ACTIVATE: A Pilot Randomized Activity Coaching Trial to Increase Vitality and Energy During Post-operative Pelvic Radiation Therapy for Endometrial Cancer
Phase: NA
Conditions: Radiation Therapy, Gynecologic Cancer, Exercise Therapy
Sponsor: Inova Health Care Services

ACTIVATE Trial | Avani Rao 
PROTOCOL VERSION DATE: 05/12/2025  
 
Page   of 48 
 
 
OFFICIAL STUDY TITLE: ACTIVATE: A PILOT RANDOMIZED 
ACTIVITY COACHING TRIAL TO INCREASE VITALITY AND ENERGY 
DURING POST-OPERATIVE PELVIC RADIATION THERAPY FOR 
ENDOMETRIAL CANCER 
PROTOCOL 
NCT NUMBER: NCT06746428 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Document Date: May 12th, 2025 
      

ACTIVATE Trial | Avani Rao 
PROTOCOL VERSION DATE:  05/12/2025 
 
ACTIVATE: A pilot randomized Activity Coaching Trial to Increase Vitality and Energy 
during post-operative pelvic radiation therapy for endometrial cancer 
 
 
Inova Protocol #: 
INOVA-2024-91  
Funding Source: 
Inova Schar Cancer Institute 
Protocol Date: 
 
May 12th, 2025 
Study Principal Investigator: 
Dr. Avani Rao 
Inova Health Systems 
3300 Gallows Road 
Falls Church, Virginia 22042 
606-269-2839 
Avani.Rao@inova.org 
Site Principal Investigator(s) (PI): 
Dr. Avani Rao 
Inova Health Systems 
3300 Gallows Road 
Falls Church, Virginia 22042 
606-269-2839 

ACTIVATE Trial | Avani Rao 
1 
 
PROTOCOL VERSION DATE:  05/12/2025 
 
 
 
 
 
 
 
Study Exempt from IND Requirements per 21 CFR 312.2(b) as determined by FDA. 
 
Protocol Type / Version # / Version Date: 
Amendment / 2 / 05/12/2025 
 

ACTIVATE Trial | Avani Rao 
2 
 
PROTOCOL VERSION DATE:  05/12/2025 
SUMMARY OF CHANGES 
Inova Study #:  INOVA-2024-91 
External IRB Protocol #: 
 
 
Protocol Date:05/12/2025 
 
 
 
Protocol Modification #: 1 
 
 
 
REVISION HISTORY 
# 
Section 
Page(s) 
Summary of Changes 
Consent 
Change 
(Y/N) 
1. 
Table 
1.Sched
ule of 
study 
procedu
res; 9.3 
17 and 30 Removed vital signs as a data element for collection and 
kept only height and weight at enrollment 
 
2. 
9.2;11.
1.4 
29 and 35 Added option to collect PROs using a paper survey or 
allow our clinical research coordinators to interview the 
patient by phone or in-person 
 
3. 
All 
1-47 
Protocol Version Date was updated from “8/14/2024” to 
“05/12/2025” 
 
4. 
 
 
 
 
5. 
 
 
 
 
 
 
 

ACTIVATE Trial | Avani Rao 
3 
 
PROTOCOL VERSION DATE:  05/12/2025 
ABSTRACT 
The integration of exercise therapy is recommended for cancer patients and survivors to 
mitigate the side effects of therapy and the risk of recurrence. Cancer patients, however, 
often experience barriers to meeting the recommended guidelines. It is well documented 
that at least two-thirds of cancer patients are unable to adhere to the recommendation of 
exercise due to symptoms and barriers, with women being more likely than men to report 
barriers to adherence to exercise. Patients with low adherence report higher symptom 
burden including pain and fatigue. Radiation treatment, with usually a daily treatment 
schedule, poses additional barriers to engaging in routine exercise and there is a large gap 
in data to guide the incorporation of exercise therapy into the treatment of patients 
receiving radiation given these unique challenges. The available data is limited largely to 
men with prostate cancer, which reports improvement in a number of symptoms with 
exercise during treatment.   
The most common gynecologic malignancy in the United States is endometrial cancer, 
and the incidence continues to rise. Many women with endometrial cancer will be 
recommended to undergo pelvic radiation therapy to reduce recurrence risks. For women 
undergoing pelvic radiation therapy, fatigue-limiting activities of daily living (ADLs) is a 
common acute side effect of therapy. Although it is accepted that exercise helps 
treatment-related fatigue in the general cancer population, patient-specific factors (more 
advanced age, post-operative status, and the prevalence of baseline obesity and co-
morbidities) and treatment-specific factors (daily radiation for 5 weeks, often concurrent 
chemotherapy) pose significant challenges with the feasibility of endometrial cancer 
patients to engage in exercise. 
This study will explore the feasibility of conducting a randomized trial of a personalized 
exercise coaching program to encourage physical activity for women undergoing 
adjuvant pelvic intensity-modulated radiation therapy treatment for endometrial cancer to 
guide the design of future studies to test the hypothesis that a relationship with an 
exercise coach will increase adherence to exercise. Such a follow-up study will be suited 
to investigate the effect of exercise to treat or mitigate fatigue, to identify successful 
strategies for improving adherence to exercise, and to understand which population of 
patients may benefit most from a targeted program to increase motivation and overcome 
barriers to exercise. 
In this pilot study, a total of 16 women treated with total or modified radical 
hysterectomy and surgical staging for Stage I-IVA endometrial cancer who are planned to 
complete pelvic external beam radiation therapy as part of their adjuvant treatment will 
be included. The intervention is an exercise coaching program which will consist of 
weekly check-ins for 10 weeks with a certified exercise coach with expertise in caring for 
oncology patients. The purpose of each check-in is to address readiness for exercise, 
identify barriers, and develop an individualized plan for exercise for the week with a goal 
of increasing activity to 150 minutes of moderate activity per week using any form of 
activity that is enjoyable and accessible to the patient. This will be accomplished by 
shaping behavior through personalized recommendations. Patients will be randomized to 

ACTIVATE Trial | Avani Rao 
4 
 
PROTOCOL VERSION DATE:  05/12/2025 
either an immediate- or delayed-start of their exercise coaching program. Women 
randomized to the immediate-start group will start the intervention during the first week 
of radiation therapy and continue through and post-completion of radiation. Women 
randomized to the delayed-start group will start the intervention at 6-8 weeks post-
radiation, a more typical period in survivorship where exercise counseling may begin. 
Participants will be asked to wear an activity monitor to track steps and moderate activity 
minutes and to complete assessments of patient-reported cancer-related fatigue, 
bowel/urinary toxicity, sexual health, and quality of life and participate in a six-minute 
walk test (6MWT) at predefined time points throughout the study. 
The primary objective of this study is to evaluate the feasibility of conducting a 
randomized trial with an exercise coaching program as the intervention, with the 
secondary objective to provide initial efficacy on improving treatment-related fatigue, 
understand the prevalence of baseline fatigue, and explore potential behavioral 
mechanisms (mediators) and variables that influence the strength of the intervention 
effect (moderators) for a follow-up study. 
 
 
 

ACTIVATE Trial | Avani Rao 
5 
 
PROTOCOL VERSION DATE:  05/12/2025 
ABBREVIATIONS AND DEFINITIONS 
Abbreviation 
Definition of Terms 
6MWT 
Six-Minute Walk Test 
ADLs 
Activities of daily living 
AE 
Adverse Event 
ASCO 
American Society of Clinical Oncology 
BP 
Blood pressure 
CFR 
Code of Federal Regulations 
CRF 
Cancer-related fatigue 
CRP 
C reactive protein 
DSM 
Date Safety and Monitoring 
ECOG 
Eastern Cooperative Oncology Group 
EORTC QLQ-C30 
European Organization for Research and Treatment of Cancer 
Quality of Life Questionnaire 
EPIC 
Expanded Prostate Cancer Index Composite 
FACIT-F 
Functional Assessment of Chronic Illness Therapy – Fatigue 
FDA 
Food and Drug Administration 
FFIS 
Fatigue functional impact scale 
FWA 
Federal wide Assurance 
Fx 
Fraction 
GCP 
Good clinical practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HR 
Heart rate 
ICF 
Informed consent form 
ID 
Identification 
IL-1 
Interleukin-1 
IMRT 
Intensity-modulated radiotherapy 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ISCI 
Inova Schar Cancer Institute 
MRN 
Medical Record Number 
NCCN 
National Comprehensive Cancer Network 
ORI 
Office of Research Integrity 
PHI 
Protected Health Information 
PI 
Principal Investigator 
PR 
Patient-Reported Outcomes Measurement Information System 
QoL 
Quality of Life 
RR 
Respiratory rate 
RT 
Radiation Therapy 
RTOG 
Radiation Therapy Oncology Group 
SAE 
Serious adverse event 
sIL-6R 
Systemic interleukin-6 soluble receptor 
sTNF-RII 
Soluble TNF receptor type II 

ACTIVATE Trial | Avani Rao 
6 
 
PROTOCOL VERSION DATE:  05/12/2025 
 
 
PROTOCOL SYNOPSIS 
Study Title: 
ACTIVATE: A pilot randomized Activity Coaching Trial 
to Increase Vitality and Energy during post-operative 
pelvic radiation therapy for endometrial cancer 
Source of Funding: 
Inova Schar Cancer Institute 
Study Rationale: 
The integration of exercise therapy is recommended for 
cancer patients and survivors to mitigate the side effects of 
therapy and reduce recurrence risks. Cancer patients, 
however, often experience barriers to meeting the 
recommended guidelines. It is well documented that at least 
two-thirds of cancer patients are unable to adhere to the 
recommendation of exercise due to symptoms and barriers, 
with women being more likely than men to report barriers 
to adherence to exercise. For women undergoing pelvic 
radiation therapy, fatigue-limiting activities of daily living 
(ADLs) is a common acute side effect of therapy; however, 
patient-specific factors (more advanced age, post-operative 
status, and the prevalence of baseline obesity and co-
morbidities) and treatment-specific factors (daily radiation 
for 5 weeks, often concurrent chemotherapy) pose 
significant challenges with the feasibility of endometrial 
cancer patients to engage in exercise. 
Despite the known benefits of exercise, there is a notable 
lack of data on how to effectively integrate exercise into the 
treatment regimens of women receiving pelvic radiation 
therapy. Most existing studies focus on other cancer types 
or on male patients, leaving a significant gap in the 
literature regarding female patients with gynecological 
malignancies. 
In this pilot study, a total of 16 women treated with total or 
modified radical hysterectomy and surgical staging for 
Stage I-IVA endometrial cancer who are planned to 
complete pelvic external beam radiation therapy as part of 
their adjuvant treatment will be included. The intervention 
is an exercise coaching program which will consist of 
weekly check-ins for 10 weeks with a certified exercise 
coach with expertise in caring for oncology patients. The 

ACTIVATE Trial | Avani Rao 
7 
 
PROTOCOL VERSION DATE:  05/12/2025 
purpose of each check-in is to address readiness for 
exercise, identify barriers, and develop an individualized 
plan for exercise for the week with a goal of increasing 
activity to 150 minutes of moderate activity per week using 
any form of activity that is enjoyable and accessible to the 
patient. This will be accomplished by shaping behavior 
through personalized recommendations. Patients will be 
randomized to either an immediate- or delayed-start of their 
exercise coaching program. Women randomized to the 
immediate-start group will start the intervention during the 
first week of radiation therapy and continue through and 
post-completion of radiation. Women randomized to the 
delayed-start group will start the intervention at 6-8 weeks 
post-radiation, a more typical period in survivorship where 
exercise counseling may begin. Participants will be asked to 
wear an activity monitor to track steps and moderate 
activity minutes and to complete assessments of patient-
reported cancer-related fatigue, bowel/urinary toxicity, 
sexual health, and quality of life and participate in a six-
minute walk test (6MWT) at predefined time points 
throughout the study. 
The primary objective of this study is to evaluate the 
feasibility of conducting a randomized trial with an exercise 
coaching program as the intervention, with the secondary 
objective to provide initial efficacy on improving treatment-
related fatigue, understand the prevalence of baseline 
fatigue, and explore potential behavioral mechanisms 
(mediators) and variables that influence the strength of the 
intervention effect (moderators) for a follow-up study.  
Study Objective(s): 
Primary: 
The primary objective of this study is to evaluate the 
feasibility of conducting a randomized trial of an exercise 
coaching program to encourage physical activity for women 
treated with adjuvant pelvic intensity-modulated radiation 
therapy treatment for endometrial cancer. 
 
