A Mobile Health Exercise Intervention for Older Patients With Myeloid Neoplasms
Phase: NA
Conditions: Intervention
Sponsor: University of Rochester

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UNIVERSITY OF ROCHESTER MEDICAL CENTER
WILMOT CANCER INSTITUTE
A mobile health exercise intervention for older patients with myeloid neoplasms
October 22, 2021
Study Principal Investigator:
Kah Poh (Melissa) Loh, MBBCh BAO
Division of Hematology/Oncology
University of Rochester Medical Center 
James P Wilmot Cancer Center 
601 Elmwood Ave, Box 704 
Rochester, NY 14642
Email: Kahpoh_loh@URMC.Rochester.edu
Study Sub-Investigators:
Supriya G. Mohile, MD, MS
Division of Hematology/Oncology
University of Rochester Medical Center 
James P Wilmot Cancer Center 
601 Elmwood Ave, Box 704 
Rochester, NY 14642
Email: Supriya_Mohile@URMC.rochester.edu
Karen Mustian, PhD, MPH
Department of Surgery
University of Rochester Medical Center 
James P Wilmot Cancer Center 
601 Elmwood Ave, Box 704 
Rochester, NY 14642
Email: Karen_mustian@URMC.rochester.edu
Michelle Janelsins, PhD
Department of Surgery
University of Rochester Medical Center 
James P Wilmot Cancer Center 
601 Elmwood Ave, Box 704 
Rochester, NY 14642
Email: Michelle_janelsins@urmc.rochester.edu 
Martha Susiarjo, PhD
Department of Environmental medicine
University of Rochester Medical Center 
601 Elmwood Ave, Box 704 
Rochester, NY 14642
Email: Martha_susiarjo@urmc.rochester.edu 

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Study Personnel: 
Terri Lloyd 
James P Wilmot Cancer Center 
601 Elmwood Ave, Box 704 
Rochester, NY 14642
Phone: (585) 276-5652/ Fax: (585) 273-1042
Email: Terri1_Lloyd@URMC.Rochester.edu
Chandrika Sanapala
James P Wilmot Cancer Center 
601 Elmwood Ave, Box 704 
Rochester, NY 14642
Phone: (585) 275-4391/ Fax: (585) 273-1042
Email: Chandrika_Sanapala@URMC.Rochester.edu
Biostatistician:
Eva Culakova, PhD
Department of Surgery
University of Rochester Medical Center 
James P Wilmot Cancer Center 
601 Elmwood Ave, Box 704 
Rochester, NY 14642
Email: eva_culakova@URMC.rochester.edu
Exercise Physiologist:
Michelle Porto
James P Wilmot Cancer Center 
601 Elmwood Ave, Box 704 
Rochester, NY 14642
Phone: (585) 276-5652/ Fax: (585) 273-1042
Email: Michelle_porto@URMC.Rochester.edu

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Study Schema (Aim 2)

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TABLE OF CONTENTS
Sections
Page
Study Schema…………………………………………………………………..3
1.0. Background………………………………………………………………..5
2.0. Aim and Hypothesis………………………………………………..……...10
3.0. Subject Design and Population………………..…………………………..11
4.0. Recruitment and Consent…………………………….…………………....13
5.0. Registration……….……………………………………………………….15
6.0. Intervention………………………………………………………………..16
7.0. Treatment Protocol………………………………………………………...22
8.0. Data Handling and Statistical Consideration……………………………...31
9.0. Data Management…………………………………………………………34
10.0. Risks/Benefits……………………………………………........................37
11.0. Data Safety and Monitoring……………………………………………...38
12.0. References………………………………………………………………..40

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1.0. Background
1.1. Myeloid neoplasms are diseases of aging
MN are a group of diseases that include acute myeloid leukemia (AML), myelodysplastic 
syndrome (MDS), MDS/myeloproliferative neoplasm (MPN) overlap, chronic 
myelomonocytic leukemia (CMML), and atypical chronic myeloid leukemia (aCML).1 
Over 60% of MN are diagnosed in adults aged ≥60 years.2,3 For fit older patients with 
AML (i.e., without significant comorbidities or disabilities), the standard first-line 
treatment consists of intensive inpatient chemotherapy. Intensive chemotherapy provides 
the best chance for durable remission, but it is associated with a high treatment-related 
mortality (60-day mortality: 15-20%).4,5 Intensive therapy is utilized in <1% of older 
patients with AML seen in the community oncology setting, due to various reasons such 
as distance to tertiary centers and need for hospitalizations.6 In the last decade, low-
intensity outpatient treatments with reduced treatment-related mortality rates, such as 
hypomethylating agents (HMA), have become available.7–9 These treatments have 
permitted more older patients with AML, including those with comorbidities and 
disabilities, to receive leukemia-directed therapy.10 Furthermore, given the recent FDA 
approval of HMA combination therapy for AML (e.g., HMA and venetoclax), which has 
similar or better efficacy than intensive therapy,11 HMA-based therapies will be used 
more widely in older patients with AML. For older patients with other MN requiring 
chemotherapy, HMA are often the treatment of choice.12 Thus, HMA are now standard of 
care for older patients with MN. HMA are typically given continuously until progression, 
death, or stem cell transplant.
1.2. Even with HMA, a high percentage of older patients with MN experience physical 
function decline and symptoms (e.g., fatigue, mood disturbances).
In prior studies, up to 98% of older patients with MN receiving intensive chemotherapy 
experience physical function decline and symptoms.13–15 Our group and others have also 
shown that 73% of older patients with MN receiving HMA had impairments in physical 
function and 33% reported mood disturbances.16,17 Physical function decline and 
symptoms can lead to reduced quality of life (QoL), treatment interruptions, and shorter 
survival.13,18–22 Therefore, it is imperative to develop interventions for older patients 
receiving HMA that prevent physical function decline and improve symptoms so that 
they can maintain their QoL and continue to receive cancer treatments.
1.3. Older patients with MN can exercise and may derive benefits from exercise. 
Exercise may prevent physical function decline and improve symptoms.23–26 Older adults 
can derive benefits from exercise even if they only maintain or minimally improve 
physical activity from baseline.27 A previous systematic review has shown that exercise is 
safe in frail older adults.28 Three pilot studies evaluated exercise in 50 older patients with 
MN (only one receiving HMA was included) and showed that they can exercise and that 
it was safe. In addition, exercise improved physical function, fatigue, mood disturbances, 
and QoL.29–31 In our own pilot work, older patients with MN receiving HMA reported 

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walking at least an average of 2k-3k steps/day, which is comparable to prior exercise 
studies in older patients with solid tumors, suggesting that they have similar exercise 
capacity. Overall, our pilot data and prior studies suggest that older patients with MN can 
exercise safely and may benefit from it, but exercise interventions tailored to this 
population are limited.32
1.4. Exercise for Cancer Patients (EXCAP): 
Dr. Mustian (co-investigators) developed EXCAP, an individually tailored, low- to 
moderate-intensity, home-based walking and progressive resistance exercise program 
designed for patients with cancer and delivered by an exercise physiologist. By design, 
EXCAP is tailored to the physical capacity of patients with cancer. Our data from >300 
older patients undergoing active cancer treatments from 4 phase 2/3 studies demonstrated 
that they were able to perform the walking (average steps walked/day=4k-11k at post-
intervention) and resistance exercises (15-22 min/day, 2-4 days/week).23,27,33,34 EXCAP 
also improved physical function, fatigue, and mood in patients with solid tumors.35–37 In 
older patients with solid tumors, we have shown that EXCAP improved physical function 
(measured using the Short Physical Performance Battery, SPPB), mood, and QoL, but 
effect sizes were small (Cohen’s d=0.10-0.30).23,27,38 Older patients had lower exercise 
adherence than their younger counterparts (average steps walked/day=4k vs. 5k at post-
intervention).
1.5. The use of a mobile health (mHealth) application (app) may improve exercise 
adherence in older patients with MN.
Exercise adherence can be a challenge in older patients with MN due to comorbidities, 
symptoms, lack of exercise self-efficacy, and limited access to exercise oncology 
professionals and facilities.39–42 mHealth has the potential to improve exercise adherence 
by enhancing exercise self-efficacy and by helping to address barriers to exercise in real 
time.43,44 In our systematic review of studies in the cancer population, however, we found 
that older patients with MN are rarely included in mHealth exercise studies.43
1.6. PointClick Care Mobile App:
We have worked with a mHealth company (PointClickCare, formerly TouchStream) to 
upgrade an app (TouchStream) for monitoring older patients (12 had MN) receiving 
cancer treatment.16 Our pilot data suggest that the app is usable and feasible (Table 1). I 
conducted interviews with 16 patients to elicit barriers and facilitators for adaptation of 
the app and revision of the study protocol. Patients indicated their willingness to exercise 
and preferred a structured exercise program in combination with the app over physicians’ 
recommendations to exercise without a structured program and app.
1.7. Several mechanisms are associated with physical function decline, fatigue, and mood 
disturbances. 

