The Impact of Inspiratory Muscle Strength Training and Personalized Exercise Prescription on Metabolism, Cardiovascular Function, and Cardiorespiratory Fitness in Lymphoma Survivors
Phase: NA
Conditions: Hodgkin Lymphoma, Non Hodgkin Lymphoma
Sponsor: University of Colorado, Denver

Protocol and Analysis 
 
Project Title: The impact of inspiratory muscle strength training and personalized exercise 
prescription on metabolism, cardiovascular function, and cardiorespiratory fitness in lymphoma 
survivors 
 
NCT: NCT05938127 
 
Version Date: 8/28/2024 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 1 
CF-146, Effective 7/10/11 
 
Project Title: The impact of inspiratory muscle strength training and personalized 
exercise prescription on metabolism, cardiovascular function, and 
cardiorespiratory fitness in lymphoma survivors 
 
 
Protocol #: 22-1216 
 
 
 
Principal Investigator: Ryan Marker, PT, PhD 
 
Co-investigators:  
Travis Nemkov, PhD  
 
 
 
 
Lavanya Kondapalli, MD 
 
Study MD: Lavanya Kondapalli, MD 
 
Version Date:  
8.28.24 
 
  
 
 
PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change 
Brief Rationale  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 2 
CF-146, Effective 7/10/11 
 
Contents 
1. STATEMENT OF COMPLIANCE ................................................................................................... 3 
2. LIST OF ABBREVIATIONS ............................................................................................................ 4 
3. SYNOPSIS ...................................................................................................................................... 4 
4. RATIONALE AND BACKGROUND ................................................................................................ 6 
5. RESEARCH METHODS ................................................................................................................. 7 
5.1 Outcome Measures ............................................................................................................... 7 
5.2 Description of Population to be Enrolled ............................................................................... 9 
6. STUDY DESIGN AND RESEARCH METHODS .......................................................................... 11 
6.1 Experimental Design ........................................................................................................... 11 
6.2 Screening and Recruitment ................................................................................................. 12 
6.3 Study Procedures ................................................................................................................ 12 
6.4 Summary of Knowledge to be Gained ................................................................................. 15 
6.5 Potential Obstacles .............................................................................................................. 15 
7 STATISTICAL CONSIDERATIONS ............................................................................................... 16 
8. RISKS AND JUSTIFICATION OF PROCEDURES AND DATA COLLECTION TOOLS ............. 16 
8.1 Potential Risks and Risk Mitigation ..................................................................................... 16 
8.2 Potential Benefits ................................................................................................................. 18 
8.3 Assessment of Potential Risks and Benefits ....................................................................... 19 
9 STUDY DISCONTINUATION ........................................................................................................ 19 
9.1 Discontinuation of Study ...................................................................................................... 19 
10 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM STUDY ........................................ 19 
11 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS ......................................................... 20 
11.1 Definition of Adverse Events (AE) ..................................................................................... 20 
11.2 Definition of Serious Adverse Events (SAE) ..................................................................... 20 
11.3 Classification of an Adverse Event .................................................................................... 20 
12 UNANTICIPATED PROBLEMS ................................................................................................... 21 
12.1 Definition of Unanticipated Problems (UAPs) .................................................................... 21 
12.2 Reporting of Unanticipated Problems ................................................................................ 21 
13 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS ............................ 22 
13.1 Informed Consent Process ................................................................................................ 22 
13.2 Confidentiality and Privacy ................................................................................................ 22 
13.3 Future Use of Stored Specimens or Data ......................................................................... 23 
13.4 Data Safety Monitoring ...................................................................................................... 23 
13.5 Quality Assurance and Quality Control ............................................................................. 24 
13.6 Data Handling and Record Keeping .................................................................................. 24 
13.6 Protocol Deviations ............................................................................................................ 24 
13.7 Publication and Data Sharing Policy ................................................................................. 25 
13.8 Conflict of Interest Policy ................................................................................................... 25 
14 REFERENCES ............................................................................................................................ 25 
 
 
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 3 
CF-146, Effective 7/10/11 
 
1. STATEMENT OF COMPLIANCE 
This is an investigator-initiated study.  The principal investigator (PI), Dr. Ryan Marker, is 
conducting the study and acting as the sponsor.  As the sponsor-investigator, both the 
legal/ethical obligations of a PI and those of a sponsor will be followed. 
 
The trial will be carried out in accordance with Good Clinical Practice as required by 
applicable United States (US) laws and applications, including but not limited to United 
States (US) Code of Federal Regulations applicable to clinical studies (45 Code of 
Federal Regulations Part 46). 
 
The PI will assure that no changes to the protocol will take place without documented 
approval from the Colorado Multiple Institutional Review Board (COMIRB). All personnel 
involved in the conduct of this study have completed Human Subjects Protection Training.  
 
I agree to ensure that all staff members involved in the conduct of this study are informed 
about their obligations in meeting the above commitments.  
 