Secondary: 
1) To collect initial efficacy evaluation of the exercise 
coaching program on patient-reported fatigue, 
bowel/urinary toxicity, QoL, cognitive function, 
sexual function and satisfaction, and self-efficacy, as 

ACTIVATE Trial | Avani Rao 
8 
 
PROTOCOL VERSION DATE:  05/12/2025 
well as distance walked during 6MWT between the 
immediate and delayed-start group from baseline to 
pre-specified time points (end of RT, 5-7 weeks post 
RT, and 16-19 weeks post RT) to guide statistical 
planning for follow-up study. 
2) To measure the prevalence of fatigue at baseline in 
the population of endometrial cancer patients 
recommended pelvic radiation therapy using data 
collected in the screening process. 
3) To explore potential behavioral mechanisms 
(mediators) and variables that influence the strength 
of the intervention effect (moderators). 
Test 
Product(s)/Agent(s): 
The exercise coaching program will consist of weekly 
check-ins for 10 weeks with a certified exercise coach with 
expertise in caring for oncology patients. 
Study Design: 
Pilot feasibility study using randomization of immediate 
versus delayed intervention. 
Participant Population 
Key Criteria for 
Inclusion and 
Exclusion: 
Inclusion Criteria: 
• At least 18 years of age 
• Pathologic diagnosis of endometrial cancer (any 
histology, Stage I-IVA) 
• Has undergone modified radical or radical 
hysterectomy 
• Plan to receive adjuvant treatment with pelvic external 
beam radiation therapy at ISCI 
• ECOG performance status of 0-1 
• Patient has a computer, smart phone, or tablet for 
virtual access to the web-based platform and email 
• Able to read, understand and provide written informed 
consent 
• Deemed appropriate for unmonitored exercise by 
treating physician based on the following evidence-
based criteria (1) 
o Walk without any assistance or assistance 
device 
o Absence of significant cognitive impairment 
o Absence of high risk for falls 
• Participant does not need to refrain from any activity 
 
Exclusion Criteria: 
• Unable to schedule and attend coaching visits 

ACTIVATE Trial | Avani Rao 
9 
 
PROTOCOL VERSION DATE:  05/12/2025 
• Participation in a regular exercise program of ≥150 
minutes of moderate intensity exercise a week at 
baseline 
• Unable to perform the five-times stand test 
• Medical comorbidities including: 
o Unstable angina 
o Uncontrolled dysrhythmias 
o Acute pulmonary embolus 
o Active pulmonary infection 
Number of 
Participants: 
16 participants randomized 1:1 to immediate start or 
delayed start intervention 
Stratification will be performed to divide the number of 
patients with no to mild fatigue (0-3 numeric rating scale) 
from patients with moderate to severe fatigue (4-10) 
because it is possible that the intervention effect is variable 
depending on baseline level of fatigue. 
Study Duration: 
Each participant’s participation will last up to 6 months. 
Study Phases: 
 
Screening 
 
Study Treatment 
 
 
 
 
 
 
 
 
Follow-Up 
Screening for eligibility and obtaining consent 
 
The exercise coaching program will consist of weekly 
check-ins for 10 weeks with a certified exercise coach with 
expertise in caring for oncology patients with a goal of 
increasing activity to 150 minutes of moderate activity per 
week. This will be accomplished by shaping behavior 
through personalized recommendations. Women 
randomized to the immediate start group will start the 
intervention during the first week of radiation therapy and 
continue through and post-completion of radiation. Women 
randomized to the delayed start group will start the 
intervention at 6-8 weeks post-radiation. 
 
Steps, active minutes, patient-reported fatigue, 
bowel/urinary toxicity, QoL, cognitive function, sexual 
function and satisfaction, and self-efficacy, as well as 
distance walked during 6MWT. 

ACTIVATE Trial | Avani Rao 
10 
 
PROTOCOL VERSION DATE:  05/12/2025 
Efficacy Evaluations: 
Steps, active minutes, and heart rate measured by a Fitbit 
device 
 
PROMIS Short Form v1.0 – Fatigue 13a (FACIT-Fatigue) 
 
EPIC Prostate Bowel and Bladder assessment (short form) 
 
PROMIS-29 Profile v2.1 QoL (physical function, anxiety, 
depression, sleep disturbance, pain interference/intensity, 
ability to participate in social roles and activities) 
 
PROMIS Short Form v2.0 – Cognitive Function 4a 
 
PROMIS Sexual Function and Satisfaction v2.0 Brief 
Profile (Female) 
 
PROMIS Short Form v1.0 – Self-Efficacy for Chronic 
Conditions – Managing Daily Activities 4a and Managing 
Symptoms 4a  
 
6MWT 
Safety Evaluations: 
Patients can communicate any concerns or safety issues 
during their weekly check-ins with the exercise coach. They 
will also be provided with information for contacting an on-
call doctor as part of usual care to report any concerning 
symptoms should they occur outside of the standard 
evaluation schedule. 
Statistical and 
Analytical Plan: 
This study will enroll 16 patients. At the Inova Schar 
Cancer Institute Fairfax location, approximately 24 patients 
will undergo a course of pelvic radiation per year. 
Additionally, approximately 24 patients will undergo a 
course of pelvic radiation per year across Inova Loudoun, 
Inova Alexandria, and Inova Fair Oaks Hospitals. With the 
goal of the study to evaluate adherence to and the 
acceptability and feasibility of the intervention as part of a 
pilot study, the sample size was determined with the goal to 
complete accrual of the study within 1 year, accruing across 

ACTIVATE Trial | Avani Rao 
11 
 
PROTOCOL VERSION DATE:  05/12/2025 
all 4 sites. 
 
Primary Objective Analytical Plan 
Feasibility of conducting a randomized trial of this nature 
will be evaluated on the basis of process feasibility and 
resources and data-management feasibility. 
The process feasibility will be evaluated on: 
1. Recruitment acceptability from the provider and 
patient perspective: 
a. Provider acceptability of the intervention will be 
defined as the proportion of patients identified on 
pre-screening by the PI that the primary clinician 
agrees of patient suitability for offering enrollment 
on the trial and proceeding to completion of 
screening steps if patient is interested in the study. 
We set an a priori goal of 50% provider 
acceptability. 
b. Patient acceptability of the intervention will be 
defined as the proportion of patients who agreed to 
consent and then proceed to completion of screening 
steps. We set an a priori goal of 50% patient 
acceptability. 
2. Appropriateness of the screening criteria: 
a. Screening criteria appropriateness will be defined as 
the proportion of patients who are screened who 
proceeded to allocation of intervention groups. We 
set an a priori goal of 50% of appropriateness of the 
screening criteria. 
3. Adherence to the exercise coaching session 
intervention: 
a. Individual adherence to coaching sessions will be 
defined as complete adherence when engaging in 10 
of the 10 planned exercise coaching sessions and 
high adherence as engaging in at least 7 of the 
planned 10 exercise coach check-ins. We set an a 
priori goal of overall 70% participant adherence to 
the coaching sessions, to be analyzed per cohort (6 
of 8 participants in each arm demonstrating high 
adherence as defined above). 
4. Adherence to the physical activity monitor usage to 

ACTIVATE Trial | Avani Rao 
12 
 
PROTOCOL VERSION DATE:  05/12/2025 
track steps and active minutes: 
a. Individual adherence to the physical activity monitor 
will be defined as wearing the activity tracker for at 
least 8 hours a day for 70% of the days in the study. 
Heart rate will be used to determine wear-time. We 
set an a priori goal of overall 70% participant 
adherence to the physical activity monitor, to be 
analyzed per cohort (6 of 8 participants in each arm 
demonstrating adherence as defined above). 
5. Adherence to recommendation of 150 minutes per 
week of moderate physical activity: 
a. Individual adherence to regular physical activity will 
be defined as meeting the recommendation of 150 
minutes of moderate physical activity per week, 
based on the Physical Activity Guidelines for 
Americans developed by the U.S. Department of 
Health and Human Services (HHS). The target for 
participant adherence is set at an a priori goal of 
70%. 
 
The resource and management feasibility will be assessed 
based on the capacity of the exercise coach and research 
team to perform the required tasks of the protocol: 
 
1. Adherence to the timeline of study procedures and 
human and data management issues that could 
potentially arise during a full‐scale RCT will be 
tracked. Adherence to the study timeline for 
completion of required patient surveys and 6MWT as 
well as appropriate scheduling (patient attendance not 
required) of the exercise coaching sessions and follow-
ups will be a proxy measurement of research resource 
and human data management acceptability. We set an 
a priori goal of 80% adherence.  
 
Secondary Objective Analytical Plan 
1. Changes in patient-reported fatigue, bowel/urinary 
toxicity, QoL, cognitive function, sexual function and 
satisfaction, and self-efficacy, as well as distance 
walked during 6MWT from baseline to pre-specified 
time points (end of RT, 5-7 weeks post RT, and 16-19 
weeks post RT) within and between each group will be 

ACTIVATE Trial | Avani Rao 
13 
 
PROTOCOL VERSION DATE:  05/12/2025 
compared using two-sample t-test or Wilcoxon Rank 
Sum test when appropriate. Repeated measure 
models/linear mixed effect models may also be used to 
explore the changes in self-reported questionnaires 
over time among different treatment groups. Data will 
be analyzed based on the intention-to-treat principle 
and used to estimate treatment effect size for future 
trial design. 
2. Prevalence of fatigue at baseline in the population of 
endometrial cancer patients receiving pelvic radiation 
therapy will be reported using data collected in the 
screening process. 
3. Exploratory analysis of potential behavioral 
mechanisms (mediators) and variables that influence 
the strength of the intervention effect (moderators) will 
be performed. 
Data and Safety 
Monitoring Plan: 
Internal quality assurance team will be responsible for 
monitoring the safety and data acquisition for this study. 
 
 
 
 
 
 
 
 
 
 

ACTIVATE Trial | Avani Rao 
14 
 
PROTOCOL VERSION DATE:  05/12/2025 
TABLE OF CONTENTS 
SUMMARY OF CHANGES .............................................................................................. 2 
ABSTRACT ........................................................................................................................ 3 
ABBREVIATIONS AND DEFINITIONS ......................................................................... 5 
PROTOCOL SYNOPSIS ................................................................................................... 6 
TABLE OF CONTENTS .................................................................................................. 14 
TABLE 1: SCHEDULE OF STUDY PROCEDURES .................................................... 17 
1. BACKGROUND .......................................................................................................... 20 
1.1 
Study Disease(s) or Condition(s) ....................................................................... 20 
1.2 
Product(s) / Agent(s) .......................................................................................... 20 
1.3 
Rationale............................................................................................................. 20 
1.4 
Relevant Literature and Data.............................................................................. 22 
1.5 
Compliance Statement........................................................................................ 24 
 
24 
 
OBJECTIVES ............................................................................................................ 24 
Primary Objective ......................................................................................................... 24 
2.1 
Secondary Objective .......................................................................................... 24 
 
SETTINGS ................................................................................................................ 25 
3.1 
Study Sites .......................................................................................................... 25 
3.2 
Community Involvement.................................................................................... 25 
3.3 
Outside of Organization ..................................................................................... 25 
 
RESOURCES AVAILABLE .................................................................................... 25 
4.1 
Conducting Research.......................................................................................... 25 
4.2 
Medical Resources ............................................................................................. 26 
 
INVESTIGATIONAL PLAN.................................................................................... 26 
5.1 
General Schema of Study Design....................................................................... 26 
5.2 
Product(s) / Agent(s) .......................................................................................... 27 
5.3 
Allocation to Treatment Groups and Blinding/Randomization ......................... 27 
 
STUDY TIMELINE .................................................................................................. 27 
6.1 
Individual Participation ...................................................................................... 27 
6.2 
Study Timeline ................................................................................................... 27 
 