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Potential mechanisms include inflammatory dysregulation, neuroimmunological changes, 
energy imbalance, and skeletal muscle changes (e.g., mitochondrial dysfunction, decline 
in neural function, reduced satellite cell function, defects in calcium homeostasis);45,46 
these are often inter-related.47,48 Inflammatory dysregulation, in particular, has strong 
mechanistic evidence because of its association with frailty in older adults49,50 and 
because it can affect virtually every biological system (the most relevant are the 
muscular, cardiovascular, and cerebrovascular systems).45 
1.8. Tumor necrosis factor (TNF)α and related inflammatory cytokines are associated 
with physical function decline, fatigue, mood disturbances, and worsening QoL in older 
patients with MN. 
TNFα is involved in early inflammatory responses and is regarded as the “master 
regulator” of inflammation.51,52 Preclinical studies demonstrate that cancer and 
chemotherapy increase serum TNFα and related cytokine levels [e.g., interleukin-1β (IL-
1β), interleukin-6 (IL-6), interleukin-8 (IL-8)].53–55,56(p),57 Activation of TNFα and related 
cytokine pathways leads to physical function decline, fatigue, and mood disturbances,58–
62 which are abrogated by inhibition of these pathways.62,63 In older adults with MN, we 
have shown that higher baseline serum TNFα levels were associated with shorter 
survival. In patients with MN, our group and others also found that increased serum 
TNFα, soluble TNF receptor 1 (sTNFR1), and related cytokine levels were associated 
with physical function decline, fatigue, mood disturbances, and worsening QoL.64–66 
Exercise reduces inflammation, which may explain how exercise prevents physical 
function decline and improves fatigue and mood disturbances.67,68
1.9. Understanding exercise-induced changes in the TNFα and related cytokine pathways 
may help to tailor exercise prescriptions for older patients with cancer in clinical practice. 
In patients with higher serum TNFα levels, a lower dose of exercise may be sufficient to 
decrease serum TNFα levels and prevent physical function decline. However, the 
epigenetic regulation of TNFα in the context of exercise is not well characterized. DNA 
methylation is an epigenetic mechanism that can be stably inherited throughout cell 
divisions.69 DNA methylation is the addition of methyl groups to the DNA molecule at 
the CpG sites where a cytosine nucleotide is followed by a guanine.70 DNA methylation 
of the TNFα gene promoter region decreases TNFα gene and protein expression.71,72 Prior 
studies have shown that exercise increases TNFα gene promoter methylation and 
decreases TNFα gene and protein expression.73–76 A better understanding of the TNFα 
and related cytokine pathways can identify biomarkers to help tailor exercise 
prescriptions.
To summarize, we chose the TNFα pathway as our translational focus because 1) our 
preliminary data showed that higher serum TNFα and soluble TNF receptor 1 levels were 
associated with physical function decline, mood disturbances, and shorter survival;64 2) 
exercise increases TNFα gene promoter methylation and decreases TNFα gene and 
protein expression;73–76 3) it will allow us to expand our preliminary data and explore 
other TNFα related cytokine pathways (e.g., IL-1β, IL-6, IL-8); and 4) we have the 

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expertise to reliably measure, analyze, and interpret TNFα gene promoter methylation 
and TNFα gene and protein expression in a clinical trial.77 While we focus on older 
patients with MN, this population serves as a model for studying an individually tailored 
mHealth exercise intervention among vulnerable older patients receiving prolonged 
cancer treatments to prevent physical function decline and improve symptoms. Findings 
from our studies will inform research and practice for a large proportion of older patients 
who are currently understudied in behavioral intervention trials. This work is also highly 
novel and may lay the foundation for the use of biomarkers in the design of behavioral 
interventions to improve outcomes in older patients with cancer. 
Summary of knowledge/Proposed Solution: 
No mHealth exercise intervention is currently available for older patients with MN 
receiving outpatient chemotherapy, specifically HMA. TNFα and related cytokines are 
associated with physical function decline, fatigue, and mood disturbances. Based on our 
expertise and prior studies, we propose to integrate the content of EXCAP into the 
PointClick Care app to enhance older patients’ adherence to exercise and to understand 
exercise-induced changes in physical function, fatigue, mood, QoL, and TNFα and 
related cytokine pathways.
The mobile app and EXCAP have been studied individually in previous studies.16,23,33,34,78 
In this study, we plan to combine them for older patients with MN receiving outpatient 
chemotherapy including HMA.

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2.0. Aim and Hypothesis
2.1. Primary Aim
To develop a mobile app delivery platform integrating EXCAP and adapt its content, 
format, and delivery for older patients with MN receiving HMA using feedback from 
15 patients.
2.2. Secondary Aim
To assess the feasibility of a mobile health exercise intervention (GO-EXCAP Mobile 
App) over 8± 4 weeks in a single-arm pilot study in 25 patients with myeloid 
neoplasms receiving outpatient chemotherapy (including HMA).
2.3. Exploratory Aim
To examine relationships among TNFα and related cytokine gene promoter 
methylation and gene and protein expression.
2.2.1. Hypothesis
The GO-EXCAP Mobile App will be feasible in older patients with myeloid neoplasms 
receiving outpatient chemotherapy.
2.2.1. Feasibility metrics
The feasibility of the GO-EXCAP Mobile App will be evaluated based on the 
following: 
a) Percentage of patients wearing the activity tracker and entering resistance exercise 
data into the mobile app.
b) Percentage of patients performing both walking and resistance exercises during the 
study period days. 
c) Recruitment rates (percentage of patients who are approached and agree to enroll).
d) Retention rates (percentage of patients who are enrolled and complete post-
intervention assessments).

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3.0. Study Design and Population
3.1. Study Settings 
Wilmot Cancer Institute (WCI), University of Rochester Medical Center (including WCI-
affiliated community practices such as Interlakes Oncology, Dansville, Pluta, Olean, 
Wellsville)
3.2. Study Type
Aim 1: Qualitative study
Aim 2: Single-arm pilot study
3.3. Study Population
Aim 1: We will obtain feedback from 15 older patients receiving HMA. Our planned 
sample size (N=15) will allow us to achieve thematic saturation.79,80 To obtain 15 
patients, we will consent up to 20 patients to account for screen fail or withdrawal.
Aim 2: We will recruit 25 older patients receiving outpatient chemotherapy (see Section 
8.2.2 for sample size justification). To obtain 25 patients, we will consent up to 45 
patients to account for screen fail or withdrawal.
3.4. Inclusion and Exclusion Criteria
Inclusion criteria 

Age ≥60 years (conventional definition of older age in clinical trials of MN)81–83

Have a diagnosis of MN

Receiving outpatient chemotherapy (e.g., HMA)

English speaking

Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

No medical contraindications for exercise per oncologist

Able to walk 4 meters as part of Short Physical Performance Battery measured 
walk (with or without assistive device)

Able to provide informed consent
Exclusion criteria 

Platelet count of 10,000 per microliter or less in the most recent blood draw (due 
to risk of spontaneous bleeding) prior to transfusion (i.e., patients are allowed to 
enroll if their platelet count is 10,000 per microliter or less but is scheduled to 
receive transfusion the day of consent)
Each subject’s eligibility will be documented on redcap. This will be printed and signed 
and dated by the principal investigator.
3.5. Number of Subjects

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Aim 1: We plan to enroll 15 patients in 3 months. In any given week, between 10 and 20 
older patients with MN are receiving HMA at the Wilmot Cancer Institute. In a previous 
qualitative study conducted in this population, recruitment rate was close to 100%.84 
Therefore, we expect to be able to recruit 15 patients in 3 months. 
Aim 2: Annually from 2012-2017, four oncologists saw approximately 150 patients with 
MN aged ≥60 at the Wilmot Cancer Institute, and 70% received outpatient HMA. In prior 
studies of older patients (including MN) enrolled on behavioral pilot intervention studies 
at our institution, the recruitment rate was 65-75%.85,86 Therefore, we expect to be able to 
recruit 25 patients in 18 months. 
3.6. Gender of Subjects
The gender ratio of patients to be enrolled on the study will be similar to the gender ratio 
of myeloid neoplasms in older adults (approximately 1.2:1 Male to female ratio).87 
3.7. Age of Subjects
We will recruit patients with myeloid neoplasms aged 60 and above (from date of 
consent, confirmed on electronic medical record). 
3.8. Racial and Ethnic Origin
Myeloid neoplams affects all races with similar rates. Whites, African American and 
Hispanics make up approximately 65%, 30% and 5%, respectively, of the older 
population in Rochester, New York.88 As we limited enrollment to English-speaking 
patients, we anticipate a higher percentage of whites in our study. The study has no 
enrollment restrictions based upon race or ethnic origin.
3.9. Vulnerable Subjects
No special classes of subjects such as fetuses, neonates, children, pregnant women, 
prisoners, institutionalized individuals or other vulnerable populations will be recruited.

