before a short rest. Sets will be 
separated by a rest of 60-240 seconds.  
 
At baseline testing, study staff will determine participants’ one rep maximum for various weighted 
exercises. The starting weights for the intervention will be based on this measurement.  
 
Intensity can be varied by adjusting the number of reps per set, the number of seconds of rest, or the 
weight being used.  
 
6.1.3 Combined aerobic and resistance exercise training  
 
The AE+RE intervention will involve a combination aerobic and resistance exercises within session, with 
approximately half of each session devoted to AE and half devoted to RE (See Appendix E). Aerobic 
sets will be completed before resistance sets within each session.  
 
6.2 Waitlist Control Arm  
 

 
 
16 
The waitlist control group will spend 24 weeks waitlisted for the intervention, during which time they will 
follow the same schedule of evaluations as the intervention group but will not receive exercise sessions. 
After completing 24-week assessments, the control group will receive a digital copy of sessions 
recorded during the intervention group and an outline of sessions for 24 weeks.  
 
 
7.0    GUIDELINES FOR ADVERSE EVENT REPORTING 
 
 
7.1 Adverse Event Reporting/Institutional Policy 
 
In accordance with institutional policy, all adverse events which in the opinion of the principal 
investigator are unexpected and related or possibly related to the research and serious or suggest that 
the research places research participants or others at greater risk of physical or psychological harm 
than was previously known or recognized be reported to the IRB within 10 calendar days of learning of 
the problem. 
 
Definitions: 
 
Adverse Event - Any untoward medical occurrence in a participant, such as any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or disease 
temporally associated with the intervention.  
 
Life-threatening Adverse Event – Any adverse event that places the participant, in view of the 
investigator, at immediate risk of death from the reaction.  
 
Unexpected Adverse Event – An adverse event is “unexpected” when its nature (specificity), severity, 
or frequency are not consistent with (a) the known or foreseeable risk of adverse events associated with 
the intervention; and are also not consistent with (b) the characteristics of the subject population being 
studied including the expected natural progression of any underlying disease, disorder or condition any 
predisposing risk factor profile for the adverse event. 
 
Serious Adverse Event (SAE) – Any adverse event occurring that results in any of the following 
outcomes: 
• 
death  
• 
a life-threatening adverse event (real risk of dying) 
• 
inpatient hospitalization or prolongation of existing hospitalization 
• 
a persistent or significant disability/incapacity 
• 
a congenital anomaly 
• 
requires intervention to prevent permanent impairment or damage 
 
Attribution - The following are definitions for determining whether an adverse event is related to a 
medical product, treatment or intervention procedure: 
 
• 
An adverse event is related or possibly related to the research procedures if in the opinion 
of the principal investigator, it was more likely than not caused by the research procedures. 
 

 
 
17 
• 
Adverse events that are solely caused by an underlying disease, disorder or condition of the 
subject or by other circumstances unrelated to either the research or any underlying disease, 
disorder or condition of the subject are not “related or possibly related.”  
 
• 
If there is any question whether or not an adverse event is related or possibly related, the 
adverse event should be reported. 
 
All adverse events will be reported to the University of Washington IRB according to UW guidelines.  
 
7.1.1 Adverse Event Grading 
 
Adverse events will be graded as Mild, Moderate, or Severe using the NCI Common Terminology 
Criteria for Adverse Events (CTCAE) Version 5.0 as a guide: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcae_v5_quick_reference_5
x7.pdf See Appendix A, Data and Safety Monitoring Plan.  
 
 
8.0     DATA AND SAFETY MONITORING  
 
 
The Principal Investigator will meet with study staff on a monthly basis to review participant’s adverse 
events, verify CTCAE grade, and provide attribution, and to review response data.  
 
This study will employ a Data and Safety Monitoring Plan (DSM; see Appendix A) to outline how 
participant safety and confidentiality will be managed throughout the study. The PI and co-investigators 
have clinical licensure (RN or MD) and will review quarterly the following study data provided by the 
research team: 
 
• 
Number of participants  
• 
List of adverse event and responses that have occurred in the specified time frame  
• 
Cumulative table of adverse events by type and grade, including deaths as outlined in the 
protocol-specific DSM  
• 
Premature terminations of the intervention and other safety issues  
At each review, the PI and co-I’s will determine whether: 
• 
The trial should continue as originally designed 
• 
The trial should be changed 
• 
The trial should be terminated 
• 
Outcome results should be released prior to the reporting of the study results 
 
 
9.0  DATA MANAGEMENT/CONFIDENTIALITY 
 
 
This project’s varied recruitment strategies involve different types of contact with identifiable health 
information prior to enrollment. Recruitment streams 2 and 3 outlined in section 4.3.1 will involve 
potential participants either 1) contacting the study team directly or 2) providing consent for the study 

 
 
18 
team to make contact.  
 