PARTICIPANT SELECTION .................................................................................. 28 

ACTIVATE Trial | Avani Rao 
15 
 
PROTOCOL VERSION DATE:  05/12/2025 
7.1 
Eligibility Criteria .............................................................................................. 28 
 
RECRUITMENT METHODS .................................................................................. 28 
8.1 
Methods .............................................................................................................. 28 
8.2 
Materials ............................................................................................................. 29 
 
STUDY PROCEDURES ........................................................................................... 29 
9.1 
Screening Visit ................................................................................................... 29 
9.2 
Participant Survey of Patient-Reported Outcomes and Information .................. 29 
9.3 
Study Intervention Visits .................................................................................... 30 
9.4 
Unscheduled Visits ............................................................................................. 32 
9.5 
Non-compliance and Lost to Follow-Up ............................................................ 32 
 STUDY ADMINISTRATION .................................................................................. 33 
10.1 
Study Intervention(s) Administration ............................................................. 33 
10.2 
Measures to Minimize Bias: Randomization / Blinding ................................ 34 
 DATA COLLECTION AND MANAGEMENT ...................................................... 34 
11.1 
Data Collection and Management .................................................................. 34 
11.2 
Security ........................................................................................................... 35 
11.3 
Release of Locally Banked Data .................................................................... 36 
11.4 
Confidentiality ................................................................................................ 36 
 DATA ANALYTICS ................................................................................................ 37 
12.1 
Study Objectives ............................................................................................. 37 
12.2 
Analytics ......................................................................................................... 37 
 SAFETY MANAGEMENT ...................................................................................... 39 
13.1 Regulatory and Ethical Considerations ................................................................. 39 
13.2 
Clinical Adverse Events ................................................................................. 40 
 PARTICIPANT COMPENSATION AND REPORTS ............................................. 40 
14.1 
Participant Compensation ............................................................................... 40 
14.2 
Reporting Events to Participants .................................................................... 40 
14.3 
Study Results and Incidental Findings ........................................................... 40 
 ECONOMIC BURDENS AND COMPENSATION / INCENTIVE ........................ 41 
15.1 
Foreseeable Costs ........................................................................................... 41 
15.2 
Payments / Reimbursements ........................................................................... 41 
 CONSENT PROCESS .............................................................................................. 41 
16.1 
Informed Consent ........................................................................................... 41 

ACTIVATE Trial | Avani Rao 
16 
 
PROTOCOL VERSION DATE:  05/12/2025 
16.2 
HIPAA Research Authorization(s) ................................................................. 41 
16.3 
Safeguards for Vulnerable Populations .......................................................... 42 
16.4 
Documentation of Consent ............................................................................. 42 
 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION / WITHDRAWAL ............................................................... 42 
17.1 
Discontinuation of Study Intervention ........................................................... 42 
17.2 
Participant Discontinuation/Withdrawal from the Study ............................... 42 
17.3 
Early Termination Study Visit ........................................................................ 43 
 RECORDINGS .......................................................................................................... 43 
 IRB REVIEW HISTORY .......................................................................................... 43 
 COORDINATING CENTER FOR MULTI-SITE STUDIES .................................. 43 
 REFERENCES / BIBLIOGRAPHY ......................................................................... 43 

ACTIVATE Trial | Avani Rao 
17 
PROTOCOL VERSION DATE:  05/12/2025 
TABLE 1: SCHEDULE OF STUDY PROCEDURES 
Study Phase 
Screening 
Enrollment1 
RT 
Simulation 
Radiation 
Post-Radiation 
Week Number 
0 
 
1 
(Fraction 
1-5) 
(Fraction 
6-10) 
(Fraction 
11-15) 
(Fraction 
16-20) 
(Fraction 
21-25) 
5-7 weeks 
post RT 
follow-up2 
6-8 
weeks 
post 
RT 
16-19 
weeks post 
RT follow-
up3 
ALL PATIENTS 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
Review Inclusion/Exclusion Criteria 
X 
 
 
 
 
 
 
 
 
 
 
Fatigue 0-10 Numeric Rating Scale 
X 
 
 
 
 
 
 
 
 
 
 
Height and weight 
 
X 
 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
Patient-reported 
demographics/medical history 
(comorbidities) 
 
X 
 
 
 
 
 
 
 
 
 
Stages of change metric 
 
X 
 
 
 
 
 
X 
X 
 
X 
Patient-reported fatigue (FACIT-
Fatigue) 
 
X 
 
 
 
 
 
X 
X 
 
X 
Patient-reported toxicity (EPIC bowel 
and urinary short form assessments) 
 
X 
 
 
 
 
 
X 
X 
 
X 
PROMIS-29 Profile v2.1 QoL 
 
X 
 
 
 
 
 
X 
X 
 
X 
PROMIS Cognitive Function 
 
X 
 
 
 
 
 
X 
X 
 
X 
PROMIS Self-Efficacy for Chronic 
Conditions 
 
X 
 
 
 
 
 
X 
X 
 
X 

ACTIVATE Trial | Avani Rao 
 
 
(Continued) TABLE 1: SCHEDULE OF STUDY PROCEDURES 
18 
PROTOCOL VERSION DATE:  05/12/2025 
Study Phase 
Screening 
Enrollment1 
RT 
Simulation 
Radiation 
Post-Radiation 
Week Number 
0 
 
1 
(Fraction 
1-5) 
(Fraction 
6-10) 
(Fraction 
11-15) 
(Fraction 
16-20) 
(Fraction 
21-25) 
5-7 weeks 
post RT 
follow-up2 
6-8 
weeks 
post 
RT 
16-19 
weeks post 
RT follow-
up3 
6-Minute Walk Test (6MWT) 
 
X 
 
 
 
 
 
X 
X 
 
X 
Weekly Active Minute, step and heart 
rate data collection from Fitbit 
 
 
X-Active minute, step, and heart rate data collected from time of simulation to last f/u (16-19 weeks post RT) for all 
patients 
PROMIS Brief Profile Sexual 
Function and Satisfaction 
 
 
 
 
 
 
 
 
X 
 
X 
Pelvic radiation therapy with IMRT 
 
 
 
X 
X 
X 
X 
X 
 
 
 
Satisfaction survey 
 
 
 
 
 
 
 
 
 
 
X 
Recorded semi-structured exit 
interview with study PI 
 
 
 
 
 
 
 
 
 
 
X 
Early-Intervention Group 
Weekly exercise coach check-ins start 
x 10 weeks 
 
 
 
X (Patients start first check-in during first 5 fractions of RT and continue for a 
total of 10 weekly sessions. With this schedule, the final session will be post-
pelvic RT completion) 
 
 
5-10 minute bi-weekly Fitbit check-in 
call 
 
 
 
 
 
 
 
 
 
X (Once every 2 
weeks, starting the 
week after coaching 
sessions complete for 
10 weeks (total 5 
calls). 
Delayed-Intervention Group 
Weekly exercise coach check-ins start 
x 10 weeks 
 
 
 
 
 
 
 
 
 
X (Patients start first 
check-in after 5–7-
week post RT follow-

ACTIVATE Trial | Avani Rao 
 
 
(Continued) TABLE 1: SCHEDULE OF STUDY PROCEDURES 
19 
PROTOCOL VERSION DATE:  05/12/2025 
Study Phase 
Screening 
Enrollment1 
RT 
Simulation 
Radiation 
Post-Radiation 
Week Number 
0 
 
1 
(Fraction 
1-5) 
(Fraction 
6-10) 
(Fraction 
11-15) 
(Fraction 
16-20) 
(Fraction 
21-25) 
5-7 weeks 
post RT 
follow-up2 
6-8 
weeks 
post 
RT 
16-19 
weeks post 
RT follow-
up3 
up, starting 6-8 weeks 
post RT, and continue 
for a total of 10 
sessions) 
5-10 minute bi-weekly Fitbit check-in 
call 
 
 
 
X (Once every 2 weeks starting the first week of RT for a total of 10 weeks (total 
5 calls) 
 
 
1Enrollment would occur any time within 7days (before or after) simulation, prior to the start of radiation. 
25-7 week post RT follow-up intended to be soon after completion of intervention in the early-intervention group and before intervention in the delayed-intervention group for purposes of assessment.  
316-19 week post RT follow-up intended to be soon after completion of intervention in the delayed-intervention group for purposes of assessment collection.  
 

ACTIVATE Trial | Avani Rao 
20 
PROTOCOL VERSION DATE:  05/12/2025 
1. BACKGROUND 
Cancer-related fatigue (CRF) is a significant and distressing symptom for women 
undergoing pelvic radiation therapy for endometrial cancer, often severely limiting 
their ability to engage in daily activities and reducing their overall quality of life 
(QoL) (2). Although exercise has been shown to be an effective intervention for 
mitigating CRF in various cancer populations, women with gynecological 
malignancies, particularly those undergoing pelvic radiation, face unique barriers 
that make adherence to exercise challenging. These barriers include advanced age, 
post-surgical recovery, baseline obesity, and the demanding nature of radiation 
treatments, which are often compounded by concurrent chemotherapy (3-9). 
Additionally, environmental and social factors, such as lack of access to exercise 
facilities and limited support from healthcare providers or family, further discourage 
regular physical activity (10). 
Introducing a personalized exercise coaching program offers a promising strategy to 
overcome these barriers and improve adherence to exercise during treatment (3-9). 
By providing tailored exercise plans and continuous support through regular 
coaching sessions, this approach aims to empower patients to incorporate physical 
activity into their routine despite the challenges posed by their treatment and 
personal circumstances. Improved adherence to exercise not only has the potential to 
better manage CRF but also addresses other symptoms associated with cancer and its 
treatment, such as pain, urinary and bowel dysfunction, and reduced QoL (11-13). 
By enhancing adherence through personalized coaching, patients may experience 
more effective symptom management, leading to improved health outcomes and 
overall well-being during and after their cancer treatment (14, 15). However, none of 
the available literature focuses on women undergoing pelvic radiation therapy. 
1.1 
Study Disease(s) or Condition(s) 
1.1.1 Epidemiology of the Disease 
Nearly 68,000 women will be diagnosed with endometrial cancer in the 
US in 2024 (22). Also commonly called uterine cancer, endometrial 
cancer is the most frequently diagnosed gynecologic cancer and the fourth 
most diagnosed cancer in women, with a median age of diagnosis of 62 
years. While the exact cause is unknown, endometrial cancer's incidence 
and death rate have increased over the years, possibly due to factors such 
as obesity and hormone replacement therapy to manage other medical 
conditions (23). 
1.2 
Product(s) / Agent(s) 
Not applicable. 
1.3 
Rationale 
Cancer-related fatigue (CRF) is a common and distressing symptom experienced 
by cancer patients, particularly those undergoing pelvic radiation therapy for 
endometrial cancer. As the most prevalent gynecologic malignancy in the United 
States, endometrial cancer has seen a rising incidence driven by factors such as 

ACTIVATE Trial | Avani Rao 
21 
PROTOCOL VERSION DATE:  05/12/2025 
obesity and hormone replacement therapy. To reduce the risk of recurrence, many 
women with this diagnosis undergo pelvic radiation therapy to lower recurrence 
risks. However, CRF is a common acute side effect of this treatment, significantly 
limiting activities of daily living (ADLs). Although the exact prevalence of CRF in 
women with endometrial cancer undergoing pelvic radiation therapy is not well 
documented, studies suggest that CRF affects up to 93% of this patient population 
(24, 25), severely impacting their QoL and ability to adhere to treatment protocols. 
An increasing body of evidence supports using exercise as an effective intervention 
for managing CRF. Several systematic reviews and meta-analyses have 
demonstrated that exercise, including aerobic and resistance training, can 
significantly reduce the severity of fatigue during and after cancer treatment (19-
21). The ASCO-Society for Integrative Oncology guidelines strongly recommend 
exercise as a therapeutic strategy for CRF, advising that exercise regimens be 
tailored to each patient’s capabilities (26, 27). Despite this broad endorsement, the 
underlying mechanisms by which exercise mitigates CRF are not fully understood, 
and most existing studies have focused on other cancer types. There is limited 
research addressing the unique needs of women with endometrial cancer 
undergoing pelvic radiation therapy (28-30). 
Women with endometrial cancer undergoing pelvic radiation therapy face 
numerous barriers to regular physical activity, including older age, post-surgical 
recovery challenges, baseline obesity, and comorbidities. The demanding nature of 
daily radiation treatments, which often extend over several weeks and may be 
combined with chemotherapy, further complicates their ability to engage in 
exercise. Additionally, social and environmental factors, such as lack of 
encouragement from family and friends, limited access to safe exercise 
environments, and financial constraints, further reduce adherence to exercise 
recommendations, exacerbating CRF and other treatment-related symptoms (10). 
A web-based personalized exercise coaching program offers an innovative solution 
to help these patients overcome the barriers to physical activity, including those 
related to recovery, fatigue, and logistical challenges. Emerging evidence (3-9) 
suggests that these programs can effectively address these obstacles by offering 
tailored exercise plans, continuous support, and motivation, thereby improving 
adherence to recommended physical activity regimens during and after cancer 
treatment. 
Given the prevalence of CRF and its significant impact on patients’ QoL, 
interventions aimed at reducing fatigue are vital. 
The ACTIVATE trial is designed to evaluate the feasibility and potential efficacy 
of a personalized, web-based exercise coaching program for women undergoing 
postoperative pelvic radiation therapy for endometrial cancer. This study aims to 
overcome the barriers to physical activity by providing tailored exercise plans and 
continuous support through certified exercise coaches. Recognizing that 
recruitment through healthcare professionals leads to higher recruitment rates (31), 
radiation oncologists will recruit endometrial cancer patients directly from their 
practices. 