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4.0. Recruitment and Consent
Subjects will be enrolled at the University of Rochester Medical Center (URMC) Wilmot 
Cancer Center and WCI-affiliated community practices such as Interlakes Oncology, 
Dansville, Pluta, Olean, Wellsville. Study subjects will be recruited from the malignant 
hematology clinics at WCI and general oncology clinics at WCI-affiliated community 
practices. We plan to enroll 40 subjects (15 in phase 1 and 25 in phase 2) over a course of 
2 years. 
To ensure appropriate safety precautions when conducting in-person study procedures, 
the process for conducting in-person visits outlined in the Guidance for Human Subject 
Research will be followed. 
4.1. Identification of Study Subjects, Recruitment, and Consent Procedures
Study subjects will be identified in multiple ways. First, patients will be identified by 
their treating physician, the nurses that work with the physicians, and the study 
coordinator. The study coordinator will work closely with the physicians and nurses to 
identify those patients that are anticipated or have begun treatment with chemotherapy. 
Second, with permission from oncology providers, we will screen for eligible patients 
from clinic schedules. The study coordinator contacts the physician (or their designee) 
and informs them that a patient may be eligible for the study. The physician (or their 
designee) then confirms if the patient is a study candidate or not (including whether they 
are a candidate to exercise). This will be documented in the subject research chart. If 
there is a question about eligibility, the principal investigator will be contacted and will 
meet with the patient, review the medical records, and perform an assessment of 
eligibility if necessary. The same identification process will be used for all sites.
For in-person consent, below are the possible scenarios for obtaining consent.
1) Physician/Study Investigator makes the initial contact 
andprovides consent form, and patient signs consent with the 
physician on the same day: After confirming with the 
physician (or their designee) that a patient is a potential 
candidate for the study, the study staff will provide a consent 
form to the treating physician/study investigator so he/she can 
provide it to the patient during an in-person clinic visit. The 
physician/study investigator will go over every detail of the 
study during the clinic visit with patient. If agrees, the patient 
will sign the consent form with the physician/study 
investigator during the same in-person visit.
2) Study staff makes the initial contact and provides consent form, 
and patient signs consent with the study staff on the same day: 

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After confirming with the physician (or their designee) that a 
patient is a potential candidate for the study, the patient will be 
provided with an informed consent form by the study staff 
when they come in for an in-person clinic visit. The study staff 
will introduce the study to the patients and go over every detail 
of the study. If agrees, the patient will sign the consent form 
with the study staff during the same in- person visit with the 
study staff.
For verbal consent, below are the possible scenarios for obtaining consent. 
Generally two in-person visits are required prior to the start of intervention (the first 
in-person visit is to provide the wearable tracker and actigraphy, the second in-
person visit to perform the in-person assessments and provide the tablet). By 
allowing verbal consent, we will be able to mail the wearable tracker and actigraphy 
to the patient. 
1) Physician/Study Investigator makes the initial contact, study staff follows up 
with the patient on the phone, and patient provides verbal consent on the 
phone: After confirming with the physician (or their designee) that a patient is 
a potential candidate for the study, the physician/study investigator confirms 
with the patient that he/she is willing to speak with the study staff about the 
study. The study staff will then call the patient via phone. The study 
coordinator will use the verbal consent script as a written aid and will go over 
every detail of the study with the patient to recruit them for the study. Study 
staff will sign and date it to confirm that he/she followed the script and the 
patient agrees to participate in the study. An information sheet summarizing 
the study and patient' s involvement will be mailed /emailed to the patient for 
their records.
2) Physician/Study Investigator makes the initial contact and provides consent 
form, study staff follows up with the patient on the phone, and patient 
provides verbal consent on the phone: After confirming with the physician (or 
their designee) that a patient is a potential candidate for the study, the study 
staff will provide a consent form to the treating physician/study investigator 
so he/she can provide it to the patient during an in-person clinic visit. If the 
patient is interested but does not want to consent on the same day, the patient 
will bring the consent form home. The study staff will then call the patient via 
phone. The study coordinator will use the verbal consent script as a written 
aid and will go over every detail of the study with the patient to recruit them 
for the study. Study staff will sign and date it to confirm that he/she followed 
the script and the patient agrees to participate in the study. An information 
sheet summarizing the study and patient's involvement will be mailed/emailed 
to the patient for their records.

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3) Study staff makes the initial contact and provides consent form, 
study staff follows up with the patient on the phone, and patient 
provides verbal consent on the phone: After confirming with the 
physician (or their designee) that a patient is willing to speak with 
the study coordinator about the study, the patient will be provided 
with an informed consent form by the study staff when they come 
in for an in-person clinic visit. If the patient is interested but does 
not want to consent on the same day, the patient will bring the 
consent form home. The study staff will then call the patient via 
phone. The study coordinator will use the verbal consent script as 
a written aid and will go over every detail of the study with the 
patient to recruit them for the study. Study staff will sign and date 
it to confirm that he/she followed the script and the patient agrees 
to participate in the study. An information sheet summarizing the 
study and patient's involvement will be mailed/emailed to the 
patient for their records.
4.1.1. Informed Consent
Informed consent will be obtained from the patient by the study investigators or 
coordinators. Consent documents will be signed by the patient and maintained in 
the patient record with copies provided to the patient. For verbal consent, 
documents will be maintained in the patient record with copies provided to the 
patient.
4.1.2. Baseline Measures and Study Procedures
After consent, the patient will complete baseline measures. Study coordinator will 
be available to assist the patient. The study coordinator will obtain information 
necessary to complete the forms capturing clinical data from the patient’s medical 
records when the patient is unable to provide this information in sufficient detail 
(e.g. type of myeloid neoplasms, antecedent hematologic malignancies, treatment 
regimen). 
For patients consented at Olean, Wellsville, and Dansville, they will be asked to 
meet with the study coordinator at the Wilmot Cancer Institute/Strong Memorial 
Hospital to conduct research activities. No research activities will be conducted at 
these sites.
4.1.3. Human Subject Protection
Ethical standards for human subjects will be strictly followed in accordance with 
the University of Rochester Research Subject Review Board Investigator Guidance 
policy.89 

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4.1.4. Participation
Current state, federal, and institutional regulations concerning informed consent 
will be followed. Participation in this study is voluntary. Participants are free not to 
take part or to withdraw at any time, for whatever reason, without risking loss of 
present or future care they would otherwise expect to receive. In the event that a 
patient does withdraw from the study, the information they have already provided 
will be kept in a confidential manner. Participants may discontinue participation in 
the study at any time if they decide they do not wish to take part any longer. 
Participants may be withdrawn from the study by research personnel if it is deemed 
in their best interest to no longer participate.
4.1.5. Duration
Aim 1: The qualitative portion of the study will involve one semi-structured 
interview. Interviews with the patients will be held in person in a private space 
(clinic or office space). Interviews will be audio-recorded and led by study 
investigators and will last 30 minutes. These recordings will be uploaded to Box, 
and the recordings will be deleted from the audio-recorder.
Aim 2: Study participants will be consented to actively participate, receive phone 
calls or meet with the research study team at the baseline visit (week 0) and 8± 4 
weeks after the intervention (week 8± 4). The research team may contact 
participants in the future to gain further information first hand regarding patients’ 
overall health and treatment, the study team may decide to take participants off the 
study without their consent if the study is stopped. Additionally, study participant 
data will be kept for 7 years at URMC, even after the study is closed or a study 
participant passes away. It will be maintained in a locked database with password 
access only (See Section 9).

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5.0. Registration
5.1. To register a participant who meets the eligibility criteria and who has signed the 
informed consent document, study staff will log on to OnCore and enter the information 
outlined in section 5.2 below. 
5.2. Information Requested at Registration
5.2.1
Site
5.2.2
Most recent IRB approval date
5.2.3
Eligibility verification 
5.2.4
Verification that consent form has been signed and who signed by (patient 
and/or health care proxy) and date signed
5.2.5
Treatment facility (Wilmot Cancer Center)
5.2.6
Participant’s identification
5.2.6.a
First and last names 
5.2.6.b
Birth date (MM/DD/STREAM)
5.2.6.c
Gender
5.2.6.d
Race 
5.2.6.e
Five-digit zip code
5.2.6.f
Medical Record Number
5.2.6.g  Ethnicity
5.2.6.h
Patient’s preferred and alternate phone numbers
5.2.6.i
Date of baseline Visit
5.3. Initial Assessment
After consent procedures are completed, the patient, with the help of the study 
coordinator, will complete a baseline assessment (see Section 7.2). Patients who are 
eligible will be enrolled and complete study procedures. For Aim 1, this will involve one 
semi-structured interview. For Aim 2, patients will be provided with the intervention and 
will be asked to complete post-intervention assessment at week 8 (± 4 weeks).

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6.0. Intervention
6.1. EXCAP Exercise Program
The first component of the EXCAP exercise program is an individually tailored walking 
prescription and provides low to moderately intense aerobic exercise (3-5 exercise rating 
of perceived exertion on the American College of Sports Medicine [ACSM] revised 
rating scale, which is a visual analog scale ranging from 1 = “Not tired at all” to 10 = ”So 
tired, I can’t go anymore”) 7 days a week. This walking prescription will be developed 
and individually tailored for each subject according to step data reported on the web 
portal. A Garmin activity tracker, a wearable sensor-based device, will be used record the 
number of steps they walk daily during the 4-7 days baseline assessment and then with 
the help of an exercise physiologist to calculate the average number of steps they walk 
daily during that period. The wearable devices will be registered by the research team (no 
phone or mobile identification numbers will be stored with data, and no GPS data will be 
collected to identify locations). Using the baseline average number of steps walked daily, 
patients are encouraged to increase their total steps walked by a minimum of 5% per 
week, while maintaining a moderate intensity. Subjects are encouraged to reach the 
ACSM suggested 10,000 steps a day if possible (this is not mandatory). As an 
instructional and motivational tool, at the start of the exercise intervention, a table will be 
provided that includes the average number of steps walked at baseline, as well as, the 
number of steps that would represent increases of 5%, 10%, 15%, and 20% over this 
baseline amount for each of the 8 weeks of the intervention period 
The second component of the exercise program is an individually tailored therapeutic 
resistance band exercise prescription designed to provide low to moderately intense 
progressive resistance exercise [3-5 exercise rating of perceived exertion (RPE) on the 
ACSM revised rating scale] 7 days a week. Subjects are given a set of 3 color-coded 
therapeutic resistance bands representing varying levels of resistance. The exercise 
physiologist will explain the proper use of the resistance bands, safety, and the 
appropriate mechanics for performing the resistance training exercises. Subjects are 
instructed to begin with an individually determined number of sets (1 set = 8-15 
repetitions) for each of the sixteen exercises at a moderately challenging level (RPE=3-5) 
7 days a week. The exercises target the upper and lower body. The exercise physiologist 
will work with the subject to find an optimally challenging number of sets and repetitions 
with the appropriately colored resistance band for each exercise with each patient. 
Subjects are instructed to increase the intensity by changing to a different color band or 
by shortening the initial length of the band for increased resistance. They are encouraged 
to progressively increase from their individual baseline sets and repetitions to a maximum 
of 4 sets of 15 repetitions for each exercise daily over the course of the 8-week (± 4 
weeks) intervention at a rate that is optimally challenging. The therapeutic resistance 
band exercise prescription will be developed and individually tailored for each subject by 
the exercise physiologist. Each subject will report the intensity of their resistance exercise 
using 1) the rated perceive exertion (RPE) scale and 2) time spent for resistance band 
exercise by entering these data directly on the tablet.