Recruitment stream 1 will require viewing PHI prior to consent by SCCA breast oncology staff who 
routinely view this information in their normal workflow. Recruitment stream 4 will involve obtaining PHI 
prior to consent. The IRB will review and approve all procedures for viewing or obtaining PHI prior to 
consent. Women who are approached will not be undergoing any serious or sensitive treatments. 
 
All forms of data described in previous sections will be recorded on paper or computerized data forms 
with no personal identifying information. Candidates for screening will be assigned a 3-digit study ID, 
and all data collected during screening will be stored with this ID. A 3-digit number will be assigned to 
each participant, once enrolled. Only the PI and HIPAA-trained study coordinator will have access to the 
secure OneDrive spreadsheet that links names with subject study identifiers. To ensure confidentiality, 
no personal identifying information will be coded on the questionnaires or sample data. A separate 
document will contain contact information but will not contain personal data or protected health 
information that is collected as part of the study. Study data will be stored in a REDCap database that 
only the PI and the study coordinator can access. All paper data will be stored in locked file cabinets in 
a locked office and on password-protected computers located behind a secure firewall.  
Data are collected by team members who have completed training in human subject research, HIPAA, 
research integrity, research data management and confidentiality, and training to criterion on project 
protocol.  
 
 
10.0   STATISTICAL CONSIDERATIONS 
 
 
For objective 1, we will measure the feasibility of our intervention by calculating recruitment rates (% 
participants enrolled of those approached), enrollment rate (% enrolled of those eligible), lost to follow-
up (% who dropped out of those enrolled), intervention discontinuation rate (% of intervention 
participants who permanently stop the intervention for any reason by Week 24), intervention attendance 
(% exercise sessions attended), relative dose intensity (% completed sessions), and compliance (based 
on accelerometry data, self-report of exercise via questionnaires). A benchmark to determine feasibility 
includes <40% loss to follow-up. 
 
In objective 2, we will start with an analysis of the safety endpoints by calculating the number and 
percent of adverse events that occurred during the intervention and during the waitlist control period. 
This analysis will be stratified by the severity of the adverse events, the seriousness of the adverse 
events, and by the attribution of the adverse events. 
 
The results from above analyses (for Study Aim 1) will be a primary consideration to inform the 
feasibility and safety of launching a larger scale intervention from the pilot intervention. If both these 
sets of data provide indications that the study is feasible and safe, then the exploration of additional 
intervention outcomes will take place.  These data will be presented in a manuscript to describe the 
potential for this intervention.  The following analyses will explore additional intervention outcomes to 
inform the intervention’s potential to have an impact on CRF, functional capacity, physiologic changes, 
and PRO in a larger scale intervention. 

 
 
19 
 
Next, the analysis will explore the impact of the intervention on the outcome of CRF in intervention 
participants versus waitlist control participants using generalized linear models (GLM) comparing 
baseline to 24-week measurements. This analysis will be repeated for the additional outcomes of 
functional capacity, i.e., submaximal exercise capacity; physiologic changes, i.e., thigh IMF:SM, 
abdominal depots of fat (VAT, SQ, RP, and IP fat), and body weight; and patient reported outcomes, i.e., 
QOL, perceived well-being, and fatigue. These analyses will be performed according to the intent-to-
treat principle, where outcomes are analyzed by intervention assigned, regardless of the level of 
adherence. A secondary per protocol analysis will be conducted, and these results will be reported and 
interpreted together with the intent-to-treat analysis. This per protocol analysis will include only those 
participants who (a) completed all clinic visits and who completed at least 85% of the required physical 
activity. In addition, this secondary analysis will investigate factors related to a lack of intervention 
adherence, which will include baseline measures of perceived well-being, mood disturbance, 
perceptions of PA, fatigue, and insomnia. 
 