 
 
Sponsor-Principal Investigator:   Ryan J Marker, PT, PhD 
 
  
 
 
 
 
 
 
                        Print/Type Name  
 
 
 
 
 
Signature:  
 
 
 
 
Date: 1-17-2023 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 4 
CF-146, Effective 7/10/11 
 
2. LIST OF ABBREVIATIONS 
AE 
Adverse event 
CRF 
Cardiorespiratory fitness 
VO2max 
Maximal uptake of oxygen 
CTRC 
Clinical and Translational Research Center 
QC 
Quality control 
REDCap 
Research Electronic Data Capture 
SAE 
Serious Adverse Event 
UAP 
Unanticipated Problem 
BMI 
Body mass index 
AHWC 
Anschutz Health and Wellness Center 
IMST 
Inspiratory muscle strength training 
6MWT 
6-minute walk test 
SBP 
Systolic blood pressure 
NO 
Nitric Oxide 
ROS 
Reactive Oxygen Species 
CVD 
Cardiovascular disease 
 
 
 
 
 
 
 
 
 
 
3. SYNOPSIS 
Protocol title: 
The impact of inspiratory muscle strength training and personalized exercise 
prescription on metabolism, cardiovascular function, and cardiorespiratory 
fitness in lymphoma survivors 
 
 
Objectives & 
hypotheses: 
 
Cancer survivorship has been steadily improving as a result of earlier 
detection and improved therapies. Behind cancer recurrence, the primary 
cause of morbidity and mortality among survivors stems from the onset of 
cardiovascular disease that arises in part due to cardiotoxic chemo and 
radiation therapies. The increased risk of cardiovascular disease is 
particularly high in specific survivor populations, such as lymphoma 
survivors. Although exercise has been demonstrated to improve both 
recovery after cancer therapy and quality of life, both physical and logistical 
hurdles may prohibit certain patients from accessing this intervention. High-
resistance inspiratory muscle strength training (IMST) is a time-efficient (~5 
minutes/day) form of exercise that employs an affordable, handheld device 
which impedes inspiratory breathing to train the diaphragm and accessory 
respiratory muscles and has demonstrated improvements in both 
cardiovascular health (9 mmHg reduction in systolic blood pressure, 45% 
improvement in vascular endothelial function) and improve exercise 
tolerance (12% increase in treadmill exercise time) in generally healthy 
midlife/older adults. Therefore, this approach may circumvent preventative 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 5 
CF-146, Effective 7/10/11 
 
hurdles to exercise, and augment the effects of exercise for capable 
survivors. 
 
Primary Objectives: 
Aim 1: Assess the feasibility of recruitment, assessment, and delivery of 
the proposed investigation. 
Objective: Measure the recruitment rate of eligible participants (total 
recruitment, enrolled participants/month), assessment completion (number of 
valid assessments/participant), and intervention delivery (session 
attendance/participant, total participants completing intervention and control 
intervention), in order to inform a robust subsequent efficacy trial. 
 
Aim 2: Determine the impact of 6 weeks of IMST alone and combined 
with a 12-week individualized exercise program on improving systolic 
blood pressure in lymphoma survivors. 
Hypothesis: Participants receiving IMST, compared to those receiving sham 
(low-resistance) IMST, will demonstrate significantly greater improvements 
in systolic blood pressure (SBP) after IMST alone and combined with a 12-
week exercise program. 
 
Secondary Objective:  
Aim 3: Determine the impact of 6 weeks of IMST alone and combined 
with a 12-week individualized exercise program on improving measures 
of cardiorespiratory fitness, physical performance, and cardiovascular 
health in lymphoma survivors. 
Hypothesis: Participants receiving IMST, compared to those receiving sham 
IMST, will demonstrate significantly greater improvements in 
cardiorespiratory fitness (estimated VO2max), physical performance (6 minute 
walk test [6MWT]), and molecular markers of cardiovascular health (nitric 
oxide and reactive oxidative species production) after IMST alone and 
combined with a 12-week exercise program. 
Aim 3: Identify molecular signatures of cardiovascular fitness in 
lymphoma survivors using mass spectrometry-based metabolomics and 
quantify impact of BfitBwell and IMST interventions. 
 
Endpoint: 
Primary Endpoints: 
Feasibility: Total participants recruited, enrolled participants per month, 
valid assessments per participant, session attendance per participant, total 
participants completing the intervention (and control intervention). 
 
Efficacy: SBP at baseline, post-IMST, and post-IMST+BfitBwell 
 
Secondary Endpoints: 
Metabolomic exercise profiles at baseline, post-IMST, and post-
IMST+BfitBwell 
6MWT at baseline, post-IMST, and post-IMST+BfitBwell 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 6 
CF-146, Effective 7/10/11 
 
Estimated VO2max at baseline, post-IMST, and post-IMST+BfitBwell 
Molecular markers of cardiovascular health (nitric oxide [NO] and reactive 
oxygen species [ROS] production) at baseline, post-IMST, and post-
IMST+BfitBwell 
 
Population: 
Sample size 
Maximum number of participants that can be enrolled is 24.  
Minimum number of participants to be enrolled is 18.  
 