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6.2. PointClick Care Mobile App
PointClick Care is a mobile app that is preloaded on a tablet. The app was initially 
designed with the goal of helping people live independently. The app provides assistance 
in managing medications, chronic health conditions, doctor appointments, and activities 
of daily living including reminders to exercise. The PointClick Care app is connected to a 
data plan (which will be paid for by the study) for internet access, as well as a web portal 
that is accessible using a desktop or laptop computer of which internet access is required. 
The University of Rochester IT department has been contacted. As per the University 
policy for devices, the hard drive must be encrypted to protect any patient data. 
PointClick Care encrypts all PointClick Care data transferred between backend servers 
and the tablets. Communications to the server is validated by signed trusted server 
certificate. Data at rest is always encrypted. PointClick Care caches data on the tablet, 
and stores data on a PointClick Care server. On the tablet the cache in encrypted, the 
backend server hosts a Microsoft SQL Server database. The volume used by SQL Server 
is encrypted. Only the PointClick Care app, with a valid authentication key, can read this 
data. PointClick Care has a means to disable the PointClick Care app on a tablet. This 
feature only works, however, if the Tablet is connected to the server. 
6.2.1 Tablet Device
The tablet device contains the PointClick Care app. The default screen displays the 
schedule for the day including doctor appointments, to-do-list and reminders (such as 
taking medications, or exercising) (Figure 2). Activities displayed on the tablet can only 
be entered through the web portal (i.e. have you walked at least 4000 steps today?). Users 
can select whether the tasks are completed on the tablet and they can manually enter the 
number of daily steps. The system also allows the user to create questionnaires.
Figure 2: Default screen of the PointClick Care application

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6.2.2. Web-Portal
The web portal is accessed through a web address (https://client.PointClick 
Caresolutions.com) using a computer by the investigators and exercise 
physiologist and/or patients if they wish. The homepage displays the patient’s 
information and a list of activities followed by the date and time, and whether the 
tasks have been completed (Figures 3 and 4). This function will allow the exercise 
physiologist to monitor for exercise adherence at a distance.
Figure 3: Homepage of the web-portal
User can access the profile by clicking “see more…” or “details”. There are 
several functions on the web portal (Figure 3). The toolbar includes “home”, 
“calendar”, “medications”, “health”, “contacts”, “alerts” and “reports”. Under 
“calendar” tab, activities can be entered as events (e.g. have you walked at least 
4000 steps today). Events can be entered as single or recurring events, and this 
can be displayed as a day or month view. Under “medications” tab, a list of the 
medications can be entered along with the time, strength, dosage, frequency and 
indication. Users are reminded to take their medications from the tablet device, 
and enter their compliance to generate a compliance report. Under “health” tab, 
vital signs or point of care information such as weight, blood pressure or blood 
glucose levels can be entered through the tablet, or electronically linked from the 
a monitoring system (weighing scale, glucometer or blood pressure cuff) to the 
web portal. A questionnaire can also be generated and questions can be tailored to 
cancer patients i.e. pain level measured using a Likert-scale. Under “contacts” tab, 
user can enter caregivers or healthcare teams’ contact information, and they can 
be contacted directly from the tablet. Finally the “report” tab generates reports on 
all the aforementioned functions. Of note, automatic reminders can be generated 
and sent to providers if tasks are not completed or certain threshold of vital signs 
are met. For the purpose of this study, we are asking patients to enter their 
exercise data. They are encouraged to use other functions to assist with care 
coordination but are not required to do so.

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Figure 4: Main profile page on the PointClick Care web portal
6.3. GO-EXCAP Mobile App
We plan to integrate the content of the EXCAP exercise program into the PointClick Care 
mobile app (Figure 5). Older patients will participate in the EXCAP exercise program 
and enter exercise data into the mobile app. In addition, they will complete a symptom 
inventory and enter any barriers to exercise into the mobile app weekly. The study team 
(physiologist) logs into the web portal 2x/week to monitor intervention adherence, 
provide feedback, and adjust exercise prescriptions. These recommendations are 
available to the patients - they are automatically displayed via the mobile app daily. 
Patients can interact with the physiologist directly or via the mobile app. 
Symptom reporting and management is an important component of our intervention 
because symptoms are common barriers to exercise. Based on our pilot data,16,90 we 
selected 15 common symptoms experienced by patients with MN based on the Patient-
Reported Outcomes version of the Common Terminology Criteria for Adverse Events 
(PRO-CTCAE).91 We will assess symptoms weekly. These symptoms will be recorded 
on the web portal (described above). Study coordinator will log on to the web portal at 
least weekly to ensure that the symptom surveys are being completed. If the symptom 
surveys are not completed, the study coordinator will remind the patient during the 
weekly calls. For each symptom, we will use standardized severity-based algorithms and 
self-management strategies based on established protocols (Figure 6).92–94 A symptom 
report will be generated at clinic visits. In addition, these reports will be provided to the 
clinic nurses on a weekly basis.
Therefore, the mobile app serves as a tracking, teaching, and self-management device 
that is tailored to the individual. We will adapt the intervention content, format, and 
delivery of the app based on feedback from patients.

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In the case that participants are unable to use the PointClickCare mobile app (i.e. 
company no longer operating), we will administer the exercise surveys and symptom 
inventories as REDCap surveys. The surveys will be disseminated via email. If the 
PointClickCare mobile app is no longer available, current subjects who are enrolled in the 
study will transition to use of the REDCap surveys and will terminate use of the mobile 
app. The previously collected data and subsequent analysis will remain unaffected and 
there will be no changes made to the study aims. Current subjects will be verbally 
notified of this change. 
Figure 5: Proposed GO-EXCAP Mobile App
Figure 6: Example of severity-based algorithm/self-management strategies

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7.0. Treatment Protocol
7.1 Study Outline
Patients who receive HMA and other outpatient chemotherapy typically have declines in 
their blood counts during the 1st month of therapy before improvements are noted. 
Therefore, we will initiate our intervention at cycle 2 the earliest. HMA and other 
common chemotherapy are administered daily as an infusion or subcutaneous injection 
for 5-10 days every 4 weeks. There are outpatient chemotherapy that are pill-based as 
well (e.g., enasidenib, ivosidenib) and are also dosed every 4 weeks. We will consent 
patients and they will complete measures during routine visits. They will complete 
baseline measures during the 4th week of a chemotherapy cycle up to day 1 of the 
subsequent cycle prior to chemotherapy administration (study week 0) (Figure 1). The 
intervention will start during the 1st week of of a new cycle (study week 1) and will last 
8± 4  weeks. The post-intervention measures will be completed 2 cycles later during the 
4th week of the cycle (study week 8± 4). To illustrate this, if the intervention starts in 
cycle 2 week 1, baseline measures will take place on cycle 1 week 4, and post-
intervention assessment will place on cycle 3 week 4. If the intervention starts in cycle 6 
week 1, baseline measures will take place on cycle 5 week 4, and post-intervention 
assessment will place on cycle 7 week 4.
At the screening visit, we will confirm if the patient is eligible using the eligibility criteria 
above. Once we confirm their eligibility, we will obtain either in-person or verbal 
consent. The patient will then complete a demographic questionnaire that asks about the 
participant’s age, gender, race, ethnicity, education level, marital status, employment 
status, and Eastern Cooperative Oncology Group (ECOG) performance status as well as 
their cancer and treatment characteristics (see Section 7.2). 
For Aim 1, one interview will be conducted with each participant in a private space for 
approximately 30 minutes. First, we will explain the rationale and demonstrate the use of 
the GO-EXCAP Mobile App. Second, we will elicit preferences for the content, format, 
and delivery of the intervention (Table 2). Collectively, the findings will be used to adapt 
the intervention. 
Table 2: Intervention features and example of adaptation based on feedback from 
patients
Feature
Goal
Example of Adaptation
Content
To confirm the frequency, 
intensity, and duration of the 
exercises and appropriate 
percentage increment of steps 
and resistance band training 
exercise.
If patients report that they are less able to 
exercise on the days of chemotherapy, we will 
plan to maintain rather than increase the number 
of steps and intensity of resistance training 
exercises during those days.
Format
To elicit preferences regarding 
the format of the training manual 
If patients prefer an electronic training manual, 
we will develop this and incorporate it into the 
mobile app.     