For objective 3, the analysis will explore the impact of AE vs RE vs combined AE+RE on safety 
outcomes using generalized linear models (GLM) comparing pre-intervention measurements to post-
intervention measurements. Next, this analysis will be repeated for the additional outcomes of CRF, 
functional capacity, physiologic changes, and patient reported outcomes of QOL, perceived well-being, 
and fatigue.  
 
In addition, we will explore potential moderators of the intervention, namely baseline BMI and physical 
activity, and adherence to the intervention for Objectives 2 and 3, and as guidance in designing the 
subsequent large-scale intervention. First, we will stratify upon BMI to explore whether the intervention 
showed greater benefit in those with higher BMI.  Then we will repeat this for baseline physical activity 
to explore whether the intervention showed greater benefit in those with lower baseline physical activity. 
Next, the level of adherence to the intervention will be evaluated by examining the accelerometry data 
output in conjunction with the self-reported physical activity data.  We will also conduct qualitative 
analyses utilizing data from the elicitation interviews conducted at the end of the intervention. This 
analysis will summarize data collected from the participants’ into themes.  
 
 
 

 
 
20 
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23 
Appendix A – Data & Safety Monitoring 
 
BRIEF STUDY OVERVIEW 
This is a pilot study of a 2-arm SMART-design exercise intervention among breast cancer survivors with 
reduced cardiorespiratory fitness.  
 
OVERSIGHT RESPONSIBILITIES 
Oversight of the trial is provided by Dr. Kerryn Reding, the Principal Investigator (PI), and co-
investigators, Rachel Yung, MD and Richard Cheng, MD (“co-investigators” throughout).   
 
MONITORING PROCEDURES 
Dr. Reding assures that informed consent is obtained prior to performing any research procedures, that 
all subjects meet eligibility criteria, and that the study is conducted according to the IRB-approved 
research plan.   
 
Study data are accessible at all times for the PI to review. The PI and co-investigators review study 
conduct (accrual, drop-outs, protocol deviations) on a monthly basis.  The PI reviews adverse events 
(AE) individually in real-time and with co-investigators in aggregate on a monthly basis.  The PI and co-
investigators review serious adverse events (SAEs) in real-time.  The PI ensures all protocol deviations, 
AEs, and SAEs are reported to the IRB according to the applicable regulatory requirements. 
 
COLLECTION AND REPORTING OF SAEs AND AEs 
For this study, the following standard AE definitions are used: 
 
Adverse event:  Any unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the use of a medical treatment or intervention 
procedure, regardless of whether it is considered related to the medical treatment or intervention 
procedure. 
 
Serious Adverse Event:  Any AE that results in any of the following outcomes: 
• 
Death 
• 
Life-threatening  
• 
Event requiring inpatient hospitalization or prolongation of existing hospitalization 
• 
Persistent or significant disability/incapacity 
 
AEs are graded according to the following scale: 
 
Mild:  An experience that is transient & requires no special treatment or intervention.  The 
experience does not generally interfere with usual daily activities.  This includes transient 
laboratory test alterations. A mild AE typically corresponds to a 1 on the NCI Common 
Terminology Criteria for Adverse Events (CTCAE).   

 
 
24 
Moderate:  An experience that is alleviated with simple therapeutic treatments.  The experience 
impacts usual daily activities.  Includes laboratory test alterations indicating injury, but without 
long-term risk. A moderate AE corresponds to a 2 on the CTCAE.   
Severe:  An experience that requires therapeutic intervention.  The experience interrupts usual 
daily activities. If hospitalization (or prolongation of hospitalization) is required for treatment it 
becomes an SAE. A severe AE corresponds to a 3 on the CTCAE.   
 
The study uses the following AE attribution scale: 
 
Not related:  The AE is clearly not related to the study procedures (i.e., another cause of the 
event is most plausible and/or a clinically plausible temporal sequence is inconsistent with the 
onset of the event).   
Possibly related:  An event that follows a reasonable temporal sequence from the initiation of 
study procedures, but that could readily have been produced by a number of other factors. 
 
Related:  The AE is clearly related to the study procedures.   
 