ACTIVATE Trial | Avani Rao 
22 
PROTOCOL VERSION DATE:  05/12/2025 
The primary objective of the ACTIVATE trial is to evaluate the feasibility of 
conducting a randomized trial of this nature, focusing on adherence to the exercise 
coaching program and the acceptability of the intervention among participants and 
providers. Given the significant barriers faced by this patient population, this 
objective is crucial to determine whether such an intervention can be successfully 
implemented in a real-world clinical setting. 
Secondary objectives include evaluating the initial efficacy of the exercise coaching 
program on patient-reported outcomes such as fatigue, bowel/urinary toxicity, QoL, 
cognitive function, sexual function, satisfaction, self-efficacy, and participation in 
the six-minute walk test (6MWT). The study will measure the prevalence of 
baseline fatigue in this population, identify potential mediators (e.g., improvements 
in sleep (32, 33), pain (34, 35), depression (34, 36)) and moderators (e.g., baseline 
fatigue severity, readiness to change) of the intervention's effects, and provide data 
to support the design of a future randomized controlled trial. 
By capturing both patient-reported measures and functional measures of fatigue 
(e.g., 6MWT), we aim to design studies to provide supportive data that could, in the 
future, inform healthcare payors for the reimbursement of exercise coaching 
personnel and programs for patients undergoing radiation treatments for cancer as a 
means of improving patient QoL and overall outcomes. 
1.4 
Relevant Literature and Data 
CRF is a common symptom in patients with cancer and is experienced by 80% of 
individuals receiving cancer therapy (2). Due to the prevalence and QoL influence 
that fatigue has on these patients, it is important to assess interventions that aim to 
reduce the impact of fatigue. Several systematic reviews explore the evidence 
supporting exercise as a treatment for CRF, with interest growing over the past five 
years (19-21). However, none of the available literature focuses on women 
undergoing pelvic radiation therapy (28-30), where CRF can affect up to 93% of 
this patient group (24, 25). For women undergoing pelvic radiation therapy for 
gynecological malignancies, fatigue limiting ADLs is a common acute side effect 
of therapy with no known mitigation recommendations (16). 
The cause of fatigue in patients with cancer is often multi-factorial and can be 
related to clinical, psychological, and behavioral factors. Potential contributing 
aspects include medical comorbidities, medications, nutritional issues, and 
psychological and physical symptoms (38). Inflammation may also be involved in 
the etiology of CRF. Researchers have proposed that tumors and the therapies used 
to remove them can activate the pro-inflammatory cytokine network, leading to 
fatigue symptoms through cytokine signaling in the body’s central nervous system 
(39). 
Various cytokines and inflammatory markers have been correlated to predict 
fatigue in cancer patients. A study of breast cancer patients receiving adjuvant 
radiation showed that localized irradiation encourages increased systemic 
interleukin-6 soluble receptor (sIL-6R) during treatment in those who reported 
elevated levels of fatigue before, during, and after treatment (40). Another study of 
patients undergoing radiation therapy for early-stage breast or prostate cancer found 

ACTIVATE Trial | Avani Rao 
23 
PROTOCOL VERSION DATE:  05/12/2025 
that increased serum levels of inflammatory markers C reactive protein (CRP) and 
IL-1 receptor antagonist were associated with increased fatigue (41). 
Approximately 20-30% of cancer survivors report persistent fatigue for years after 
treatment, correlated with elevated circulating markers of inflammation, such as 
TNF receptor type II (sTNF-RII) (42,43). Studies have also reported associations 
between CRF and variations in the immune and neuroendocrine system, including 
changes in leukocyte subsets, reactivation of latent herpesviruses, dysregulated 
cortisol levels, reduced glucocorticoid receptor sensitivity, and autonomic nervous 
system changes (38). 
Multiple observational studies report that exercise is associated with reduced risk of 
recurrence and mortality, and the integration of exercise therapy is recommended 
by NCCN and ASCO for cancer patients and survivors to reduce the relapse risk 
and mitigate the side effects of therapy, including fatigue (14,21,37). However, 
there is a lack of data to guide the incorporation of exercise therapy into treating 
patients receiving radiation therapy. The available data is largely limited to 
incorporating exercise in the radiation treatment of men with prostate cancer, which 
reports improvement in physical function domains and the potential for increased 
radiotherapy effectiveness (12,13). Reduction of fatigue in patients with both 
prostate and breast cancer receiving radiation has been reported as a result of 
exercise (11,14). 
The American College of Sports Medicine recommends that cancer patients and 
survivors participate in at least 150 minutes of moderate-intensity activity each 
week (44). Various aerobic exercise regimens have been shown to benefit fatigue, 
ranging from home-based programs to supervised, laboratory-based programs 
(44,45). However, there is inconsistent data regarding the effect of resistance 
exercise in this patient population and strategic supportive programs or personnel to 
support patients in accomplishing the recommended guidelines for activity (21,46). 
Previously, there was some concern that exercise during therapy could worsen 
fatigue or worsen side effects; however, in the recently published ASCO guidelines 
on exercise, diet, and weight management during cancer treatment, an expert panel 
performed a systematic review of the medical literature leading to a 
recommendation for oncology providers to recommend aerobic and resistance 
exercise during active treatment with curative intent to mitigate side effects of 
cancer treatment based on data suggesting exercise interventions during active 
treatment reduce fatigue, preserve cardiorespiratory fitness, physical functioning 
and strength and in some populations improve QoL and reduce anxiety and 
depression. Furthermore, the guidelines outline that exercise intervention during 
treatment has a low risk of adverse events (37). The ASCO-Society for Integrative 
Oncology guidelines strongly recommend exercise as a therapeutic strategy for 
CRF, advising that exercise regimens be tailored to each patient’s capabilities (26, 
27). Therefore, exercise during treatment should be encouraged, and it is important 
that the magnitude of benefit be quantified to support ongoing efforts to integrate 
exercise during treatment and reduce barriers to exercise for patients. 
Studies have shown that a web-based personalized exercise coaching program can 
effectively address many barriers cancer patients face when trying to engage in 

ACTIVATE Trial | Avani Rao 
24 
PROTOCOL VERSION DATE:  05/12/2025 
regular physical activity. These barriers often include limited access to exercise 
facilities, lack of time, and the need for programs tailored to individual health 
conditions and preferences. For instance, a study on the remote inclusion of 
vulnerable users in mHealth intervention design found that web-based health 
programs effectively reduce barriers to participation, offering flexibility and 
accessibility that facilitate user engagement, even in populations with limited 
resources and mobility (47). Similarly, a study demonstrates that personalized web-
based health interventions, such as weight loss coaching, can effectively reduce 
barriers to participation by offering flexibility and accessibility, which are crucial 
for engaging users with diverse needs and limitations (7). The integration of 
personalized coaching elements, such as tailored exercise plans and regular 
feedback, further enhances the effectiveness of these programs by ensuring that the 
exercise regimens are specifically designed to meet each patient's unique needs and 
capabilities. 
 
1.5 
Compliance Statement 
This study will be conducted in full accordance with all applicable Inova Health 
System’s Federalwide Assurance (FWA), Research Policies and Procedures, and all 
applicable Federal and State laws. These regulations include, but are not limited to, 
45 CFR 46 and Good Clinical Practice (GCP). 
The investigators will perform the study in accordance with this protocol, will 
obtain consent using the IRB-approved informed consent form (Appendix 1), and 
will report unanticipated problems involving risk to participants or others and 
potential serious or continuing non-compliance in accordance with the Inova 
Health System’s Office of Research Policies and Procedures and all federal 
requirements. Data collection, recording, and reporting will be accurate and ensure 
the privacy, health, and welfare of research participants during and after the study. 
 OBJECTIVES 
 
Primary Objective 
• The primary objective of this study is to evaluate the feasibility of conducting a 
randomized trial of an exercise coaching program to encourage physical activity 
for women treated with adjuvant pelvic intensity-modulated radiation therapy 
treatment for endometrial cancer. 
2.1 
Secondary Objective 
• To collect initial efficacy evaluation of the exercise coaching program on 
patient-reported fatigue, bowel/urinary toxicity, QoL, cognitive function, sexual 
function and satisfaction, and self-efficacy, as well as distance walked during 
6MWT between the immediate and delayed-start group from baseline to pre-
specified time points (end of RT, 5-7 weeks post-RT, and 16-19 weeks post-
RT) to guide statistical planning for follow-up study. 
• To measure the prevalence of fatigue at baseline in the population of 

ACTIVATE Trial | Avani Rao 
25 
PROTOCOL VERSION DATE:  05/12/2025 
endometrial cancer patients who are recommended pelvic radiation therapy, 
using data collected in the screening process (Appendix 2). 
• To explore potential behavioral mechanisms (mediators) and variables that 
influence the strength of the intervention effect (moderators). 
 SETTINGS 
3.1 
Study Sites 
The following investigative sites will be conducting this study: 
Inova Alexandria Hospital 
4320 Seminary Rd. 
Alexandria, VA 22304 
Inova Fair Oaks Hospital 
3600 Joseph Siewick Dr. 
Fairfax, VA 22033 
Inova Loudoun Hospital 
44045 Riverside Pkwy. 
Leesburg, VA 20176 
Inova Center for Personalized Health 
8100 Innovation Park Dr. 
Fairfax, VA 22031 
3.2 
Community Involvement 
A patient advocate will be invited to partner with the research team to provide 
insights to ensure that the study remains focused on patient needs and perspectives 
throughout its implementation by (1) helping to identify potential issues related to 
patient safety, consent, or privacy, (2) suggesting adjustments to make the study 
more comfortable or less burdensome, (3) ensuring that communication with study 
participants is clear, respectful, and responsive, and (4) helping to plan and 
implement follow-up activities, such as communicating results and designing future 
research studies based on current learnings.  
3.3 
Outside of Organization 
Not applicable. 
 RESOURCES AVAILABLE 
4.1 
Conducting Research 
The Inova Schar Cancer Institute is uniquely suited to be successful at an 
integrative exercise oncology and radiation therapy study. We anticipate needing 
up to 12 months to recruit 16 patients for the study. At the Inova Schar Cancer 
Institute Fairfax location, approximately 24 patients will undergo a course of pelvic 
radiation per year. 
Additionally, approximately 24 patients will undergo a course of pelvic radiation 
per year across Inova Loudoun, Inova Alexandria, and Inova Fair Oaks Hospitals. 
With the goal of the study to evaluate adherence to and the acceptability and 
feasibility of the intervention as part of a pilot study, the sample size was 
determined with the goal of completing accrual of the study within one year, 

ACTIVATE Trial | Avani Rao 
26 
PROTOCOL VERSION DATE:  05/12/2025 
accruing across all four sites. 
One dedicated day each week will be devoted to identifying possible patients who 
are eligible and monitoring upcoming survey time points each week by the study PI 
and team. The research team will be assigned to survey gathering at specified time 
points. 
4.2 
Medical Resources 
The physicians from the clinics are the medical resources for the subjects. 
 INVESTIGATIONAL PLAN 
5.1 
General Schema of Study Design 
This is a pilot feasibility study using a randomization of immediate versus delayed 
intervention. 
See Table 1: Schedule of Study Procedures. 
5.1.1 Hypothesis: This is a pilot study, so there is no hypothesis. However, we 
have set a priori criteria for evaluating the primary outcomes of the study. 
This study will explore the feasibility of conducting a randomized trial of 
an exercise coaching program to encourage physical activity for women 
undergoing adjuvant pelvic intensity- modulated radiation therapy 
treatment for endometrial cancer to guide the design of future studies to 
investigate the effect of exercise to treat or mitigate fatigue, to identify 
successful strategies for improving adherence to exercise, and to 
understand which population of patients may benefit most from a targeted 
program to increase motivation and overcome barriers to exercise. 
 