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(i.e. paper, audio, video, or a 
combination).
Delivery
To elicit preferences in the 
administration of the 
intervention (i.e. in-person, 
through the app, or a 
combination of both).
If patients prefer the intervention to be 
administered entirely through the app (without 
the baseline visit with an exercise physiologist), 
we will develop a video to demonstrate the 
exercise techniques on the mobile app.
For Aim 2: Participants will be provided with an activity tracker to measure daily steps 
over 4-7 days. After baseline measures (including blood samples), participants will meet 
with an exercise physiologist in-person and/or via zoom/phone who will demonstrate 
how to perform the exercises and the basic features of the mobile app. Both the 
assessments and teaching will be conducted either at Dr. Mustian’s Physical Exercise, 
Activity and Kinesiology (PEAK) laboratory and/or virtually via zoom/phone. 
Alternatively, if requested, certain assessments and teaching will be completed at the 
cancer center. Patients will be provided with the GO-EXCAP Mobile App on a tablet 
which will be equipped with cellular connectivity. The Exercise Physiologist and/or study 
coordinator will ensure successful set up of tablet device for the subjects and he/she will 
also provide in-person instructions on the use of the mobile app. The study coordinator 
will also be available to answer any potential subsequent questions in regards to the use 
of the app.
For Wilmot affiliated sites (except for Olean, Dansville, and Wellsville where research 
activities will not be conducted), similar procedures will be used if participants are 
willing to travel to Wilmot Cancer Institute/Strong Memorial Hospital. For participants 
who are not willing to travel, our study coordinator will perform assessments at the 
affiliated sites. Blood samples will also be collected. Teaching will be conducted either 
in-person or via zoom. Assessments that are required to be performed at the PEAK lab 
will be omitted if participants are not willing to travel..
From study week 1-8 (± 4), participants will perform the exercises at home. Participants 
will enter their daily steps from the activity tracker, time spent for resistance band 
exercises, and exercise intensity into the mobile app. They will enter any barriers to 
exercise on the app and complete the PRO-CTCAE questionnaire weekly. These data will 
be transferred automatically from the app to a Web portal. The study team (physiologist) 
will log into the Web portal twice a week to monitor adherence, provide feedback, and 
adjust exercise prescriptions. These recommendations will be available to each 
participant via the app or directly. Participants can interact with the physiologist via the 
app or directly. The study coordinator will also call the patients weekly to answer any 
questions. The algorithms for symptom reporting and management developed in Aim 1 
will be incorporated into the app. To ensure safety, participants will answer questions 
weekly on the app to determine ongoing appropriateness of exercise (e.g., no interval 
cardiac symptoms) and ensure there are no new medical contraindications to exercise.95

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Mid-intervention (study week 3-5): We will conduct an in-person or zoom/phone 
interview (approximately 30 min) with participants. A three-week window will be used to 
conduct interviews with participants. App functionality, usability, and barriers to 
adherence will be elicited.
Post intervention (study week 8± 4 weeks; chemotherapy delay is common due to 
cytopenias): We will collect the same measures as baseline (including blood samples) and 
usability data. An exit interview (approximately 30-45 min) will be conducted with 
participants either in-person or via zoom/phone to elicit app functionality, usability, and 
barriers to adherence. Participants who complete both the baseline and post-intervention 
measures will receive $50. They may keep the exercise kit and activity tracker (value 
$150). 
Procedures at the affiliated sites will follow the baseline assessments.
7.2. Baseline Assessment of the Participants
Demographics, clinical and treatment/cancer characteristics will be collected. 
7.2.1. Socio-Demographics and Clinical Characteristics
Patient’s age, race, ethnicity, gender, highest level of education achieved, 
employment status, marital status, and ECOG performance status will be captured 
from the patients. The socio-demographics and clinical characteristics will only 
be collected at baseline.
7.2.2. Cancer and Treatment Characteristics 
Type of myeloid neoplasms, prior hematologic malignancies, cytogenetic risk 
group and treatment regimen will be abstracted from the medical records. This 
information will be collected at baseline only.
7.2.3. Outcomes of Interest (Baseline and post-intervention unless otherwise 
specified)
For patient-reported questionnaires, if we are unable to provide assessment forms 
to the participants, these will be mailed to them at least 1 week ahead of time. For 
assessments that needed to be conducted in-person (including blood sample 
collection), these may be omitted when appropriate for safety of the patients.
7.2.3.1. Physical Function 
Short Physical Performance Battery (SPPB): The SPPB is an objective 
physical assessment evaluating lower extremity physical function.96 It is 
comprised of a four-meter walk, repeated chair stands and a balance test. 
Impairment on SPPB testing has been shown to be predictive of short-term 

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mortality and nursing home admission in community-dwelling older 
adults. We will also perform the virtual SPPB via the phone/zoom, which 
evaluates the participants’ perceived ability to perform above tests 
(walking, repeated chair stands, and balance). 
7.2.3.2. Fatigue
Brief Fatigue Inventory (BFI): BFI is a 9-item, patient-report instrument 
with established reliability and validity that we have used in previous 
studies.97 The BFI allows for the rapid assessment of fatigue level in 
cancer patients and identifies those patients with severe fatigue. The 
reliability and validity of the BFI were demonstrated in a study of 305 
cancer patients and 290 community-dwelling adults.98 
7.2.3.3. Depression
Center for Epidemiological Studies Depression Scale (CES-D): The CES-
D
 is a 20-item depression scale developed and validated for use with a 
variety of populations.99 It is in a format similar to that of the Beck 
Depression Inventory, but with less emphasis on physical symptoms of 
depression that may be confounded with disease symptoms or treatment 
side effects. It has been shown to reliably and validly measure depression 
in cancer populations.100 
7.2.3.4. Quality of Life (QOL) 
Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu): The 
FACT-Leu scale was created by combining the Functional Assessment of 
Cancer Therapy-General module (FACT-G) and a sub-scale made up of 
17 leukemia-specific items.101 It been tested and determined to be a valid, 
reliable, and efficient instrument for evaluating leukemia-specific health-
related QoL.
7.2.3.5. Self-efficacy for Exercise and Exercise Adherence
Self-Efficacy for Exercise scale: This is a 9-item scale to measure self-
efficacy for exercise and higher score indicates higher self-efficacy.102
Actigraphy (research-grade). The actigraph is a small, lightweight, non-
invasive device worn on the waist (clipped to clothes or worn as a 
waistband). The actigraph contains an accelerometer that quantifies 
duration and intensity of physical activity and sedentary behavior 
throughout the day and week. We will use an actigraph that provides 
calculated energy expenditure values for active energy expenditure in 
kilocalories and total energy expenditure in metabolic equivalents per time 
in kilocalories/min/kg. We will use software supplied by the manufacturer 

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to determine bouts of moderate or higher activity during each assessment 
period (T1, T2, and T3). This is a research-grade device that complements 
the commercial-grade wrist-worn Garmin activity tracker.
Exercise Readiness: This will be assessed using the Physical Activity 
Readiness Questionnaire (PAR-Q+) form. This is designed to assess 
patients’ readiness to participate in more physical activity or engage in a 
fitness appraisal. 
7.2.3.6. Other Geriatric Assessment Measures 
Activities of daily living (ADL): ADLs are measures of self-care. ADL 
independence will be assessed using the Katz Index of Independence in 
Activities of Daily Living, commonly referred to as the Katz ADL. The 
Katz ADL is the most appropriate instrument to assess functional status as 
a measurement of the client’s ability to perform activities of daily living 
independently. Clinicians typically use the tool to detect problems in 
performing activities of daily living and to plan care accordingly. The 
Index ranks adequacy of performance in the six functions of bathing, 
dressing, toileting, transferring, continence, and feeding. Clients are 
scored yes/no for independence in each of the six functions. A score of 6 
indicates full function, 4 indicates moderate impairment, and 2 or less 
indicates severe functional impairment.
Instrumental Activities of Daily Living (IADL): Self-reported functional 
status will be assessed using the IADL subscale of the Multidimensional 
Functional Assessment Questionnaire: Older American Resources and 
Services (OARS). The IADL subscale consists of seven questions rated on 
a three-point Likert scale. It measures the degree to which an activity can 
be performed independently.
Fall History: A self-reported history of falls in the past three months will 
be recorded. A history of a recent fall has been demonstrated to be 
independently predictive of increased risk for chemotherapy toxicity in 
older cancer patients.20 
6-minute walk test (6MWT): The 6MWT measures functional endurance 
and aerobic capacity.103 It measures the distance walked by the patient 
over a time of 6 minutes. We will also assess gait analyses using the BTS 
G-SENSOR. The BTS G-SENSOR is a small non-invasive device worn 
on a waist belt to provide functional evaluation of walking that includes 
accelerometers, gyroscopes, and magnetometers, allowing the spatio-
temporal parameters of subject’s gait to be measured as well as their 
pelvic rotations and swing leg accelerations. It provides objective and 
quantitative data that is related to muscles activity and kinematic 
parameters.

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Nutrition: Screening for nutritional deficit will be performed with body 
mass index (BMI) evaluation and self-reported weight loss.  
 