AEs are identified by participant self-report at each study follow up assessments (12-, 24-, 36- and 48-
weeks). Participants will be asked about medical or mental health events that have happened since the 
previous assessment visit. AEs may also be identified during supervised (in-person or remote) exercise 
sessions, with an event either occurring or being reported during such sessions.   
 
SAEs and specific procedure-associated AEs are reported to the PI and co-investigators within 24 
hours. In addition, all AEs are reported according to the University of Washington AE reporting 
guidelines.  
 
MANAGEMENT OF RISKS TO SUBJECTS 
 
Expected AEs 
Expected AEs associated with the exercise intervention include:   
• 
Fatigue 
• 
Muscle Soreness 
• 
Mild Shortness of Breath 
• 
Mild Tachycardia  
• 
Transient increase in blood pressure 
• 
Lightheadedness  
• 
Excessive Sweating 
• 
Muscle strain or sprain 
 
AE Management 
Participants experiencing a mild AE (e.g. fatigue or muscle soreness) related to the intervention will 
have discretion as to whether they want to continue with the intervention exercise regimen. They will be 

 
 
25 
advised to rest if they want to stop during an intervention session or want to skip a session due to mild 
AE.  
 
Mild lightheadedness will be treated with slightly more caution than other mild AEs. Participants will be 
instructed that if during exercise, they experience lightheadedness they should immediately discontinue 
the exercise. If the lightheadedness persists after discontinuation, they will be instructed to consult a 
medical professional. If the lightheadedness resolves, the participant can resume normal activities, 
including the exercise regimen. 
 
If a participant experiences a moderate or severe AE, they will be instructed to cease the exercise 
regimen for recovery, if necessary, and the PI and co-investigators will evaluate whether re-entry to the 
exercise regimen is acceptable. 
 
If a participant experiences an SAE, they will be instructed to cease the exercise regimen.  
 
DATA ANALYSIS PLANS 
As this is a pilot study, there will be insufficient numbers to conduct a well-powered interim analysis. 
The study team will examine SAEs and expected AEs in aggregate at the midpoint of the study to 
examine whether disproportionate SAEs or AEs have occurred in the intervention participants. While 
there is unlikely to be statistical power in interim analysis, we will conduct bi-variate statistical analysis 
consisting of chi-square tests to evaluate the proportion of SAEs and AEs in intervention participants 
versus control participants. The investigators will review this statistical analysis. Discussions of whether 
sufficient evidence exists for stopping the trial early will involve consideration of whether the AEs are 
related or unrelated to the study activities. 
 
PLAN FOR DATA MANAGEMENT  
Compliance of regulatory documents and study data accuracy and completeness will be maintained 
through an internal study team quality assurance process.  
 
Confidentiality throughout the trial is maintained by recording all study data on paper or computerized 
forms with no personal identifying information. A 3-digit number will be assigned to each subject. Only 
the PI and the HIPAA-trained study coordinator will have access to the file that links names with subject 
study identifiers. To ensure confidentiality, no personal identifying information will be coded on the 
questionnaires or sample data. A separate document will contain contact information but will not contain 
personal data or protected health information that is collected as part of the study. Study data will be 
stored in a REDCap database that only the PI and the study coordinator can access. All paper data, 
including consent forms, will be stored in locked file cabinets in a locked office and on password-
protected computers located behind a secure firewall. 
 
 

 
 
26 
Appendix B – STUDY SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
27 
Appendix C – MRI PROTOCOL 
 
General Overview   
 
This appendix details the abdominal imaging (ABD_LOC and ABD_FAT) and thigh skeletal muscle 
imaging (3Plane_LOC_Thigh and T1 AX DB Left Thigh_TE36) for participants in the “Investigating 
Various Adaptive-Training Exercise Programs for Improving Cardiorespiratory Fitness After Breast 
Cancer Treatment” (ACTIVATE) study. This is a 30-min MR exam. Contact the study team for any 
clarification on this exam.  Different sections of this protocol are as follows:  
 
 
 
MRI Protocol– List of Sequences 
 
Body Composition with localizers 
ABD LOC  
 
T1 AX ABDOMEN FAT (L2-L4)  
3Plane_LOC_thigh 
T1 AX DB Left thigh_TE36 
 
 
 
*Please place the following information in the Patient Registration Window before the 
exam begins: 
 
- Place with the study ID number in the MRN Field. 
- Place the acrostic in the Patient Name Field.   
- These should be given to you by the Study Coordinator.   
 