5.1.2 Study Design: A total of 16 women treated with radical or modified 
radical hysterectomy for Stage I-IVA endometrial cancer who are planned 
to complete pelvic external beam radiation therapy as part of their 
adjuvant treatment will be included. Patients will be randomized to either 
an immediate- or delayed-start of their exercise coaching program. 
Women randomized to the immediate-start group will start the 
intervention during the first week of radiation therapy and continue 
through and post-completion of radiation. Women randomized to the 
delayed-start group will start the intervention at 6-8 weeks post-radiation, 
a more typical period in survivorship where exercise counseling may 
begin. Participants will be asked to wear an activity monitor to track steps 
and moderate activity minutes and to complete assessments of patient-
reported cancer-related fatigue, bowel/urinary toxicity, sexual health, and 
quality of life and participate in a six-minute walk test (6MWT) at 
predefined time points throughout the study. 
 

ACTIVATE Trial | Avani Rao 
27 
PROTOCOL VERSION DATE:  05/12/2025 
5.1.3 Study Treatment 
The intervention is an exercise coaching program which will consist of 
weekly check-ins for 10 weeks with a certified exercise coach with 
expertise in caring for oncology patients. The purpose of each check-in is 
to address readiness for exercise, identify barriers, and develop an 
individualized plan for exercise for the week with a goal of increasing 
activity to 150 minutes of moderate activity per week using any form of 
activity that is enjoyable and accessible to the patient. This will be 
accomplished by shaping behavior through personalized 
recommendations. The coach will review Fitbit data, reinforce motivation 
and adherence, provide tailored suggestions to increase activity, and 
address barriers to achieving 150 minutes per week of moderate activity. 
The coach may use MedBridge to create and customize a home exercise 
program using a vast library of exercise videos and instructions. These can 
be personalized to meet each patient’s specific needs and can be easily 
shared through the MedBridge platform. MedBridge is HIPAA compliant 
ensuring patient information is protected and secure. If a participant 
misses their coaching session, the exercise coach will work with the 
participant to reschedule within the week and document in EMR. If the 
coach is unable to reach the participant by phone, a follow up email will 
also be sent and documented in EMR. 
5.2 
Product(s) / Agent(s) 
Not applicable. 
5.3 
Allocation to Treatment Groups and Blinding/Randomization 
Included subjects were randomly assigned in a 1:1 manner, stratified by baseline 
fatigue level, using computer-generated numbers. The PI and treating MD will be 
blinded to the randomization scheme; however, the ultimate allocation to the 
intervention will not be blinded.  
 STUDY TIMELINE 
6.1 
Individual Participation 
The study duration per participant will be up to six months. Patients will be 
requested to wear their Fitbit from the start of enrollment to the 16-19 weeks post 
RT visit, participating in standard-of-care weekly visits during RT at 5-7 weeks 
post RT, and again 16-19 weeks post RT. The ten consecutive weekly exercise 
coaching check-in sessions will start for the early intervention during the first week 
of RT and the delayed intervention at 6-8 weeks post RT. 
6.2 
Study Timeline 
6.2.1 Treatment intervention 
The exercise coaching program will consist of weekly check-ins for ten 
weeks with a certified exercise coach with expertise in caring for oncology 
patients with the goal of increasing activity to 150 minutes of moderate 

ACTIVATE Trial | Avani Rao 
28 
PROTOCOL VERSION DATE:  05/12/2025 
activity per week by shaping behavior through personalized 
recommendations.  
6.2.2 Follow-up 
Follow-up will continue for up to 19 weeks after completion of pelvic RT. 
 PARTICIPANT SELECTION 
7.1 
Eligibility Criteria 
Inclusion Criteria: 
• At least 18 years of age 
• Pathologic diagnosis of endometrial cancer (any histology, Stage I-IVA) 
• Has undergone modified radical or radical hysterectomy 
• Plan to receive adjuvant treatment with pelvic external beam radiation therapy at 
ISCI 
• ECOG performance status of 0-1 
• Patient has a computer, smart phone, or tablet for virtual access to the web-based 
platform and email 
• Able to read, understand and provide written informed consent 
• Deemed appropriate for unmonitored exercise by treating physician based on the 
following evidence-based criteria (1) 
o Walk without any assistance or assistance device 
o Absence of significant cognitive impairment 
o Absence of high risk for falls 
• Participant does not need to refrain from any activity 
 
Exclusion Criteria: 
• Unable to schedule and attend coaching visits 
• Participation in a regular exercise program of ≥150 minutes of moderate intensity 
exercise a week at baseline 
• Unable to perform the five-times stand test 
• Medical comorbidities including: 
o Unstable angina 
o Uncontrolled dysrhythmias 
o Acute pulmonary embolus 
o Active pulmonary infection 
 RECRUITMENT METHODS 
8.1 
Methods 
8.1.1 Recruitment 
Eligible patients will be pre-screened by PI on a weekly basis, who will 
then email the primary radiation oncologist. The primary radiation 
oncologist will determine if the intervention is acceptable to offer to the 

ACTIVATE Trial | Avani Rao 
29 
PROTOCOL VERSION DATE:  05/12/2025 
potential patient at the time of consultation, and this will inform the 
provider acceptability ratio, one of the primary outcomes of the study. The 
primary radiation oncologist will discuss the study with the patient at the 
time of consultation and, if the patient is interested, will notify the 
research team to facilitate consent for enrollment. 
8.1.2 Screening 
Participants will be screened to review inclusion and exclusion criteria 
(see Appendix 2). 
8.1.2.1 Screen Failures 
Screen failures are defined as participants who consent to 
participate in the study but are not subsequently entered into the 
study. Individuals who do not meet the criteria for participation 
in this trial (screen failure) cannot be rescreened due to the 
timeline of intervention with respect to the radiation therapy. 
8.1.3 Projected Participants 
Recruitment will stop when 16 participants have completed the study. 
8.2 
Materials 
8.2.1 Flyer 
During clinic visits, the provider or research staff can introduce the study 
to participants and hand them a flyer (Appendix 3). Flyers may also be 
placed within the clinic, such as waiting rooms, reception desks, bulletin 
boards, and examination rooms. The flyer will include a brief description 
of the study, eligibility criteria, what participation involves, potential 
benefits, and risk, as well as contact details for more information.  
8.2.2 Social Media 
Not applicable. 
 STUDY PROCEDURES 
9.1 
Screening Visit 
9.1.1 Informed Consent/Assent/HIPAA Authorization (Appendix 4) 
The Informed Consent Process will take place at screening. 
9.1.2 Review of Inclusion/Exclusion Criteria, Demographics and Medical 
History 
9.1.3 Fatigue 0-10 Numeric Rating Scale 
9.2 
Participant Survey of Patient-Reported Outcomes and Information 
All patient-reported outcomes and information (Appendix 5) will be collected using 
the web-based survey platform REDCap unless the participant prefers paper 
surveys, in which case paper surveys will be provided. Alternatively, a clinical 

ACTIVATE Trial | Avani Rao 
30 
PROTOCOL VERSION DATE:  05/12/2025 
research coordinator may conduct the survey by interview either by phone or in 
person, based on participant preference. Web-based surveys can be completed on a 
tablet in the clinic or at home, with automatic email reminders sent through 
REDCap or by the research coordinator (see Appendices 5 and 6). Reminders will 
be sent 1 and 2 days after the initial survey invitation and 1 day before the survey 
window closes. The research coordinator may also reach out to participants by 
phone to remind them to complete the survey and provide verbal assistance as 
needed.  
9.3 
Study Intervention Visits 
9.3.1 Enrollment 
Enrollment would occur any time within 7 days (before or after) 
simulation, prior to the start of radiation. Items to be completed at 
enrollment: 
- 
Randomization 
9.3.1.1 Height and weight 
9.3.1.2 Patient-reported demographics/medical history (comorbidities) 
- 
Stages of change metric 
- 
All patients will be provided with a Fitbit device and provided detailed 
instructions on its use (Appendix 7). Data monitoring will start with 
the time that the Fitbit is provided to the patient after consents are 
signed and will continue to the end of study enrollment.  
- 
The following baseline assessments are collected: 
o FACIT-F 
o EPIC Bowel and Urinary short form assessments 
o PROMIS-29 QoL Metric 
o PROMIS Cognitive Function 
o PROMIS Self-Efficacy for Chronic Conditions 
o 6MWT 
9.3.2 RT Simulation 
Items to be completed at RT Simulation: 
- 
Fitbit data will be collected on all patients.  
9.3.3 Week 1-4 of pelvic RT (Fraction 1-20) 
Items to be completed at weeks 1-4 of RT: 
- 
Fitbit data will be collected on all patients.  
9.3.4 Week 5 of pelvic RT (Fraction 21-25) 
Items to be completed at week 5 of RT: 
- 
Fitbit data will be collected on all patients.  
- 
The following assessments are collected: 

ACTIVATE Trial | Avani Rao 
31 
PROTOCOL VERSION DATE:  05/12/2025 
o FACIT-F 
o EPIC Bowel and Urinary short form assessments 
o PROMIS-29 QoL metric 
o PROMIS Cognitive Function 
o PROMIS Self-Efficacy for Chronic Conditions 
o 6MWT 
9.3.5 Week 5-7 Post-pelvic RT 
Items to be completed at week 5-7 post RT: 
- 
Fitbit data will be collected on all patients.  
- 
The following assessments are collected: 
o FACIT-F 
o EPIC Bowel and Urinary short form assessments 
o PROMIS-29 QoL metric 
o PROMIS Cognitive Function 
o PROMIS Self-Efficacy for Chronic Conditions 
o 6MWT 
o PROMIS Brief Profile Sexual Function and Satisfaction 
(Female) 
9.3.6 Week 16-19 Post-pelvic RT 
Items to be completed at week 16-19 post-pelvic RT: 
- 
Fitbit data will be collected on all patients.  
- 
The following assessments are collected: 
o FACIT-F 
o EPIC Bowel and Urinary short form assessments 
o PROMIS-29 QoL metric 
o PROMIS Cognitive Function 
o PROMIS Self-Efficacy for Chronic Conditions 
o 6MWT 
o PROMIS Brief Profile Sexual Function and Satisfaction 
(Female) 
- 
Satisfaction survey 
- 
Recorded semi-structured exit interview with research PI (Appendix 
8) 
9.3.7 Weekly Exercise coach check-ins x 10 weeks 
- 
Early intervention cohort: Check-in #1 (60 minutes) to occur during 
the first week of RT (Fx 1-5). Check-in #2-10 (30 minutes) will 
continue weekly starting Fx 6-10, and continue through the 
completion of RT and post-RT for a total of 10 sessions. 
- 
Delayed intervention cohort: Check-in #1 (60 minutes) to occur after 
the 5-7 week follow-up starting 6-8 weeks after pelvic-RT. Check-in 
#2-10 (30 minutes) will continue weekly a total of 10 sessions. 