Cognition; Montreal Cognitive Assessment (MOCA): A 30-point cognitive 
screen test with excellent sensitivity for individuals with mild dementia 
and mild cognitive impairment. It can also be used to trend changes in 
cognitive status over time. If in-person assessment is not possible, MOCA-
blind will be conducted via zoom/phone.
Comorbidity (baseline only); OARS Physical Health Section: Patients self-
report their coexisting medical conditions and also rate the degree to 
which their illness causes impairment in daily activities. The OARS 
Physical Health Section has been shown to correlate significantly with 
health professional ratings of comorbidity as well.
Social Support (baseline only); OARS Medical Social Support survey: A 
13-question survey asking patients to identify the number of support 
persons involved in their medical care as well as the degree to which they 
felt supported in a variety of situations.  
Medications (baseline only): We will record all prescription and non-
prescription medications, dosage and frequencies from the medical 
records. Polypharmacy is defined as the use of 5 or more medications.
7.2.4. Complete blood count (CBC)
Blood counts measured by standard CBC with differential procedures will be 
abstracted from the patient’s medical record.
7.2.5. Muscle mass testing
The RJL Bioelectrical Impedance System is a non-invasive, easy-to administer 
and safe method of assessing lean body mass. BIA involves passing a small 
electrical current through the body and evaluating the reactance and resistance to 
flow, which are related to fat-free mass (FFM) and total body water. Prediction of 
lean body mass from BIA is as reliable as skin-fold measurements and hydrostatic 
weighing. Participants have the option to be 4 hours fasted, although it is not 
required. Participants need to be abstained from alcohol and diuretics (unless 
prescribed) for 48 hours, well hydrated (water only), and voided completely prior 
to assessment. Participants lie supine on a flat surface for approximately 5 
minutes prior to the test, to ensure a resting metabolic state. Electrodes are 
attached to the right hand (proximal phalanx of the 3rd finger and the radiocarpal 
joint), and the right foot (distal end of the 3rd and 4th metatarsal and distal end of 
the tibia and fibula). Skeletal muscle mass will then be calculated from the lean 
body mass.

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7.2.6. Muscle strength testing
Upper extremity muscle strength will be assessed using a handgrip 
dynamometer.104 
The Handgrip Dynamometer Test is a grip strength test used to assess the 
maximal voluntary contraction generated by the arm muscles. The test is 
administered with the patient standing in anatomical position; the elbow joint 
angle will be held constant at 90 degrees with the medial distal humeral 
epicondyle held 2 inches from the torso. Trials will be performed in an alternating 
bilateral sequence for a total of six attempts (three with each arm). The best score 
of the three trials will be used for right and left limbs to calculate static strength. 
The surgically involved arm(s) will be noted for data analysis. The handgrip 
dynamometer test has been previously used in a number of URCC NCORP 
protocols and has shown to be a reliable clinical method of assessing upper 
extremity strength.
Lower and upper extremity muscle strength will be assessed using the isokinetic 
muscular strength test. We will use an isokinetic knee flexion/extension for lower 
extremities and seated shoulder diagonal for upper extremities. If seated shoulder 
diagonal cannot be performed (e.g., prior shoulder injury), elbow 
flexion/extension will be performed instead. An exercise physiologist will provide 
a full orientation to the isokinetic machine including: aligning subject into 
position, setting range of motion, and conducting a warm up set. The exercise 
physiologist will be present during the test to ensure proper form and subject 
comfort. After the warm up set, subjects will complete a single set per side. 
Subjects will exert maximal force through their entire range of motion, moving at 
a set speed in degrees per second against the lever arm. Subjects will rest for 
approximately 3 minutes between sets. This isokinetic protocol will allow us to 
measure peak torque, maximal work, total work, and average power for each 
movement. We will use a Biodex System 4 Pro, which has been used successfully 
in over 1,000 research studies and is both safe and accurate in measuring 
muscular function.120
Muscle activation during strength testing (isokinetic muscular strength test) will 
be assessed using electromyography sensors. The BTS FREEEMG 1000 is a 
wireless EMG system that directly measures muscle activity. The system uses 
eight miniaturized probes with active electrodes for signal acquisition and 
transmission for EMG, angles, speed, acceleration, and pressure assessment. The 
probes include on-board memory. The subject will have full range of motion 
during task execution. BTS FREEEMG can measure the movement of any muscle 
activity, is analyzed by the BTS EMG-Analyzer software, and integrates with the 
BioDex. Probes will be applied to subject’s skin surface over the muscle used 
during knee flexion and extension and elbow flexion extension repetitions.

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Height and weight will be assessed using the Blue Bell Bio-Medical SR 
Instruments Model 500. We will also measure waist circumference with a Gulick 
tape measure. Height, weight, and waist circumference will be assessed at each 
PEAK lab visit to help estimate body composition. Waist circumference will be 
measured from the narrowest portion above the umbilicus and below the zyphoid 
process. 
7.2.7. Heart Rate Variability (HRV): HRV measures variation in consecutive 
heartbeat intervals. It provides acute measures of physiological recovery. HRV 
data will be collected for 5 minutes and assessed using the Firstbeat® system. 
Firstbeat® is a portable device consisting of two electrodes (one above and below 
the ribcage) placed on the patient. 
7.3. Post-Intervention Assessment of the Participants
At the post-intervention assessment, all subjects will continue to wear their Garmin 
activity tracker for 4-7 days. Study staff will collect the tablet from the participants. 
Participants will keep the EXCAP exercise kit. In addition to the assessments above, we 
will assess the intervention usability. We will also conduct an exit interview either in-
person or via zoom/phone to elicit app functionality and barriers to adherence to the 
intervention.
7.3.1. Intervention Usability105,106
System Usability Scale is a standardized questionnaire used to assess participants’ 
perceptions of usability. This robust and reliable scale consists of a 10-item 
questionnaire with each item rated on a 5-point Likert scale (see Appendix). The 
scores for each question will be converted to a new number (odd-numbered 
questions are calculated as the scale position minus 2, and even-numbered 
questions are calculated as 5 minus the scale position), added together, and then 
multiplied by 2.5 to get the final score (ranging from 0 to 100).
7.4. Assessment of inflammatory markers (Exploratory Aim 2)
Using blood samples, we will assess the blood concentrations of several inflammatory 
markers. All blood draws will occur in the Wilmot Cancer Center, a UR-affiliated lab, or 
medical office if needed (in the latter case, we will use a trained study staff member to 
transport the samples to our storage facility). The location will be selected to minimize 
subject burden and if possible we will perform blood draws at the same time as a 
regularly scheduled medical blood draws. The blood will be drawn by trained staff. The 
time of day will be noted, with future assessments at approximately the same time of day 
during post-testing. Fasted blood samples (4-6 hours prior to blood with encouragement 
to maintain hydration) will be drawn. If the blood sample is not fasted, we will still 

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collect the blood sample and note the last time the person ate in the research record. All 
subjects will be provided with a $10 gift card for a café at URMC.
A total of approximately 50 mL of blood (around 4-5 tablespoons) will be drawn at 
baseline and post-intervention. All tubes will be collected by a study team member, 
processed, and then transferred to a secured -80°C freezer in lab space maintained by Dr. 
Janelsins in the Department of Surgery. We will collect the following:
1. One red-top tube for serum (9 mL each). This tube will be inverted 10 times, allowed 
to clot for 30 minutes at room temperature, centrifuged for 15 min at 1600 g and then 
frozen at -20°C or -80°C. These will be used to assess inflammation (cytokines, etc.).
2. Two purple-top EDTA tubes for DNA methylation and plasma analyses (9 mL each, 
18 mL total). This tube will be inverted 10 times and allowed to sit at room temp for 
30 minutes, centrifuged for 15 min, and then frozen at -20°C or -80°C. 
3. Two green-top tubes for peripheral blood mononuclear cells (9 mL each, 18 mL 
total). These will be pre-cooled and processed per SOP. This tube will be inverted 10 
times and allowed to sit at room temp for 30 minutes, centrifuged for 15 min, and 
then frozen at -20°C or -80°C. 
4. Two paxgene tubes for gene expression analyses (2.5 mL each, 5 mL total). This tube 
will be inverted 10 times and allowed to sit at room temp for 2-24 hours. Then they 
will be frozen at -20°C and moved to -80°C for long-term storage.
Inflammatory cytokines will be assessed using the latest available technology (e.g., in 
vitro enzyme-linked immunosorbent assay; ELISA). These assays will assess the 
concentration of inflammatory cytokines including TNFα, sTNFR1, sTNFR2, IL-1β, IL-
6, sIL-6R, IL-8, IL-10. Cytokine analyses will be performed at Dr. Michelle Janelsin’s 
lab.
For DNA methylation analysis, genomic DNA will be isolated from peripheral 
mononuclear cells with a DNeasy Blood and Tissue Kit (Qiagen) and quantified with the 
NanoDrop 1000 spectrophotometer. TNFα gene promoter methylation will be quantified 
using bisulfite pyrosequencing.107 Briefly, genomic DNA (1000 ng) will be bisulfite 
converted (converts cytosine to uracil but leaves 5-methylcytosine residues unaffected) 
using the Epitect Plus Bisulfite Conversion Kit (Qiagen). Using TNFα-specific primers, 
the region of interest will be amplified by PCR with the PyroMark PCR kit (Qiagen). 
Pyrosequencing analysis will be used to measure DNA methylation in the TNFα 
promoter region from −360 to +50 base pairs (containing 12 CpG sites) using the 
PyroMark Advanced Q24 (Qiagen).108 We selected these 12 CpG sites based on a prior 
study which showed that total methylation and methylation at -245 bp correlated with 
serum TNFα levels.108 Methylation at -170bp and -120bp also predicted response to a 
lifestyle behavioral intervention.108 In addition, the majority of known regulatory 
transcription factor binding sites (e.g. NF-κB, Sp-1, Egr1)109 within the TNFα gene 
promoter region are located in this region. Other cytokine gene promoter methylation will 
be analyzed as per TNFα (promoter regions will be determined based on previous 
studies).110–112 DNA methylation analyses will be performed at Dr. Martha Susiarjo’s lab.