 
Participating 
sites: 
University of Colorado – Anschutz Medical Campus 
University of Colorado at Boulder 
 
 
Description of 
study 
intervention: 
18-week intervention (6-week IMST or sham alone + 12-week personalized 
exercise and IMST or sham)  
 
 
Study 
duration: 
2 years 
 
 
Participant 
duration:  
5 months 
4. RATIONALE AND BACKGROUND 
4.1 Rationale 
Cancer survivorship has been steadily improving as a result of earlier detection and improved 
therapies. Behind cancer recurrence, the primary cause of morbidity and mortality among 
survivors stems from the onset of cardiovascular disease that arises in part due to cardiotoxic 
chemo and radiation therapies. The increased risk of cardiovascular disease is particularly high in 
specific survivor populations, such as lymphoma survivors. Although exercise has been 
demonstrated to improve both recovery after cancer therapy and quality of life, both physical and 
logistical hurdles may prohibit certain patients from accessing this intervention. High-resistance 
inspiratory muscle strength training (IMST) is a time-efficient (~5 minutes/day) form of exercise 
that employs an affordable, handheld device which impedes inspiratory breathing to train the 
diaphragm and accessory respiratory muscles and has demonstrated improvements in both 
cardiovascular health (9 mmHg reduction in systolic blood pressure, 45% improvement in 
vascular endothelial function) and improve exercise tolerance (12% increase in treadmill 
exercise time) in generally healthy midlife/older adults. Therefore, this approach may circumvent 
preventative hurdles to exercise, and augment the effects of exercise for capable survivors. The 
goal of this proposal is to determine the effects of 6 weeks of low-barrier, time-efficient IMST 
on physical fitness and cardiovascular (CV) health in lymphoma survivors and identify 
cooperative effects in combination with a 12-week individualized exercise training program 
(BfitBwell). Mechanisms of IMST and exercise response will be further elaborated using 
metabolomics to define metabolic pathway utilization as a function of endurance and 
cardiorespiratory fitness. 
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 7 
CF-146, Effective 7/10/11 
 
4.2 Background 
As the quality of cancer diagnosis and treatment improves, 14 million cancer survivors are alive 
in the United States today and 19 million are expected by 2024.1-3 Among current survivors, 2 in 
3 will survive beyond 5 years after diagnosis, though this number decreases to 2 in 5 for 10-year 
survivorship.1-3 Exercise within this population is a demonstrated intervention to improve both 
recovery after therapy and quality of life.4 As such, the BfitBwell program was established 
between the CU Cancer Center and the Anschutz Health and Wellness Center to provide 12-week 
personalized exercise prescriptions for ~150 cancer survivors each year to maximize 
survivorship.5,6 Focusing on specific treatment-related causes of morbidity and mortality will 
further improve outcomes for cancer survivors. The 2nd highest cause of death in survivors behind 
cancer recurrence is cardiovascular disease (CVD; ischemic heart disease, stroke, or heart failure). 
Lymphoma patients have high incidence rate ratio of CVD compared to common cancers,7 which 
is attributed to cardiotoxic therapies such as anthracycline chemotherapy and radiation to the heart 
and vasculature.8-11 Ultimately, CVD diagnosis in cancer survivors results in a ~4-fold increased 
risk for all-cause mortality7 and therefore prevention or mitigation of CVD offers a therapeutic 
opportunity to improve lymphoma survivorship.   
  
CVD results from impaired CV function including increased blood pressure (BP), 
decreased vascular endothelial (VE) function, and arterial stiffening12 mediated by increased 
oxidative stress13 and decreased nitric oxide (NO) bioavailability.14 Aerobic exercise training is 
one of the most well-characterized interventions for improving CV function.6-9 However, only 
14% of cancer survivors15 are able to adhere to current aerobic exercise guidelines of 75-150 
minutes per week16,17 due to time constraints, physical limitations, cost, and transportation 
requirements. Inspiratory muscle strength training (IMST) offers an alternative CV intervention 
that circumvents many of these issues. IMST employs an affordable handheld device which 
impedes inspiratory breathing to train the diaphragm and accessory respiratory muscles.18 Previous 
work has demonstrated that repeated inhalations using an IMST device for as little as 5 min per 
day, 6 days/week over 6 weeks, has significant benefits for CV health (improved inflammatory 
and oxidative stress profiles, decreased BP and increased VE function), and increased time to 
exhaustion (TTE) during a standardized treadmill test.19  
  