ACTIVATE Trial | Avani Rao 
32 
PROTOCOL VERSION DATE:  05/12/2025 
9.3.8 Bi-weekly active attention control check-ins x 10 weeks 
- 
Early intervention cohort: Check-ins, once every 2 weeks, with an 
approximately 5-minute telephone call by a research coordinator to 
start the week following completion of their exercise intervention 
(approximately 5 weeks after pelvic RT) for a total of 5 calls. 
- 
Delayed intervention cohort: Check-ins, once every 2 weeks, with an 
approximately 5-minute telephone call by a research coordinator 
starting during the first week of RT (Fx 1-5) and continue for 10 
weeks for a total of 5 calls. 
- 
The research coordinator will inquire about their use of the Fitbit 
device, such as if they are wearing it regularly, any technical issues, 
and if they are syncing their data without discussing physical activity. 
 
9.4 
Unscheduled Visits 
We do not expect any unscheduled visits, but if the physician of record needs 
additional assessments, then these would be unrelated to the study intervention 
unless there is an indication that they would no longer be fit for participation in the 
research study due to an unanticipated change in status or patient circumstances. 
9.5 
Non-compliance and Lost to Follow-Up 
The following actions must be taken if a participant fails to return to the clinic for a 
required study visit: 
9.5.1 The adherence to the Fitbit will be routinely monitored during exercise 
check-ins or during the active-monitoring check-ins and data will be 
recorded for analysis using the PittBit dashboard. Email reminders may be 
sent to participants who are found not to be wearing their Fitbit as 
instructed (see Appendix 6). 
9.5.2 For missed visits, the site will attempt to contact the participant and 
reschedule the missed visit and discuss with the participant the importance 
of maintaining the assigned visit schedule and ascertain if the participant 
wishes to and/or should continue in the study. 
9.5.3 Before a participant is deemed lost to follow-up, the investigator or 
designee will make every effort to regain contact with the participant 
(where possible, 3 telephone calls and, if necessary, a certified letter to the 
participant’s last known mailing address or local equivalent methods). 
These contact attempts should be documented in the participant’s medical 
record or study file. 
9.5.4 Should the participant continue to be unreachable, he/she/they will be 
considered to have withdrawn from the study with a primary reason of lost 
to follow-up. 
9.5.5 Definition of Non-compliance: A patient will be considered non-compliant 
to the exercise coaching intervention arm if they fail to engage in 70% of 
the weekly check-ins. A patient will be considered non-compliant to the 

ACTIVATE Trial | Avani Rao 
33 
PROTOCOL VERSION DATE:  05/12/2025 
physical activity monitor if they do not wear the Fitbit activity tracker for 
at least 8 hours a day for 70% of the days in the study. As this is a pilot 
study, patients will not be removed from study due to non-compliance, as 
the primary outcome is to evaluate adherence. 
 STUDY ADMINISTRATION 
10.1 Study Intervention(s) Administration 
10.1.1 Study Intervention Description 
The intervention is an exercise coaching program which will consist of 
weekly check-ins for 10 weeks with a certified exercise coach with 
expertise in caring for oncology patients. The purpose of each check-in is 
to address readiness for exercise, identify barriers, and develop an 
individualized plan for exercise for the week with a goal of increasing 
activity to 150 minutes of moderate activity per week using any form of 
activity that is enjoyable and accessible to the patient. This will be 
accomplished by shaping behavior through personalized 
recommendations. Patients will be randomized to either an immediate- or 
delayed-start of their exercise coaching program. Women randomized to 
the immediate-start group will start the intervention during the first week 
of radiation therapy and continue through and post-completion of 
radiation. Women randomized to the delayed-start group will start the 
intervention at 6-8 weeks post-radiation, a more typical period in 
survivorship where exercise counseling may begin. Participants will be 
asked to wear an activity monitor to track steps and moderate activity 
minutes and to complete assessments of patient-reported cancer-related 
fatigue, bowel/urinary toxicity, sexual health, and quality of life and 
participate in a six-minute walk test (6MWT) at predefined time points 
throughout the study. 
Once a participant consents to the research study, they will be scheduled 
with the exercise coach based on their treatment group assignment 
(immediate or delayed start). The exercise coach will record the 
participation in the Epic chart, which will automatically send a message 
via Epic (MyChart) to the participant with instructions for their first 
session (Appendix 9). The participant will be asked to complete an intake 
form to provide the exercise coach with necessary information for their 
first meeting (Appendix 10). After each of the 10 coaching sessions, the 
exercise coach will document the encounter in Epic using the Subjective, 
Objective, Assessment, Postural Assessment and Observations template 
(SOAP; Appendix 11). 
10.1.2 Study Intervention Materials 
All enrolled patients will be provided with resistance bands that can be 
utilized for a number of exercise classes that they might be referred to by 
their exercise coach. All participants will receive a de-identified Fitbit 
device for active minute tracking. Patients will be able to keep their 

ACTIVATE Trial | Avani Rao 
34 
PROTOCOL VERSION DATE:  05/12/2025 
resistance bands and Fitbit device after completion of the study. The 
device will be unregistered from the de-identified account used for study 
participation, and patients will be able to create their own accounts to 
continue to use their devices at their discretion. 
10.1.3 Dosing and Administration 
Not applicable. 
10.2 Measures to Minimize Bias: Randomization / Blinding 
Randomization will be utilized to allocate patients between early and delayed 
intervention arms. This study will be nonblinded to the patient given the nature of 
the intervention and nonblinded to the physician due to the nature of the clinical 
relationship, likely leading to a high chance of patient divulging of the participation 
in the intervention arm if they are randomized to the exercise coaching 
intervention. Bias with regard to patient factors will be minimized due to the use of 
randomization. Bias regarding the rate of activity due to Fitbit monitoring will be 
present in this study but assumed to be equal between the two groups as both usual 
care and the intervention groups will be given a Fitbit for monitoring and the use of 
an attention control check-ins in both intervention groups. 
 DATA COLLECTION AND MANAGEMENT 
11.1 Data Collection and Management 
11.1.1 Fitbit Data Collection 
Each participant will be given a Fitbit device at the time of study 
enrollment. A de-identified Fitbit account will be created for all users, 
which will then be the account from which the data will be retrieved, 
maintaining individual patient privacy without PHI. The account username 
and passwords associated with their device will be de-identified. A log of 
the de-identified account usernames with the participant ID number will 
be kept in a password-protected file and stored on the research hard drive. 
With appropriate consent in place, the research-allocated Fitbit device will 
be registered on the Fitbit Application Programming Interface (API) on 
the Fitbit developer site to enable scripted, automated data collection of 
pre-defined data elements to be collected on the study. The de-identified 
data of all patients will be stored and evaluated in real-time by the 
research team using a platform called PittBit. PittBit is a web-based 
application that creates a dashboard of the synched Fitbit data from 
participants, including active minutes, steps, and heart rate data. Each 
Fitbit de-identified account will be canceled and, therefore, unregistered 
from the API at the end of an individual participant’s follow-up period so 
that no additional data from the Fitbit can be accessed after the study 
window. The participant will be able to keep their Fitbit after completing 
the study. 

ACTIVATE Trial | Avani Rao 
35 
PROTOCOL VERSION DATE:  05/12/2025 
11.1.2 Storage and Future Use 
Fitbit data collected on the PittBit application are de-identified. They will 
be limited to patient active minutes, steps, and heart rate from enrollment 
to the end of the follow-up time period, after which the Fitbit account 
created for study purposes will be canceled and unenrolled from the API. 
Hence, no further data collection is possible. Clinical data will be recorded 
in a limited dataset that will be maintained for the life of the study. The 
patient name will be omitted, but MRN will be retained until the dataset is 
completed and removed from the final dataset. Data will be maintained in 
a password-protected spreadsheet on the research drive, with only study 
team members granted access. 
11.1.3 Retention/Access 
Only designated research team members and the Principal Investigator 
will have access to PitBitt, the dataset, and the password. The data on 
PittBit is fully de-identified, and the study dataset will not be transferred 
or shared with any external institutions without amendment to this 
protocol and required approvals (institutional and by law). The quality 
management Program within the ISCI will maintain oversite of this study. 
The data fields retained will be listed in 11.1.4. 
11.1.4 Data Fields 
Data will be retrieved from: 
- 
Fitbit Device 
- 
EPIC 
- 
Aria 
- 
Raystation 
- 
Patient web-based surveys using REDCap (or paper surveys or 
interview if patient preference) 
 
Data to be collected include: 
- 
From medical chart:  
o Variables in data tracker sheet (Appendix 12) 
- 
FitBit Active minutes, steps, heart rate and last sync, using PittBit data 
platform  
- 
Patient self-report: REDCap web-based surveys  (or paper surveys or 
interview if patient preference) per protocol 
- 
Subjective notes from exit interview 
11.2 Security 
The study is registered and approved by the Fitbit company and will be performed 
in compliance with both Fitbit regulations and the Inova IRB. 
All personnel involved with this project are trained on the use and protection of 
patient information as required by Inova. 

ACTIVATE Trial | Avani Rao 
36 
PROTOCOL VERSION DATE:  05/12/2025 
All personnel involved with study activities and/or data will have completed 
appropriate training in patient privacy and human subjects regulations. 
A backup of the dataset will be stored as a password-protected file on Dr. Avani 
Rao’s office computer, which remains locked when she is not directly accessing it. 
A backup will be retained every three months. 
11.2.1 Anonymization, De-Identification and/or Destruction 
Fitbit logins and passwords will be anonymous for each participant. A 
code will be generated for all data collected once the dataset has been 
validated to replace participant identifiers and maintained only by the PI 
and delegated research team. Fitbit data collected on the PittBit 
application are de-identified and will be limited to patient active minutes, 
steps, and heart rate from enrollment to the end of follow-up time period. 
Each individual Fitbit de-identified account will be cancelled and 
therefore unregistered from the API at the end of an individual 
participant’s follow-up period so that no additional data from the Fitbit 
can be accessed after the study window. The participant will be able to 
keep their Fitbit after completing the study. 
All data will be saved under password protection with password access 
granted only to the PI and critical research team members.  
11.3 Release of Locally Banked Data 
Not applicable. 
11.4 Confidentiality 
All data and records generated during this study will be kept confidential in 
accordance with Inova Health System institutional policies and HIPAA on 
participant privacy. The Investigator and other site personnel will not use such data 
and records for any purpose other than conducting the study. 
No identifiable data will be used for future use without first obtaining IRB approval 
or determination of exemption. The investigator will obtain a data use agreement 
between the provider of the data and any recipient researchers through the Office of 
Research, Business Office, before sharing a limited dataset. 
All data will be kept confidential. Fitbit data collected on the PittBit application are 
de-identified and will be limited to patient active minutes, steps, and heart rate from 
enrollment to the end of follow-up time period. The study data will be stored on the 
research drive using password protection, which will only be accessed by the 
research team. When dataset is verified, the PHI will be removed and replaced with 
a code/participant ID that will remain in a separate password protected file.  
11.4.1 Certificate of Confidentiality 
Not applicable. 

ACTIVATE Trial | Avani Rao 
37 
PROTOCOL VERSION DATE:  05/12/2025 
 DATA ANALYTICS 
12.1 Study Objectives 
Primary: 
The primary objective of this study is to evaluate the feasibility of conducting a 
randomized trial of an exercise coaching program to encourage physical activity for 
women treated with adjuvant pelvic intensity-modulated radiation therapy 
treatment for endometrial cancer. 
Secondary: 
1)  To collect initial efficacy evaluation of the exercise coaching program on patient-
reported fatigue, bowel/urinary toxicity, QoL, cognitive function, sexual function 
and satisfaction, and self-efficacy, as well as distance walked during 6MWT 
between the immediate and delayed-start group from baseline to pre-specified 
time points (end of RT, 5-7 weeks post RT, and 16-19 weeks post RT) to guide 
statistical planning for follow-up study. 
2) To measure the prevalence of fatigue at baseline in the population of endometrial 
cancer patients recommended pelvic radiation therapy using data collected in the 
screening process. 
3) To explore potential behavioral mechanisms (mediators) and variables that 
influence the strength of the intervention effect (moderators). 
 