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For gene expression, RNA will be extracted using the RNeasy Mini Kit (Qiagen) 
according to the manufacter’s protocol and quantified using the NanoDrop 
spectrophotometer.107 cDNA will be will be prepared by RT-PCR using Superscript IV 
reverse transcriptase and random hexamers (Invitrogen). qPCR analysis will be 
conducted using the Applied Biosystems QuantStudio 5 Real-Time PCR system using 
TNFα and cytokine gene-specific primers. Relative expression of TNFα and related genes 
will be calculated using the comparative Ct method, and measurements will be 
normalized to expression of two reference genes. Gene expression analyses will be 
performed at Dr. Martha Susiarjo’s lab.
All human biological materials will be disposed of in adherence with the University of 
Rochester Office of Environmental Safety Biosafety Level II requirements. All 
laboratories used in the current study have received appropriate biosafety certifications 
by the University of Rochester Institutional Biosafety Committee and undergo routine 
inspections. All samples will be de-identified before being stored. 
7.5. Data specimen banking for future research
We will bank blood samples for use in future studies to assess other inflammatory 
markers and genome wide DNA methylation analysis. We will also keep remaining 
samples for future research by Dr. Loh and her research team. The consent form includes 
a section asking whether subjects agree to have their samples banked for future studies by 
Dr. Loh and her research team.
Genome wide DNA methylation [with subsequent DNA methylation age (DNAm age 
analysis) will be performed at Genomic Shared Resource at Roswell Park Cancer 
Institute. We are in the process of obtaining an MTA with Roswell. After processing, 
stored blood is aliquoted and identified using study ID. No patient identifiers are included 
in the label. Aliquotes will be sent to Roswell Park. DNA methylation microarray assay 
will be performed using the Illumina Infinium® Methylation EPIC Array platform, an 
oligonucleotide array that interrogates >850,000 CpG dinucleotides per sample, in 
accordance with the manufacturer’s instructions. The raw data will be processed by the R 
package “minfi”, and converted to methylation ß-value, ranging from 0 to 1, with 0 being 
unmethylated and 1 being fully methylated, to represent the methylation level of each 
CpG site. Potential residue batch effects will be inferred from the data using a Surrogate 
Variable Analysis (SVA), and the ComBat algorithm will be used for correction. 
Rigorous quality-control criteria will be used for filtering at both the locus and sample 
levels. The final data will be supplied to the DNAm age estimation algorithms.

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8.0. DATA HANDLING AND STATISTICAL CONSIDERATIONS:  
8.1. Data Handling
8.1.1. The same protocols and procedures for data quality and control that are 
readily used for the NCI Community Oncology Research Program (NCORP) 
Research Base protocols currently being overseen by our office (which have 
accrued over 1,000 patients in the previous year) will be used for this study. 
Patients will fill out forms generated from RedCap and this information will be 
entered into RedCap (Section 9.5). Study personnel will perform SPPB and the 
scores will be entered into RedCap.   
8.1.2. It is anticipated that allowing for the appropriate number of evaluable 
participants and by checking self-report measures for completeness, we will have 
a full complement of data. Every effort will be made to encourage and facilitate 
participants’ completion of all questionnaires and all items on the questionnaires 
for each study assessment.  In the event that missing data occur, every effort will 
be made to contact participants via phone and obtain the data or to find out why 
the questionnaires or items are missing.  The reasons for missing data will be 
documented. Missing questionnaire items will be treated in accordance with the 
documented scoring procedures. Although it is very unlikely that missing values 
will not occur randomly, we will confirm their randomness.  Multiple 
imputation113 will be applied to (1) give more accurate statistical tests and 
standard errors for key treatment effect parameters and to (2) give some indication 
of the sensitivity of the analyses to missing data.  The causes and pattern of the 
missing data will be examined and taken into consideration in the design of future 
studies.
8.1.3. Data collected with the tablets and Garmin activity trackers will only be 
accessed by the following: 1) The research team including the exercise 
physiologist, 2) The treating physician and their designee, and 3) PointClick Care 
company. The research team and exercise physiologist will each have a username 
and password to access the tablets and devices. The PointClick Care company 
will have access to the data on the tablets. As discussed above, PointClick 
Care encrypts all PointClick Care data transferred between backend servers and 
the tablets. Communications to the server is validated by signed trusted server 
certificate. Data at rest is always encrypted. PointClick Care caches data on the 
tablet, and stores data on a PointClick Care server. On the tablet the cache in 
encrypted, the backend server hosts a Microsoft SQL Server database. The 
volume used by SQL Server is encrypted. Only the PointClick Care app, with a 
valid authentication key, can read this data. If the electronic data is breached, 
PointClick Care has a means to disable the PointClick Care app on a tablet. This 
feature only works, however, if the Tablet is connected to the server. We will also 
inform the study participants if the breach has occurred. Users are not able to exit 
the app from the tablet. If the tablet is lost or stolen, PointClick Care has a means 
to disable the PointClick Care app as soon as it is turned on. If the tablet is 

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broken, it will be replaced with a new one (all data within the tablet will be 
erased).
8.1.4. We are currently communicating with OPRA regarding the need for a data 
use agreement with the PointClickCare company.
8.2. Data Analysis and Sample Size:
8.2.1. Analysis Plan for Aim 1
Our planned sample size (N=15) will allow us to achieve thematic saturation. We 
will conduct and audio-record all interviews, which will be transcribed by a 
professional transcription service. We will analyze the qualitative data using 
grounded theory and constant comparative methods, with coding to structure data 
into categories and create groups according to the broader issues or themes.114 An 
audit trail of the coding activity will be kept. We will critically examine the data 
collection and analysis process and reach consensus on key themes from patient 
feedback to be used to adapt the intervention in preparation for Aim 2. 
8.2.2. Analysis Plan for Aim 2
The feasibility of the GO-EXCAP Mobile App will be evaluated based on the 
following: a) Percentage of patients wearing the activity tracker and entering 
resistance exercise data into the mobile app and b) Percentage of patients 
performing both walking and resistance exercises during the study period days. 
Recruitment rates (percentage of patients who are approached and agree to enroll) 
and retention rates (percentage of patients who are enrolled and complete post-
intervention assessments) will also be described
We will consider the intervention feasible if 1) ≥70% of patients wear the activity 
tracker and enter resistance exercise data into the mobile app on at least 50% of 
the study period days, and 2) ≥70% of patients performed both walking and 
resistance exercises on at least 50% of the study period days. We chose these 
criteria based on our previous mobile app study16 and on published exercise 
studies in older patients with AML.29,30 We will report percentage of adherence 
with 95% exact confidence interval (CI) calculated by the Clopper-Pearson 
method. We anticipate that about 20-30% of the participants will withdraw before 
post-intervention assessment due to rapid disease progression or death. These 
patients will not be included in the feasibility analysis because their withdrawals 
from the study are not related to the intervention. With 25 patients enrolled we 
anticipate at least 17 patients to be evaluable for our feasibility aims. When we 
estimate the percentage of adherence, a 95% CI will span approximately +/- 25%. 
For example, if we observe 12/17 (71%) patients complete the tasks, the CI will 
be 44-90%. 

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We will also tabulate the recruitment rates, retention rates, and intervention 
usability, and collect the reasons patient decline to be enrolled. In addition, we 
will evaluate the distribution and describe the following measures using 
descriptive statistics: 1) activity levels, 2) physical function (SPPB/vSPPB), 3) 
fatigue (BFI), 4) depression (CES-D Scale), 5) quality of life (FACT-Leu), and 6) 
Other geriatric assessment measures. Differences in activity levels, physical 
function, fatigue, depression, quality of life, and other geriatric assessment 
measures between pre- and post-treatment will be assessed using paired t-tests or 
Wilcoxon signed rank tests. Anticipated sample size of more than 12 patients with 
baseline and follow-up data will be sufficient to obtain the preliminary estimates 
of the outcomes measures.115,116 
Qualitative data from the exit interviews will be analyzed as per Aim 1. 
Interviews will be conducted, audio-recorded, and transcribed. Two trained 
“coders” will utilize a multi-step process using coding and content analysis, with 
coding to structure data into categories and creating groups according to the 
themes.114 We will identify themes that emerge within each content area. I will 
discuss these results with my study personnel and Dr. Mohile every two weeks to 
critically examine the data collection and analysis process, provide critical 
feedback on emerging codes, and reach consensus on principal themes to be used 
to optimize the intervention. For every five patients, we will use the principal 
themes to optimize the intervention in an iterative process. We will identify 
patients who are not entering their daily steps or the resistance training data into 
the app. For these patients, we will elicit specific barriers and explore the 
relationship between these barriers and exercise adherence. We anticipate that the 
barriers to exercise adherence will be modifiable (e.g., symptoms, lack of self-
motivation, and lack of knowledge of the benefits of exercise) or non-modifiable 
(e.g., caregiving obligations, hospitalizations). The intervention will be optimized 
based on the following modifiable barriers, such as: a) Symptoms (e.g., fatigue, 
soreness): Monitor symptoms with automated self-management feedback and/or 
notification to the healthcare team; b) Lack of self-efficacy: Provide reassurance 
and motivational messages through the app; c) Lack of knowledge: Provide 
education on the benefits of exercise.  
8.2.3. Analysis Plan for Exploratory Aim
Descriptive analysis will be used to describe cytokine gene promoter methylation 
(global % methylation of the gene promoter region and % methylation of each of 
the identified CpG sites) and gene and protein expression at baseline and post-
intervention. Changes from baseline to post-intervention will be compared using 
paired t-tests. We will use Spearman’s correlation to assess relationships between 
methylation status and gene and protein expression, as well as activity level and 
clinical measures. We will adjust for multiple comparisons using the Benjamini–
Hochberg method.117