 
 

 
 
28 
Series Name:  
ABD_LOC (REF A) 
Series Description: Abdominal Localizer 
Notes: 
Perform multi-plane abdominal localizer (coronal and sagittal). A sagittal plan that 
appreciates L2-L4 will be used in planning future series. 
 
Series Prescription Details 
 
Series Rx Notes 
Prescribe series from: 
Localize the lumbar region 
Orientation: 
Coronal and Sagittal 
Number of Slices 
3-5 sagittal slices; 8-10 coronal slices 
Breath-holding: 
Yes 
 
Image Parameters 
Image Parameter 
Value 
Slice Thickness  
5mm 
Slice Gap  
5 mm 
TR 
260 
TE  
1.08 
Number of Phase 
Encodings  
143 
Percent Sampling  
75 % 
Percent Phase FOV  
100% 
Pixel Bandwidth  
1132 
Matrix  
192 x 144 
Flip Angle  
65 degrees 
 
 
 

 
 
29 
Series Name:  
ABD_FAT (REF B) 
Series Description: T1 weighted turbo spin-echo sequence acquired with 3 evenly spaced axial 
slices with 1st and 3rd centered at L2 and L4. 
Notes: 
To assess visceral fat, a series of images will be acquired to assess visceral fat 
volume. Open up field of view (FOV) to encompass all of the abdomen.  
 
Series Prescription Details 
 
Series Rx Notes 
Prescribe series from: 
ABD_LOC (Ref A) 
Orientation: 
Axial 
Number of Slices 
3 evenly spaced axial slices with 1st and 3rd centered at L2 and 
L4. 
Breath-holding: 
Yes, breath hold per slice 
 
 
 

 
 
30 
 
Image Parameters 
Image Parameter 
Value 
FOV 
Open to encompass all of the 
abdomen 
Slice Thickness  
5mm 
Slice Gap  
Variable – change distance 
factor as necessary 
TR 
800 ms 
TE  
36 ms 
Flip Angle  
180 degrees 
Matrix 
256 * 256 
Acceleration factor  
2 
Bandwidth 
305 Hz/Px 
Turbo factor 
11 
Echo trains per slice 
13 
Gating 
ECG triggering 
 
 
 
 
 

 
 
31 
Series Name:  
3Plane_LOC_Thigh (REF C) 
Series Description: Thigh Localizer 
Notes: 
Perform multi-plane localizer on thigh with additional body matrix coil.  
 
Series Prescription Details 
 
Series Rx Notes 
Prescribe series from: 
3PLANE_Loc_thigh 
Orientation: 
Coronal, Sagittal, Axial 
Number of Slices 
3-5 per orientation 
Breath-holding: 
No 
 
Image Parameters 
Image Parameter 
Value 
Slice Thickness  
5mm 
Slice Gap  
5 mm 
TR 
260 
TE  
1.08 
Number of Phase 
Encodings  
143 
Percent Sampling  
75 % 
Percent Phase FOV  
100% 
Pixel Bandwidth  
1132 
Matrix  
192 x 144 
Flip Angle  
65 degrees 
 
 
 
 

 
 
32 
 
Series Name:  
T1 AX DB Left Thigh_TE36 (REF D) 
Series Description: T1 weighted turbo spin-echo sequence acquired with 5 evenly spaced axial 
slices. The position of center slice will be determined by distance measured by 
study staff.  
Notes: 
A series of images will be acquired to assess muscle and fat composition of left 
thigh.  
Formula for slice location: 
 
* Patient’s height in inches x 0.125 = distance from distal femur 
 
* Inches x 25.4 = mm 
* Start at distal femur (condyle) and measure up “X” amount of mm to get location for center 
slice 
 
* Use left leg 
* Example: Pt Height = 64.3 inches x 0.125 x 25.4 = 204 mm 
 
Series Prescription Details 
 
Series Rx Notes 
Prescribe series from: 
3PLANE_Loc_thigh 
Orientation: 
Axial 
Number of Slices 
5 
Breath-holding: 
No 
 
Image Parameters 
Image Parameter 
Value 
Slice Thickness  
5mm 
Slice Gap  
1 mm 
TE  
36 
FOV 
256 x 256 mm2 
Base resolution 
384 x 384 pixels 
In plane resolution 
0.7 x 0.5 
 