Enhanced monitoring of exercise and IMST interventions also holds promise to improve 
survivorship. Physiological parameters such as VO2max and heart rate have been used as 
quantitative measures of physical fitness and performance underlying TTE, but they lack 
mechanistic resolution (i.e., utilized substrates and pathways). Mass spectrometry-based 
metabolomics, however, offers the ability to measure the levels of thousands of molecules that can 
contribute to these fitness parameters in a single analysis and requires minimal sample input. 
Changes in blood derived metabolic signatures are seen in healthy human subjects after IMST, 
such as correlations between fitness improvement (TTE) and increased acylcarnitines (functional 
in fat burning capacity) as well as decreased basal levels of succinate (a marker of improved tissue 
oxygenation)20. 
5. RESEARCH METHODS 
5.1 Outcome Measures   
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 8 
CF-146, Effective 7/10/11 
 
Feasibility measures. A primary outcome of this investigation is the feasibility of recruiting, 
assessing, and delivery the intervention to inform the design of a subsequent larger efficacy trial. 
These measures are total participants recruited, enrolled participants per month, valid 
assessments per participant, session attendance per participant, total participants completing the 
intervention. 
Adherence to 75% of the program (i.e. 75% of participants complete both pre and post 
assessments) and its components (i.e. participants complete 75% of prescribed exercise 
sessions, on average) will be deemed acceptable, as it is similar to adherence in the 
BfitBwell Program and other effective exercise interventions. 
 
Cardiovascular Health: Systolic blood pressure will be a primary outcome of this investigation. 
Molecular markers of cardiovascular health will be secondary outcomes. 
Casual blood pressure: Following 5 minutes of seated rest, systolic and diastolic blood 
pressure will be measured in triplicate under quiet, comfortable ambient laboratory 
conditions using a standard blood pressure cuff around the upper arm, following current 
recommendations for blood pressure evaluation.21 This will be performed by trained 
personnel at the University of Colorado Clinical and Translational Research Center 
(CTRC). 
Molecular markers: Serum will be used to perform experiments in which purchased 
cultured endothelial cells will be exposed to 10% serum from human subjects for 24 
hours. We will measure acetylcholine-stimulated production of nitric oxide (NO) and 
basal reactive oxygen species (ROS) production in endothelial cells following serum 
incubation. Serum will be collected via venipuncture performed at the CTRC and stored 
at -80°C until analysis. Samples will be transferred to the Integrative Physiology of 
Aging Laboratory at the University of Colorado Boulder for analysis. 
 
Cardiorespiratory Fitness (CRF): CRF will be assessed via estimated VO2max and is a secondary 
outcome. This will be measured by the Tecumseh Step Test. This is a valid, submaximal step 
test22 that has been used in cancer survivors previously23,24. Participants step on and off an 8” 
step for 3 min, at a metronome-controlled pace of 24 steps/min. Afterward, they immediately sit 
down, and heart rate is recorded at 30 s and 1 min after completion (using Polar H10 heart rate 
monitors). These recovery heart rates are then entered into a predictive formula, along with 
patient biometric information (age, weight, gender), to calculate an estimated VO2max25. This 
assessment is regularly performed by the BfitBwell Program with no adverse events. Participants 
will be asked to refrain from drinking caffeine for 4 hours prior to the test. 
 
Physical function. This will primarily be assessed by the 6MWT, routinely performed by 
BfitBwell Program staff at the Anschutz Health and Wellness Center (AHWC). Participants will 
be instructed to walk as far as possible in a six minute period on an indoor track. This is a 
secondary outcome. Other secondary measures of physical function will be collected by the 
BfitBwell Program, including grip strength, gait speed, timed up and go test, and 30 s sit-to-
stand. These measures will be collected as potential moderators or confounders of study 
outcomes (e.g. the influence of baseline fitness), inform the personalized exercise program, and 
provide insight on other benefits of the intervention. 
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 9 
CF-146, Effective 7/10/11 
 
Metabolomics analyses will be performed on blood samples collected during a standardized 
aerobic exercise session. Samples will be collected before exercise, immediately after, and after 
30 min of recovery. Samples will be collected with patient-centric Tasso+ devices (Tasso, Inc) 
which minimize the discomfort of collection. Approximately 0.3 mL of blood will be collected 
per sample, totaling approximately 1 mL per visit. These devices have been used with similar 
methodology in several previous investigations26. Samples will be centrifuged to isolate plasma 
and red blood cell fractions prior to storage in a -80°C freezer at the Anschutz Health and 
Wellness Center. Samples will be transferred for processing in the University of Colorado 
Cancer Center Metabolomics Core. This is a secondary outcome. Lipidomic and proteomic 
analyses will also be performed to supplement the metabolomic profiles and create hypothesis-
generating data for future trials. 
 
Other secondary outcome measures 
- 
Patient reported outcomes will collected similar to the BfitBwell Cancer Exercise 
Program and include the Functional Assessment of Cancer Therapy – General (FACT-G, 
assessing quality of life), Functional Assessment of Chronic Illness Therapy – Fatigue 
(FACIT-Fatigue), the Godin Leisure Time Physical Activity Questionnaire, and the 
Hospital Anxiety and Depression Scale (HADS). These outcomes will be collected using 
REDCap, a secure, university supported and approved data collection tool. These 
measures have been shown to be related to program adherence and outcomes27 and will 
be collected as potential confounders or moderators of the exercise program response and 
to inform on other benefits of the exercise program. 
- 
Cardiac risk factors will be collected from medical history forms regularly administered 
by the BfitBwell Program, which include: history of heart attack or surgery, history of 
cardiac catheterization, angioplasty, or pacemaker, history of valve disease or heart 
failure, current cardiac medications, history of recent smoking, high cholesterol (>200 
mg/dL). These risk factors will be included in secondary analyses to assess if participants 
at higher known risk of cardiac disease differ in their response to the intervention. 
 