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9.0. DATA MANAGEMENT 
9.1. Data Collection Table (Aim 2)
 
SCHEDULE OF DATA COLLECTION
 
Eligibility 
and 
Consent 
Form
Baseline 
Assessment 
(week 0)
Mid-
Intervention 
Assessment 
(week 3-5)
Post-
intervention 
Assessment* 
(week 8± 4)
Written Informed Consent
X
 
 
 
Demographics
 
X
 
Cancer and Treatment 
Characteristics
 
X
 
Qualitative Interview
X
X
Activity Levels (Activity 
Tracker)
X
X
Exercise Habits and 
Readiness
X
Short Physical Performance 
Batteryb/Virtual Short 
Physical Performance 
Battery
 
X
X
Brief Fatigue Inventory 
(BFI)
 
 X
 
X 
Center for Epidemiologic 
Studies Depression Scale 
(CES-D)
 
 X
 
X 
Functional Assessment of 
Cancer Therapy-Leukemia 
(FACT-Leu)
 
 X
 
X 
Self-Efficacy for Exercise
X
X
Actigraphyb,d
X
X
Geriatric Assessment 
Measures

Activities of Daily 
Living
X
X

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
Instrumental 
Activities of Daily 
Living

Fall History

6-Minute Walk 
Testb,d 

Montreal Cognitive 
Assessment (MoCA 
or MOCA Blind)
Bioelectrical Impedance 
Systema.b,d
X
X
Handgrip Dynamometerb,d
X
X
Muscle Strength Testinga.b,d
X
X
Heart Rate Variabilitya,b,d
X
X
Feasibility metrics
 
X
System Usability Scale
 
X
Complete blood count (from 
electronic medical record)
 
X
X
Blood samplesb
 
X
X
aIf patient elects to undergo the assessments at the cancer center instead of the Physical Exercise, Activity 
and Kinesiology laboratory, these assessments will not be conducted.
bMay be omitted for patient safety (i.e., if in-person assessments are not possible)
dIf research activities are conducted at Wilmot affiliated sites, these assessments may be omitted 
9.2. All hardcopy research records will be stored onsite in the URMC, in locked research 
files at the James P. Wilmot Cancer Center.  The Cancer Center is secured with electronic 
key cards. Offices within the Cancer Center are again secured by key and data is kept in 
locked file cabinets. Electronic research records are stored on the URMC’s password 
secured and firewall protected networks. These are the same methods of security used for 
patient medical records. All study data (including the electronic data kept by the 
PointClick Care company) will be kept for a period of 7 years after the study and all 
reports and publications are complete. 
9.3. All data collected for the current study will be used in post hoc analyses as 
appropriate. Data will not be used for future studies without prior consent of the patient.  
The patient’s individual research record will not be shared with their treating physician, 
unless they provide consent or the patient’s treating physician is a study physician, in 
which case they will have access to study data as a study co-investigator.  Overall study 
results will be presented to participants, faculty and staff at the URMC after completion 
of the study. Study results will be presented at professional meetings and published.

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9.4. The study coordinator will assign a numerical study ID to each participant once they 
have signed the consent form (chronologically based on the data they signed consent i.e., 
001, 002, 003…). All study forms and questionnaires will use this number and the 
participant’s first, middle, and last initials as identifiers, to ensure data integrity.  Other 
identifying information will not exist on these forms. A complete list of study participants 
with study ID, name, and contact information will be maintained separately. This linkage 
information will only be accessible to the study coordinator, study investigators, and the 
individuals responsible for maintaining the database.  
9.5. Additionally, data on the socio-demographics, clinical, cancer and treatment 
characteristics will be collected and managed by the research teams at URMC using 
REDCap electronic data capture tools hosted at URMC.118 We will also evaluate the 
medical records for clinical characteristics and outcomes, and utilize REDCap to collect 
and manage this information. 
9.5a. URMC provides the following information on the REDCap program: 
“Vanderbilt University, in collaboration with a consortium of institutional partners, 
has developed a software toolset and workflow methodology for electronic 
collection and management of research and clinical trial data, called REDCap 
(Research Electronic Data Capture). The REDCap system is a secure, web-based 
application that is flexible enough to be used for a variety of types of research. It 
provides an intuitive interface for users to enter data and real time validation rules 
(with automated data type and range checks) at the time of data entry. REDCap 
offers easy data manipulation with audit trails and functionality for reporting, 
monitoring and querying patient records, as well as an automated export mechanism 
to common statistical packages (SPSS, SAS, Stata, R/S-Plus). Through the 
REDCap Consortium, Vanderbilt has disseminated REDCap for use around the 
world. Currently, over 240 academic and non-profit consortium partners on six 
continents with over 26,000 research end-users use REDCap.119 
9.5b. According to the Clinical and Translational Science Institute (CTSI), REDCap 
is supported with the following means. “The CTSI Informatics Core, a unit of the 
SMD Academic Information Technology (AIT) Group, will serve as a central 
facilitator for data processing and management.  REDCap data collection projects 
rely on a thorough study-specific data dictionary defined in an iterative self-
documenting process by all members of the research team, with planning assistance 
from the AIT-CTSI Informatics Core. The iterative development and testing process 
results in a well-planned data collection strategy for individual studies.”119 
9.5c. The CTSI states that regarding security, “REDCap servers are housed in a 
local data center at the University of Rochester and all web-based information 
transmission is encrypted. REDCap was developed in a manner consistent with 
HIPAA security requirements and is recommended to University of Rochester 
researchers by the URMC Research Privacy Officer and Office for Human Subject 
Protection.119 

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10.0. RISKS/BENEFITS 
10.1. Risks
There are two potential risks associated with participation in the proposed study: 1) 
physical harm associated with intervention procedures, and 2) loss of confidentiality.
10.1.1. In terms of physical harm associated with intervention procedures, 
commencement of a moderate walking and progressive resistance exercise 
program is not associated with any severe side effects and risks are minimal for 
individuals with no cardiopulmonary, orthopedic, or age identified risk factors as 
determined by a physician. The absolute chance of a cardiac event among adults 
while engaging in vigorous exercise is one per year for every 15,000 to 18,000 
people. A transient increase in blood pressure may occur with all types of 
exercise. Although unlikely, a low to moderate walking and progressive resistance 
exercise program may also cause musculoskeletal effects, such as mild muscle
soreness, a muscle strain, or other related accidental injuries such as tripping. 
Overall, the risk level for participation in the proposed low to moderate intensity 
exercise program is minimal.
10.1.2. In terms of loss of confidentiality, quantitative data from participants will 
need to be stored. Though rigorous and well-tested data safety and security 
guidelines will be observed, there is still a chance that confidentiality could be 
breached and sensitive medical information could become known to persons 
outside the research team.
10.2. Benefits
Patients participating in the first aim will be paid $30 and those participating in the 
second aim will be paid $50 for their participation in the form of gift cards. For Aim 1, 
patients will receive the gift cards immediately following the interviews. For Aim 2, 
patients will be paid for completion of the post-intervention assessment. Patients in Aim 
2, patients may also keep the exercise kit and activity tracker at study completion (value 
$150).

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11.0. DATA SAFETY AND MONITORING 
Only adverse events (AEs) related to the study intervention or procedures will be 
reported. In other words, AEs related to cancer treatment will not be reported.
11.1. Adverse Event Reporting Requirements
11.1.1. Adverse events will be reported using the URCC Adverse Event form 
and/or as required by the Cancer Center Clinical Trials Office.  
11.1.2. Adverse events will be reported in accordance with the following 
guidelines:
11.1.3. Adverse event reports will be submitted in one of the following ways:
(1) By email: (pdf)
(2) By mail:
(3) By fax:
11.1.4. An unexpected adverse event is defined as any adverse experience, the 
specificity or severity of which is not consistent with the risk information. This is 
a minimal risk study as both exercise and mobile app-driven interventions have 
been shown to improve outcomes in community-dwelling older adults.  
11.1.5. A serious event refers to any event in which the outcome results in any of 
the following: death, a life-threatening adverse experience, inpatient 
hospitalization or prolongation of existing hospitalization, a persistent or 
significant disability, incapacity, or a congenital anomaly/birth defect. Important 
medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based 
upon appropriate medical judgment, they may jeopardize the participant and may 

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require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. We anticipate that any serious events will be related to standard of 
care cancer treatments and not due to the intervention. We will not collect adverse 
events related to cancer treatments.
11.1.6. Adverse events will be reported in accordance with institutional policies 
(University of Rochester, Research Subject Review Board, local IRB, URCC 
CCOP, CTO, and DSMB) as per their requirements. 
11.2. Data Safety Monitoring
11.2.1. All adverse events requiring reporting will be submitted to the current 
Project Coordinator as described in Section 11.1. Serious adverse event reports 
will be forwarded to the study chair and the Data Safety and Monitoring 
Committee (DSMC). Adverse events are entered into a protocol-specific 
spreadsheet.  
11.2.2. Adverse event rates are monitored utilizing the spreadsheet. If a serious 
adverse event is reported frequently, the study chair will conduct a detailed 
review. The DSMC Committee Chair will be notified and will determine if further 
action is required.
11.2.3. The Data Safety Monitoring Committee (DSMC) will review study 
progress and cumulative reports of adverse events every year and as needed. An 
overall assessment of accrual and adverse events will enable the committee 
members to assess whether significant benefits or risks are occurring that would 
warrant study closure.  

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