Sample Image(s) 
  

 
 
33 
 
MRI Encounter Guide  
 
REF  Series Name  
Acq time 
(~sec)  
Series Description / Notes  
Series #  
A  
ABD_LOC  
9  
Sagittal localizer for L2-L4  
B  
ABD_FAT  
3x10  
3 evenly spaced axial slices 
with 1st and 3rd slice centered 
at L2 and L4   
C 
3Plane_LOC_Thigh 
15 
Multi slice localizer of thigh 
D 
T1 AX DB Left Thigh_TE36 
20 
Use formula for REF D to plan 
slice 
 
The MRI Encounter Form must be completed for each MRI exam.  Please use this 
document as a guide to completing the MRI exam and MRI Encounter Form. 
 
 

 
 
34 
APPENDIX D – Intervention Protocol  
 
Exercise Intervention Overview 
 
Example aerobic exercises: March in place, jumping jacks, glute kicks, high knees, lateral 
shuffles, standing oblique crunch, speed skaters, mountain climbers 
 
Example resistance exercises: Weighted lifts and weight bearing functional tasks for large 
muscle groups; seated knee extensions, standing hip abduction, standing hip extension, triceps 
extension, and shoulder abduction3 
 
 
1Times do not include 10 min warm-up/cooldown per session (i.e. 20 mins total per wee k in 
Level 1 resistance training, 30 mins total per week in all other circumstances).  
 
Exercise 
Type 
Aerobic 
Strength 
Combined 
Mode 
Walking (with guided in-
home sessions provided 
1 time/week) 
Resistance activity (with 
guided in-home sessions 
provided 1 time/week) 
Both aerobic and 
resistance activities, 
starting each session 
with aerobic activities 
Frequency 3 times/week  
Level 1: 2 times/week 
Levels 2 & 3: 3 times per 
week as tolerated 
3 times/week 
Time1 
Level 1: 90 min/week 
(30 min sessions) 
Level 2: 120 min/week 
(40 min sessions)  
Level 3: 150 min/week  
(50 min sessions) 
Level 1: 60 min/week 
(30 min sessions) 
Level 2: 90 min/week 
(30 min sessions) 
Level 3: 120 min/week 
(40 min sessions) 
Level 1: 150 min/week 
(50 min sessions) 
Level 2: 150 min/week 
(50 min sessions) 
Level 3: 180 min/week  
(60 min sessions) 
Intensity2 
• 
Level 1: 
55-60% of HR (at 
peak VO2 at baseline)  
Target RPE: 12-13 
• 
Level 2:  
60-70% of baseline 
HR  
Target RPE: 13-14 
• 
Level 3:  
70-85% of baseline 
HR for duration 
Target RPE: 14-16 
• 
Level 1: 
50% of 1-rep max per 
weighted lifts (2 sets 
of 8-10 reps)  
Target RPE: 12-13 
• 
Level 2: 
60% of 1-rep max per 
weighted lift (2 sets of 
8-12 reps)  
Target RPE: 13-14 
• 
Level 3: 
70% of 1-rep max per 
weighted lift for (2 sets 
of 10-14 reps) 
Target RPE: 14-16 
When the second exercise 
regimen is added, begin at 
Level 1 in that regimen 
while continuing at the 
same level for the exercise 
regimen already underway. 
 
Sessions will include 20-40 
mins of AE and 2 sets of 8-
14 reps, with intensities 
varying based on 
participant progress 

 
 
35 
2The prescribed progression from Level 1 – 3 includes 3 weeks at Level 1, 3 weeks at Level 2, 
and the remaining 6 weeks at Level 3. However, participant exertion ratings will be measured 
after all exercise sessions. The ratings must be at 13 or lower to progress to the next level.  
3Prior to initiating any activity involving strength training, the following considerations should be 
made: 
• 
Resolve any acute arm or shoulder problems secondary to breast cancer 
treatment before exercise training 
• 
Reduce or avoid upper body exercise if exercise causes swelling or changes in 
arm/shoulder symptoms 
• 
Women with lymphedema should wear a compression garment during exercise 
• 
Be aware of risk for fracture if treated with hormonal therapy, dx of osteoporosis, or bony 
metastases