All assessments will be done by study personnel who will be blinded to IMST vs sham 
randomization. 
5.2 Description of Population to be Enrolled 
We will enroll 24 lymphoma survivors who meet the below inclusion and exclusion criteria. The 
primary outcome of this study is a decrease in SBP. Power calculations were performed using 
previously published data from the research team, which suggested an expected effect size of 
1.5.3 A priori power analysis determined that, using a two-tailed t-test with alpha=0.05, beta=0.8, 
and Cohen’s d=1.5, a sample size of 18 participants (9 per group) is required to compare the 
change in SBP between groups (IMST vs sham). To account for 25% dropout, we will recruit 12 
subjects per group and plan to enroll an equal number of women and men per group. 
5.2.1 Major Inclusion Criteria 
In order to be eligible to participate, an individual must meet all of the following criteria: 
- 
Age 18 - 80 
- 
Primary cancer diagnosis of lymphoma 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 10 
CF-146, Effective 7/10/11 
 
- 
Able and willing to participate in a supervised exercise program at the Anschutz Health 
and Wellness Center 
o Provides a signed physician exercise clearance form 
- 
SBP > 120 mmHg  
- 
Completion of curative cancer treatment over 12 months prior (individuals on 
maintenance therapy will be included) 
- 
Possession of a smartphone compatible with the IMST training application (available on 
both Android and Apple). 
 
5.2.2 Major Exclusion Criteria 
Participants will be excluded if they meet any of the following criteria: 
- 
Second active cancer diagnosis 
- 
Planned active cancer treatment or change in current treatment in the next 6 months  
- 
Severe obesity (BMI > 40 kg/m2) or underweight (BMI < 18.5 kg/m2) 
- 
Unstable weight (> 3 kg change in body mass in last 3 months) 
- 
Significant metabolic disorder (e.g. diabetes type II) 
- 
Uncontrolled thyroid disease 
- 
Recent changes in hypertensive medication (within last 3 months) 
- 
Any medical condition that would impact the safety of, or participation in, an exercise 
program, including: 
o Significant pulmonary conditions such as chronic obstructive pulmonary disease, 
emphysema, or interstitial lung disease 
o Known cardiovascular disease, significant hypertension (> 180/120), or a recent 
cardiac event (within past 6 months) 
o Orthopedic conditions such as advanced osteoarthritis, mobility-limiting 
amputations or chronic injuries, or mobility-limiting acute orthopedic injuries 
o Advanced rheumatoid arthritis or chronic widespread pain conditions such as 
fibromyalgia 
 
Enrolled participants will undergo a version of the BfitBwell Cancer Exercise Program physical 
assessment, which assesses physical fitness and function (see Outcomes). This assessment has 
been used to determine exercise safety for over 600 BfitBwell participants. Any enrolled 
participant with assessment results indicating unsafe exercise participation will be withdrawn 
and referred to their primary care provider or oncologist.  
 
The BfitBwell Program employs a Spanish-speaking cancer exercise specialist who will be 
trained in all necessary study protocols to facilitate the inclusion of Spanish-speaking 
participants. We anticipate ≤ 3 Spanish-speaking participants to enroll in this pilot and will use 
IRB approved and available short forms for informed consent. We will use available and 
validated translations of patient reported outcomes and translate other study material as needed 
for this pilot. If a fourth Spanish-speaking participant is enrolled (or before a subsequent efficacy 
trial) we will fully develop Spanish language materials for the protocol.  

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 11 
CF-146, Effective 7/10/11 
 
6. STUDY DESIGN AND RESEARCH METHODS   
6.1 Experimental Design 
This is a prospective, randomized clinical trial of IMST vs sham IMST in isolation (6 weeks) and 
in combination with an individualized exercise program (12 weeks). Following the ORBIT 
Model28, this is a Phase IIb Feasibility Trial, determining feasibility and design of a robust Phase 
III Efficacy Trial. Figure 1 shows the study protocol. 
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 12 
CF-146, Effective 7/10/11 
 