 
12.2 Analytics 
This study will enroll 16 patients. At the Inova Schar Cancer Institute Fairfax 
location, approximately 24 patients will undergo a course of pelvic radiation per 
year. Additionally, approximately 24 patients will undergo a course of pelvic 
radiation per year across Inova Loudoun, Inova Alexandria, and Inova Fair Oaks 
Hospitals. With the goal of the study to evaluate adherence to and the acceptability 
and feasibility of the intervention as part of a pilot study, the sample size was 
determined with the goal of completing accrual of the study within one year, 
accruing across all four sites. 
Primary Objective Analytical Plan 
Feasibility of conducting a randomized trial of this nature will be evaluated on the basis 
of process feasibility and resources and data-management feasibility. 
The process feasibility will be evaluated on: 
1) Recruitment acceptability from the provider and patient perspective: 
a. Provider acceptability of the intervention will be defined as the proportion 
of patients identified on pre-screening by the PI that the primary clinician 
agrees of patient suitability for offering enrollment on the trial and 
proceeding to completion of screening steps if patient is interested in the 
study. We set an a priori goal of 50% provider acceptability. 
b. Patient acceptability of the intervention will be defined as the proportion 

ACTIVATE Trial | Avani Rao 
38 
PROTOCOL VERSION DATE:  05/12/2025 
of patients who agreed to consent and then proceed to completion of 
screening steps. We set an a priori goal of 50% patient acceptability. 
2) Appropriateness of the screening criteria: 
a. Screening criteria appropriateness will be defined as the proportion of 
patients who are screened who proceeded to allocation of intervention 
groups. We set an a priori goal of 50% of appropriateness of the screening 
criteria. 
3) Adherence to the exercise coaching session intervention: 
a. Individual adherence to coaching sessions will be defined as complete 
adherence when engaging in 10 of the 10 planned exercise coaching 
sessions and high adherence as engaging in at least 7 of the planned 10 
exercise coach check-ins. We set an a priori goal of overall 70% 
participant adherence to the coaching sessions, to be analyzed per cohort 
(6 of 8 participants in each arm demonstrating high adherence as defined 
above). 
4) Adherence to the physical activity monitor usage to track steps and active 
minutes: 
a. Individual adherence to the physical activity monitor will be defined as 
wearing the activity tracker for at least 8 hours a day for 70% of the days 
in the study. Heart rate will be used to determine wear-time. We set an a 
priori goal of overall 70% participant adherence to the physical activity 
monitor, to be analyzed per cohort (6 of 8 participants in each arm 
demonstrating adherence as defined above). 
5) Adherence to recommendation of 150 minutes per week of moderate physical 
activity:   
a. Individual adherence to regular physical activity will be defined as 
meeting the recommendation of 150 minutes of moderate physical activity 
per week, based on the Physical Activity Guidelines for Americans 
developed by the U.S. Department of Health and Human Services (HHS). 
The target for participant adherence is set at an a priori goal of 70%.  
 
 
 
The resource and management feasibility will be assessed based on the capacity of the 
exercise coach and research team to perform the required tasks of the protocol: 
1) Adherence to the timeline of study procedures and human and data management 
issues that could potentially arise during a full‐scale RCT will be tracked. 
Adherence to the study timeline for completion of required patient surveys and 
6MWT as well as appropriate scheduling (patient attendance not required) of the 
exercise coaching sessions and follow-ups will be a proxy measurement of 
research resource and human data management acceptability. We set an a priori 
goal of 80% adherence.  
 
Secondary Objective Analytical Plan 

ACTIVATE Trial | Avani Rao 
39 
PROTOCOL VERSION DATE:  05/12/2025 
1) Changes in patient-reported fatigue, bowel/urinary toxicity, QoL, cognitive 
function, sexual function and satisfaction, and self-efficacy, as well as distance 
walked during 6MWT from baseline to pre-specified time points (end of RT, 5-7 
weeks post RT, and 16-19 weeks post RT) within and between each group will be 
compared using two-sample t-test or Wilcoxon Rank Sum test when appropriate. 
Repeated measure models/linear mixed effect models may also be used to explore 
the changes in self-reported questionnaires over time among different treatment 
groups. Data will be analyzed based on the intention-to-treat principle and used to 
estimate treatment effect size for future trial design. 
 
2) Prevalence of fatigue at baseline in the population of endometrial cancer patients 
receiving pelvic radiation therapy will be reported using data collected in the 
screening process.  
 
3) Exploratory analysis of potential behavioral mechanisms (mediators) and 
variables that influence the strength of the intervention effect (moderators) will be 
performed. 
 
 SAFETY MANAGEMENT 
13.1 Regulatory and Ethical Considerations 
13.1.1 Data and Safety Monitoring Plan 
The Inova PI will monitor and review the study progress, participant 
safety, and the accuracy and security of the data. 
13.1.1.1 Communication Plan 
The DSM plan is adequate as the study will be limited to only 
Inova sites. 
13.1.2  Risk Assessment 
There is very low risk to this research intervention. The integration of 
exercise therapy is recommended by NCCN and ASCO for cancer patients 
and survivors to reduce the relapse risk and mitigate the side effects of 
therapy, including fatigue (2, 13). It is possible that exercise could worsen 
fatigue or side effects of treatment, although this likelihood is felt to be 
low. Patients may feel sore from activity if they were not previously 
active, but this would be temporary and not cause a risk of harm to the 
patient. As such, this study would not be greater than minimal risk of 
harm. 
13.1.3 Potential Benefits of Trial Participation 
The integrated check-ins for each arm of the trial exercise program may 
provide benefit in improving patient-reported outcomes and support 
cancer patients in a structured format. The indirect benefits of this study 
may be that it sets up our group to continue an exercise oncology research 

ACTIVATE Trial | Avani Rao 
40 
PROTOCOL VERSION DATE:  05/12/2025 
program that can provide additional literature to healthcare payors for the 
reimbursement of exercise therapy programs for patients undergoing 
radiation treatments. 
13.1.4 Risk-Benefit Assessment 
Given that this study would be not greater than minimal risk of harm and 
the possibility of benefit to the patient herself and future women 
undergoing pelvic radiation, it is appropriate to proceed with this study. 
13.2 Clinical Adverse Events 
Clinical adverse events (AEs) will be monitored throughout the study. 
13.2.1 Adverse Events Reporting 
AEs (including serious AEs) that are felt to be study-related or possibly 
study-related will be noted in the study records and on the case report 
form with a full description including the nature, date, and time of onset, 
determination of non-serious versus serious, intensity, (mild, moderate, 
severe), duration, causality, and outcome of the event. 
SAEs are not expected because the study procedures are not greater than 
minimal risk. If any unanticipated problems related to the research 
involving risks to participants or others happen during this study 
(including SAEs), they will be reported to the IRB in accordance with 
Policy – Reporting of Adverse Events, Unanticipated Problems and Protocol 
Violations, ORI 11.16. AEs that do not meet prompt reporting requirements 
will be summarized in the narrative or other format and tracked and 
documented internally by the study team but not submitted to the IRB. 
 PARTICIPANT COMPENSATION AND REPORTS 
14.1 Participant Compensation 
Patients will be awarded reloadable gift cards at enrollment and $25.00 at each 
follow-up time point when assessments are collected and upon completion of exit 
interview. 
14.2 Reporting Events to Participants 
14.2.1 Adverse Events 
If an SAE related to the study occurs, then participating patients will be 
notified, and the consent form will be updated. 
14.3 Study Results and Incidental Findings 
It is anticipated that the results of this study will first be reported in abstract form, 
followed by presentation in a peer-reviewed manuscript. 

ACTIVATE Trial | Avani Rao 
41 
PROTOCOL VERSION DATE:  05/12/2025 
 ECONOMIC BURDENS AND COMPENSATION / INCENTIVE 
15.1 Foreseeable Costs 
15.1.1 Economic Burden to Participants: We do not anticipate that the study 
would have any costs to the participant that are required by the study.  
15.2 Payments / Reimbursements 
15.2.1 Reimbursement for Travel, Parking and Meals 
Not applicable. 
15.2.2 Payments to Participants for Time, Effort, and Inconvenience (i.e., 
compensation 
All participants will receive a $25 gift card per survey time point and upon 
completion of exit interview. 
15.2.3 Gifts 
Fitbit devices and resistance bands will be provided to all participants free 
of charge, and they will be able to keep each item after completion of the 
study. 
 CONSENT PROCESS 
16.1 Informed Consent 
The consent process will occur during screening. In-person or telephone consent 
may be used in this study and will follow the applicable regulations. Inova’s 
electronic consenting process is still under development at the time of this protocol 
development. If electronic consenting becomes an option during the time period of 
this study, then an amendment may be requested. 
16.1.1 Waiver of Consent 
Not applicable. 
16.2 HIPAA Research Authorization(s) 
The Inova Health System uses a stand-alone HIPAA Research Authorization 
compliant with federal, state, and institutional Privacy rules and regulations. 
16.2.1 Waiver of HIPAA Authorization 
Given the need for the PI to prescreen patients coming into the department 
for consultation, a partial waiver of HIPPA is requested for screening 
purposes (see Appendix 4). 

ACTIVATE Trial | Avani Rao 
42 
PROTOCOL VERSION DATE:  05/12/2025 
16.3 Safeguards for Vulnerable Populations 
16.3.1 Cognitively Impaired Individuals 
16.3.2 Pediatric Participants 
16.3.2.1 Assent 
Not applicable. 
16.3.2.2 Waiver of Assent 
Not applicable. 
16.3.2.3 Reaching Age of Majority 
Not applicable. 
16.3.3 Adults Unable to Consent 
Given the nature of this study, adults who are unable to provide consent 
will not be eligible for this study as they would be at risk of being unable 
to participate in the intervention arm as well. 
16.4 Documentation of Consent 
The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained. The authorized person obtaining the informed consent must 
also sign the ICF. A copy of the signed ICF must be available in the medical 
record.  
 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION / WITHDRAWAL  
Participants may withdraw from the study at any time without prejudice to their care. 
They may also be discontinued from the study at the discretion of the Investigator if 
there are any concerns for safety reasons related to the ability to participate in the 
study or follow-up. It will be documented whether each participant completes the 
study. If the Investigator becomes aware of any serious, related adverse events after 
the participant completes or withdraws from the study, the participants will be 
communicated based on the IRB’s directions. 
17.1 Discontinuation of Study Intervention 
Discontinuation from study intervention does not mean discontinuation from the 
study, and the remaining study procedures should be completed as indicated by the 
study protocol. If a clinically significant finding is identified (including, but not 
limited to, changes from baseline) after enrollment, the investigator or qualified 
designee will determine if any change in participant management is needed. Any 
new clinically relevant finding related to study participation will be reported as an 
adverse event (AE). 
17.2 Participant Discontinuation/Withdrawal from the Study 
Participants may voluntarily withdraw from the study or discontinue the study 

ACTIVATE Trial | Avani Rao 
43 
PROTOCOL VERSION DATE:  05/12/2025 
intervention at any time. 
17.3 Early Termination Study Visit 
When a participant is withdrawn prior to completing the study, the reason for 
withdrawal will be documented in a secure electronic database. 
 RECORDINGS 
Not applicable. 
 IRB REVIEW HISTORY 
Not applicable. 
 COORDINATING CENTER FOR MULTI-SITE STUDIES 
Not applicable. 
All patients will be under the care of the Inova Schar Cancer Institute, which 
includes campuses at Fairfax, Alexandria, Loudoun, and Fair Oaks. 
 REFERENCES / BIBLIOGRAPHY 
1. 
Integrating Physical Activity Into Cancer Care: An Evidence-Based Approach. 
Bernardo L, Becker B, editors: Oncology Nursing Society; 2017. 
2. 
Berger AM, Mooney K, Alvarez-Perez A, Breitbart WS, Carpenter KM, Cella D, 
et al. Cancer-Related Fatigue, Version 2.2015. J Natl Compr Canc Netw. 
2015;13(8):1012-39. 
3. 
Evans HEL, Galvão DA, Forbes CC, Girard D, Vandelanotte C, Newton RU, et 
al. Acceptability and Preliminary Efficacy of a Web- and Telephone-Based 
Personalised Exercise Intervention for Individuals with Metastatic Prostate 
Cancer: The ExerciseGuide Pilot Randomised Controlled Trial. Cancers (Basel). 
2021;13(23). 
4. 
Goldstein SP, Forman EM, Butryn ML, Herbert JD. Differential Programming 
Needs of College Students Preferring Web-Based Versus In-Person Physical 
Activity Programs. Health Commun. 2018;33(12):1509-15. 
5. 
Beleigoli A, Andrade AQ, Diniz MF, Ribeiro AL. Personalized Web-Based 
Weight Loss Behavior Change Program With and Without Dietitian Online 
Coaching for Adults With Overweight and Obesity: Randomized Controlled Trial. 
J Med Internet Res. 2020;22(11):e17494. 
6. 
Alley S, Jennings C, Plotnikoff RC, Vandelanotte C. My Activity Coach - using 
video-coaching to assist a web-based computer-tailored physical activity 
intervention: a randomised controlled trial protocol. BMC Public Health. 
2014;14:738. 