6.2 Screening and Recruitment 
We will recruit using several mechanisms. BfitBwell maintains an IRB approved 
recruitment registry as a part of the BfitBwell Research Database (COMIRB# 16-0692). 
Participants in the registry will be screened for major inclusion/exclusion criteria (e.g. 
cancer diagnosis, completion of treatment, age, etc.). All eligible participants will be 
contacted by study personnel by email or phone. A series of screening questions will be 
emailed via REDCap or administered over the phone (and entered into REDCap by study 
personnel). Separate REDCap forms will collect identifying information and 
inclusion/exclusion information. After reviewing the inclusion/exclusion criteria, study 
personnel will decide whether a patient qualifies or not or contact the patient with 
clarifying questions. The patient will be contacted to explain their inclusion (and next 
steps) or why they were excluded. Once the inclusion/exclusion decision is made, this will 
be recorded in the de-identified screening question form, along with reason for exclusion if 
excluded. The identifying information will be deleted for excluded participants or those 
choosing not to enroll. Any participant excluded from the study will be given information 
on potential exercise resources for them, if safe and applicable (BfitBwell alumni 
programming, or other local online or in-person programs found in 
https://www.exerciseismedicine.org/eim-in-action/moving-through-cancer/ ). 
 
Participants will also be recruited through the clinical practice of study co-investigator Dr. 
Lavanya Kondapalli, director of Cardio-Oncology, using multiple methods. Dr. Kondapalli 
will review the medical records of recent patients, identifying those who may be eligible. 
Research personnel and Dr. Kondapalli will then reach out to these participants via the 
above described process. Additionally, upcoming patient visits will also be reviewed. 
Study personnel will be available during identified appointments. Dr. Kondapalli will 
discuss the study with patients and introduce them to study personnel who will continue a 
discussion of the study and ask screening questions. Participants recruited in-person like 
this may provide informed consent during this initial meeting, if eligible and willing. Fliers 
advertising the study will be created and given to providers who have clinical relationship 
with lymphoma survivors and placed in clinical spaces frequented by lymphoma survivors. 
 
Participants will be incentivized to enroll and complete the investigation by offering the 
required participation in the BfitBwell Program for free (typical cost to participants is $177 
and the approximate true value of the program is $1800). All participants, whether 
randomized to IMST or sham IMST, participate in the BfitBwell Program.  
6.3 Study Procedures 
Consent. Informed consent will be obtained in an in-person meeting in a private space at 
the AHWC or UCH facility (for those following an appt with Dr. Kondapalli) or virtually, 
utilizing Zoom, depending on participant availability and preference. All participants will 
be required to obtain the necessary physician exercise clearance form prior to consent. 
Study personnel will review all aspects of the consent form with the participant, asking 
questions to ensure comprehension and eliciting questions from the participant. If the 
potential participant chooses to enroll in the study, the consent form will be signed. The 
preferred method of signing the informed consent will be through the REDCap e-consent 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 13 
CF-146, Effective 7/10/11 
 
framework, on provided tablets if consent performed in-person. Participants will be walked 
through each stage of reviewing and signing the consent in this format. Participants will be 
emailed a copy of the signed consent form when it is presented to them at the end of the 
consent survey or a pdf of the signed copy will be automatically emailed to them. Paper 
versions of the consent will be made available for participants who request this, with 
copies of the signed version made and given to the participant. This session will last 
approximately 45 minutes. 
 
Visits: Each timepoint (baseline[visits 1 and 2], post-IMST[visits 3 and 4], post-
IMST+BfitBwell[visits 5 and 6]) will consist of two study visits. The first visit of each 
time point (1, 3, and 5) will be performed at the University of Colorado Anschutz Medical 
Campus CTRC and AHWC. This visit will be scheduled in the morning and participants 
will be instructed to fast at least 5 hours prior to the visit (preferably an overnight fast). It 
will begin at the CTRC, where blood pressure and a blood draw (for molecular markers of 
cardiovascular health) will be performed. Participants will then walk or be transported to 
the AHWC where they will perform the BfitBwell physical assessment, consisting of the 
measures of physical fitness and function described in the Outcomes (including estimated 
VO2max and 6MWT), as well as patient reported outcomes. Participants will be told to bring 
preferred snacks or provided snacks (e.g. Cliff bars) and water prior to the BfitBwell 
assessment. This session will last approximately 2 hours. 
 
The second visit (2, 4, and 6) will include the below described exercise response session 
for metabolomic analyses (Figure 2). These sessions will be scheduled in the morning 
(before 12PM) and participants will be told to eat a ‘typical breakfast’, which will be 
recorded. These sessions will last approximately 1-1.5 hours. Session 2 will last an 
additional 30 min to allow for IMST training. 
 
Exercise Response Sessions. The exercise performed in these sessions will be similar to 
aerobic exercise sessions performed during the exercise program, with all sessions 
performed on a treadmill. This should be obtainable for participants beginning the 
program, as the intensity is low-to-moderate. Blood draws will be performed three times: 
prior to initiating exercise, immediately after (within 5 min) and at 30 min of seated rest 
after exercise. Sample collection with the Tasso+ device is patient-centric, minimizing 
discomfort, and described in the Outcomes Measures section. 
 
 
HRR = heart rate reserve 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 14 
CF-146, Effective 7/10/11 
 
 
IMST Intervention. Participants will be randomized to IMST or sham following the exercise 
response protocol in Visit 2 (prior to IMST training). Participants will then complete Visit 2. 
Receiving either IMST training or sham training by study personnel who will remain unblinded 
for the trial duration. Investigative team members not involved in outcome measure data 
collection and analysis will oversee IMST and sham training, as these duties inherently 
necessitate unblinding. Participants in the IMST group will train 6 days/week for 18 weeks 
(6 weeks of IMST only, 12 weeks of exercise+IMST). Each training session will involve 
30 breaths in against resistance Airofit Pro2 inspiratory muscle strength training device, 
consisting of 5 sets of 6 inspiratory efforts. Each effort will last approximately 2 s, with an 
additional 4 s between each effort for expiration. An inspiratory effort begins after a 
subject has fully exhaled, they then breathe in as powerfully and deeply as possible. 
Approximately 1 min will elapse for rest between each set. During week 1, participants in 
the IMST group will train at 55% of their maximum inspiratory pressure (PIMAX). 
Resistance will then be increased to 65% PIMAX for week 2 and to 75% PIMAX starting 
week 3; resistance will remain at 75% PIMAX throughout the rest of the intervention. The 
sham group will follow an identical training plan, except resistance will be set to 15% 
PIMAX throughout the entire intervention. PIMAX is determined weekly as the peak pressure 
achieved during a maximal inspiratory maneuver (i.e., inhaling against near-infinite 
resistance) performed with the Airofit Pro 2. Training is facilitated by the Airofit research 
app that will be provided to each participant. The research app walks participants through 
each training session with the appropriate timing and intensity. Adherence will be 
monitored remotely by the expert research module associated with the Airofit devices. 
Realtime feedback is displayed through the Airofit research app, helping to facilitate 
inspiratory muscle strength training by providing a count of the inspiratory maneuvers 
performed during a training session and by providing auditory feedback (a quiet verbal 
prompt) when it is time to perform the next inspiratory maneuver. All volunteers are 
provided in-person training for device operation and given written instructions. 
 
The Airofit Pro2 inspiratory muscle strength training device meets FDA guidelines for a 
Nonsignificant Risk Device because it is not: a) intended as an implant; b) purported to 
support or sustain human life; c) for a use of substantial importance in diagnosing, curing, 
mitigating, or treating disease; or d) otherwise present a potential for serious risk to health, 
safety, or welfare of a subject. The Airofit Pro2 consists of a body with an adjustable 
valve, an electronic control unit, and a mouthpiece. The body serves to regulate inspiratory 
resistance. The electronic control unit stores training information, and serve as a 
subject/investigator interface for controlling the device via the associated smartphone app. 
The valve head is a mechanical component that generates resistance to inspiration and is 
controlled by the handset. The mouthpiece is a plastic attachment to the valve head that 
subjects breathe through to facilitate inspiratory muscle strength training. No changes to 
the device are anticipated during the course of this clinical study. 
 
The Exercise Intervention will provided by the BfitBwell Cancer Exercise Program and 
will follow the standard clinical protocol of the program. The BfitBwell Cancer Exercise 
Program is a 12 week supervised exercise program for survivors of cancer treated at the 
University of Colorado Cancer Center. It provides tailored exercise training for individual 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 15 
CF-146, Effective 7/10/11 
 
participants based on National Comprehensive Cancer Network (NCCN) guidelines for 
survivorship 29 and other national recommendations 30. The program has been shown to be 
effective at improving fitness and other well-being related 5,31. In brief, exercise 
prescription takes a ‘whole-body’ approach, targeting increased aerobic endurance and 
increased strength and flexibility of large upper and lower body muscle groups. Content is 
tailored to a given individual’s preferences, goals, and health status. Aerobic exercise is 
typically performed by walking on a treadmill or indoor track, or stationary cycling, and 
resistance exercises typically consist of multi-joint exercises using free weights or body 
weight. Exercise intensity is regularly adjusted based on participants’ current health status, 
symptom experience, and ability, with the goal of maintaining a rate of perceived exertion 
(RPE, 0-10 scale) of 6-7 out of 10. Participants receive one 50 min, one-on-one exercise 
sessions per week for the first month, and one 50 min, small group (≤ 4 participants, each 
receiving an individual workout plan) session per week for the second and third months. 
Exercise sessions take place in the AHWC Fitness Center or are virtually supervised (using 
University-supported Zoom software). Programs are supplemented by at least one 
additional personalized exercise session provided by a smartphone/internet personal 
training application. Sessions are led by trained exercise physiologists with certifications 
as cancer exercise specialists. Participants receive a membership to the AHWC Fitness 
Center for the duration of the study and are able to use the facility in addition to their 
prescribed exercise. Behavioral strategies will be employed in the exercise intervention to 
promote participant adherence including: social support during supervised sessions, 
structured plans for unsupervised sessions delivered via a personal training smartphone 
application, individualized goal setting, and regular symptom monitoring with appropriate 
exercise adjustment.  
6.4 Summary of Knowledge to be Gained 
IMST offers an alternative intervention that circumvents many issues impacting a cancer 
survivor’s ability to experience the benefits of an exercise intervention. Repeated inhalations 
using an IMST device for as little as 5 minutes per day, 6 days per week, has shown 
significant benefits for cardiovascular health and increases the amount of time to exhaustion 
during a standardized treadmill test. This proposal is to determine if lymphoma survivors 
benefit from using IMST and if these benefits augment the improvements that exercise has 
on cardiovascular health. Improving how exercise and IMST are monitored also holds 
promise to improve survivorship. Physiological parameters such as VO2max and heart rate 
have been used as measurements of physical fitness and performance, but they lack the 
resolution on the molecular level that can provide key biological insights such as which fuel 
sources are preferred to generate energy during exercise. This investigation will identify new 
molecular signatures in blood that can help to better describe the current physical fitness of 
an individual. If successful, this approach will allow for improved patient care and 
management for lymphoma, but furthermore, the success of this proposal can be adapted for 
a wide variety of patients where the health of the cardiovascular system impacts disease. 
6.5 Potential Obstacles  
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 16 
CF-146, Effective 7/10/11 
 