ACTIVATE Trial | Avani Rao 
44 
PROTOCOL VERSION DATE:  05/12/2025 
7. 
Fichtner UA, Armbruster C, Bischoff M, Maiwald P, Sehlbrede M, Tinsel I, et al. 
Evaluation of an Interactive Web-Based Health Program for Weight Loss-A 
Randomized Controlled Trial. Int J Environ Res Public Health. 2022;19(22). 
8. 
Héroux M, Watt M, McGuire KA, Berardi JM. A personalized, multi-platform 
nutrition, exercise, and lifestyle coaching program: A pilot in women. Internet 
Interv. 2017;7:16-22. 
9. 
Granet J, Peyrusqué E, Ruiz F, Buckinx F, Abdelkader LB, Dang-Vu TT, et al. 
Web-Based Physical Activity Interventions Are Feasible and Beneficial Solutions 
to Prevent Physical and Mental Health Declines in Community-Dwelling Older 
Adults During Isolation Periods. J Gerontol A Biol Sci Med Sci. 2023;78(3):535-
44. 
10. 
Ng AH, Ngo-Huang A, Vidal M, Reyes-Garcia A, Liu DD, Williams JL, et al. 
Exercise Barriers and Adherence to Recommendations in Patients With Cancer. 
JCO Oncol Pract. 2021;17(7):e972-e81. 
11. 
Schumacher O, Luo H, Taaffe DR, Galvão DA, Tang C, Chee R, et al. Effects of 
Exercise During Radiation Therapy on Physical Function and Treatment-Related 
Side Effects in Men With Prostate Cancer: A Systematic Review and Meta-
Analysis. Int J Radiat Oncol Biol Phys. 2021;111(3):716-31. 
12. 
Schumacher O, Galvao DA, Taaffe DR, Chee R, Spry N, Newton RU. Exercise 
modulation of tumour perfusion and hypoxia to improve radiotherapy response in 
prostate cancer. Prostate Cancer Prostatic Dis. 2021;24(1):1-14. 
13. 
Schumacher O, Galvao DA, Taaffe DR, Spry N, Joseph D, Tang C, et al. Effect of 
Exercise Adjunct to Radiation and Androgen Deprivation Therapy on Patient-
Reported Treatment Toxicity in Men With Prostate Cancer: A Secondary 
Analysis of 2 Randomized Controlled Trials. Pract Radiat Oncol. 2021;11(3):215-
25. 
14. 
Ashcraft KA, Warner AB, Jones LW, Dewhirst MW. Exercise as Adjunct 
Therapy in Cancer. Semin Radiat Oncol. 2019;29(1):16-24. 
15. 
Denlinger CS, Sanft T, Baker KS, Broderick G, Demark-Wahnefried W, 
Friedman DL, et al. Survivorship, Version 2.2018, NCCN Clinical Practice 
Guidelines in Oncology. J Natl Compr Canc Netw. 2018;16(10):1216-47. 
16. 
Post CCB, de Boer SM, Powell ME, Mileshkin L, Katsaros D, Bessette P, et al. 
Long-Term Toxicity and Health-Related Quality of Life After Adjuvant 
Chemoradiation Therapy or Radiation Therapy Alone for High-Risk Endometrial 
Cancer in the Randomized PORTEC-3 Trial. Int J Radiat Oncol Biol Phys. 
2021;109(4):975-86. 
17. 
Liberman D, Mehus B, Elliott SP. Urinary adverse effects of pelvic radiotherapy. 
Transl Androl Urol. 2014;3(2):186-95. 

ACTIVATE Trial | Avani Rao 
45 
PROTOCOL VERSION DATE:  05/12/2025 
18. 
Andreyev J. Gastrointestinal symptoms after pelvic radiotherapy: a new 
understanding to improve management of symptomatic patients. Lancet Oncol. 
2007;8(11):1007-17. 
19. 
Hilfiker R, Meichtry A, Eicher M, Nilsson Balfe L, Knols RH, Verra ML, 
Taeymans J. Exercise and other non-pharmaceutical interventions for cancer-
related fatigue in patients during or after cancer treatment: a systematic review 
incorporating an indirect-comparisons meta-analysis. Br J Sports Med. 
2018;52(10):651-8. 
20. 
Mustian KM, Alfano CM, Heckler C, Kleckner AS, Kleckner IR, Leach CR, et al. 
Comparison of Pharmaceutical, Psychological, and Exercise Treatments for 
Cancer-Related Fatigue: A Meta-analysis. JAMA Oncol. 2017;3(7):961-8. 
21. 
Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue 
in adults. Cochrane Database Syst Rev. 2012;11:CD006145. 
22. 
Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J 
Clin. 2022;72(1):7-33. 
23. 
Ledford LRC, Lockwood S. Scope and Epidemiology of Gynecologic Cancers: 
An Overview. Semin Oncol Nurs. 2019;35(2):147-50. 
24. 
Poort H, de Rooij BH, Uno H, Weng S, Ezendam NPM, van de Poll-Franse L, et 
al. Patterns and predictors of cancer-related fatigue in ovarian and endometrial 
cancers: 1-year longitudinal study. Cancer. 2020;126(15):3526-33. 
25. 
Kang YE, Yoon JH, Park NH, Ahn YC, Lee EJ, Son CG. Prevalence of cancer-
related fatigue based on severity: a systematic review and meta-analysis. Sci Rep. 
2023;13(1):12815. 
26. 
Bower JE, Lacchetti C, Alici Y, Barton DL, Bruner D, Canin BE, et al. 
Management of Fatigue in Adult Survivors of Cancer: ASCO-Society for 
Integrative Oncology Guideline Update. J Clin Oncol. 2024;42(20):2456-87. 
27. 
Ligibel JA, Bohlke K, May AM, Clinton SK, Demark-Wahnefried W, Gilchrist 
SC, et al. Exercise, Diet, and Weight Management During Cancer Treatment: 
ASCO Guideline. J Clin Oncol. 2022;40(22):2491-507. 
28. 
Smits A, Galaal K, Winnan S, Lopes A, Bekkers RLM. Feasibility and 
Effectiveness of the Exercise Program in Endometrial Cancer; Feasibility and 
Acceptability Survivorship Trial (EPEC-FAST). Cancers (Basel). 2022;14(22). 
29. 
McCarroll ML, Armbruster S, Frasure HE, Gothard MD, Gil KM, Kavanagh MB, 
et al. Self-efficacy, quality of life, and weight loss in overweight/obese 
endometrial cancer survivors (SUCCEED): a randomized controlled trial. 
Gynecol Oncol. 2014;132(2):397-402. 

ACTIVATE Trial | Avani Rao 
46 
PROTOCOL VERSION DATE:  05/12/2025 
30. 
Rossi A, Garber CE, Ortiz M, Shankar V, Goldberg GL, Nevadunsky NS. 
Feasibility of a physical activity intervention for obese, socioculturally diverse 
endometrial cancer survivors. Gynecol Oncol. 2016;142(2):304-10. 
31. 
Reynolds SA, O'Connor L, McGee A, Kilcoyne AQ, Connolly A, Mockler D, et 
al. Recruitment rates and strategies in exercise trials in cancer survivorship: a 
systematic review. J Cancer Surviv. 2024;18(4):1233-42. 
32. 
Savard J, Simard S, Blanchet J, Ivers H, Morin CM. Prevalence, clinical 
characteristics, and risk factors for insomnia in the context of breast cancer. Sleep. 
2001;24(5):583-90. 
33. 
Carpenter JS, Elam JL, Ridner SH, Carney PH, Cherry GJ, Cucullu HL. Sleep, 
fatigue, and depressive symptoms in breast cancer survivors and matched healthy 
women experiencing hot flashes. Oncol Nurs Forum. 2004;31(3):591-5598. 
34. 
Patrick DL, Ferketich SL, Frame PS, Harris JJ, Hendricks CB, Levin B, et al. 
National Institutes of Health State-of-the-Science Conference Statement: 
Symptom Management in Cancer: Pain, Depression, and Fatigue, July 15-17, 
2002. J Natl Cancer Inst. 2003;95(15):1110-7. 
35. 
Stepanski EJ, Walker MS, Schwartzberg LS, Blakely LJ, Ong JC, Houts AC. The 
relation of trouble sleeping, depressed mood, pain, and fatigue in patients with 
cancer. J Clin Sleep Med. 2009;5(2):132-6. 
36. 
Donovan KA, Jacobsen PB. Fatigue, depression, and insomnia: evidence for a 
symptom cluster in cancer. Semin Oncol Nurs. 2007;23(2):127-35. 
37. 
Ligibel JA, Bohlke K, May AM, Clinton SK, Demark-Wahnefried W, Gilchrist 
SC, et al. Exercise, Diet, and Weight Management During Cancer Treatment: 
ASCO Guideline. Journal of Clinical Oncology. 2022;40(22):2491-507. 
38. 
Bower JE. Cancer-related fatigue--mechanisms, risk factors, and treatments. Nat 
Rev Clin Oncol. 2014;11(10):597-609. 
39. 
Aggarwal BB, Vijayalekshmi RV, Sung B. Targeting inflammatory pathways for 
prevention and therapy of cancer: short-term friend, long-term foe. Clin Cancer 
Res. 2009;15(2):425-30. 
40. 
Courtier N, Gambling T, Barrett-Lee P, Mason MD. Soluble interleukin-6 
receptor mediated fatigue highlights immunological heterogeneity of patients with 
early breast cancer who undergo radiation therapy. Adv Radiat Oncol. 
2018;3(4):552-8. 
41. 
Bower JE, Ganz PA, Tao ML, Hu W, Belin TR, Sepah S, et al. Inflammatory 
biomarkers and fatigue during radiation therapy for breast and prostate cancer. 
Clin Cancer Res. 2009;15(17):5534-40. 

ACTIVATE Trial | Avani Rao 
47 
PROTOCOL VERSION DATE:  05/12/2025 
42. 
Bower JE, Ganz PA, Desmond KA, Bernaards C, Rowland JH, Meyerowitz BE, 
Belin TR. Fatigue in long-term breast carcinoma survivors: a longitudinal 
investigation. Cancer. 2006;106(4):751-8. 
43. 
Bower JE, Ganz PA, Irwin MR, Kwan L, Breen EC, Cole SW. Inflammation and 
behavioral symptoms after breast cancer treatment: do fatigue, depression, and 
sleep disturbance share a common underlying mechanism? J Clin Oncol. 
2011;29(26):3517-22. 
44. 
Schmitz KH, Courneya KS, Matthews C, Demark-Wahnefried W, Galvao DA, 
Pinto BM, et al. American College of Sports Medicine roundtable on exercise 
guidelines for cancer survivors. Med Sci Sports Exerc. 2010;42(7):1409-26. 
45. 
Pinto BM, Frierson GM, Rabin C, Trunzo JJ, Marcus BH. Home-based physical 
activity intervention for breast cancer patients. J Clin Oncol. 2005;23(15):3577-
87. 
46. 
Strasser B, Steindorf K, Wiskemann J, Ulrich CM. Impact of resistance training in 
cancer survivors: a meta-analysis. Med Sci Sports Exerc. 2013;45(11):2080-90. 
47.  
Straand IJ, Baxter KA, Følstad A. Remote Inclusion of Vulnerable Users in 
mHealth Intervention Design: Retrospective Case Analysis. JMIR Mhealth 
Uhealth. 2024;12:e55548.