Recruitment: The recruitment of survivors meeting eligibility criteria may prove difficult 
within the study time frame. If recruitment is not progressing as planned after 
approximately 2 months, inclusion criteria will be expanded, specifically dropping the 
requirement of SBP > 120 mmHg, as IMST and exercise improve cardiovascular health 
regardless of baseline blood pressure, benefiting lymphoma survivors who are at an 
increased risk of developing CVD. 
 
Intervention adherence: Participants may struggle to adhere to the exercise prescription. If 
this occurs in a large portion of participants (>50%) strategies will be implemented to 
increase adherence based on participant feedback. Intensity can be adjusted to make the 
exercise more tolerable, or several supervised sessions could be converted to unsupervised 
sessions to reduce travel and scheduling burdens on participants. Historically, adherence to 
BfitBwell has been good (>75%) and even better when performed as part of a research 
study (>90%). 
 
Study power: The anticipated effect size of the intervention is large, possibly leading the 
study to be underpowered in the event the actual effect size is less. This pilot investigation 
will provide the necessary data to determine the sample size of a more robust subsequent 
efficacy trial. 
7 STATISTICAL CONSIDERATIONS 
Statistical significance will be defined as α ≤ 0.05. Change scores for all outcomes 
will be calculated for each participant for the post-IMST and post-BfitBwell+IMST 
timepoints. These scores will be compared between the IMST and sham IMST groups using 
paired t-tests at each timepoint. For the exploratory omics investigations, datasets will be 
generated using the metabolomics, lipidomics, and proteomics platforms. Analysis of these 
datasets will include standard uni- and multivariate, hierarchical clustering, principal 
component analyses, partial least-square discriminant analyses, uMAP, tSNE, repeated 
measure ANOVA for longitudinal experiments. In-house (Compound Discoverer, GraphPad 
Prism) or freely available (MetaboAnalyst, R) tools will be used. We will perform post-hoc 
corrections for multiple measurements (e.g. Benjamini-Hochberg adjustment to False-
Discovery Rate less than 5%) and adjustment for biological or technical statistical 
confounders. Static (single timepoint) and dynamic (longitudinal time points) molecular 
profiles will be compared to other outcomes (cardiovascular health, CRF, and physical 
function) to generate novel hypotheses. 
 
8. RISKS AND JUSTIFICATION OF PROCEDURES AND DATA 
COLLECTION TOOLS 
8.1 Potential Risks and Risk Mitigation 
 
Risks of exercise and fitness assessments: Certain risks are associated with performing 
exercise in any population, as well as specifically in cancer survivors. The likely risks of 
exercise include muscular fatigue and/or soreness, acute increase in fatigue, joint stiffness 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 17 
CF-146, Effective 7/10/11 
 
or soreness, and possible acute increase in treatment- or cancer-related symptoms. The 
more serious risks include fracture associated with unknown bone metastases, development 
of ventricular arrhythmia, myocardial infarction, cardiac arrest, and death. 
 
For adults in the general population and for cancer survivors in particular the benefits of 
exercise training outweigh the risks. Exercise interventions have been shown to be safe in 
multiple cancer survivor populations33. The discomforts of exercise training and testing 
will be explained to the participants. Participants will be informed that they can choose to 
withdraw or not participate in some or all portions of the study at any time for any reason 
(though this may result in their withdrawal from the study). Before, during, and at the 
conclusion of each exercise training and testing session, study personnel will ask 
participants about new or worsening signs and symptoms. Every exercise session will be 
supervised by qualified study personnel who are versed in exercise training for clinical 
populations and BLS-certified. Exercise intensity will be monitored by study personnel to 
decrease likelihood of an acute cardiac event, and participants will be monitored for 
symptoms including chest pain, acute shortness of breath at rest, or dizziness. Patients will 
be instructed to stay well-hydrated, and will be monitored for symptoms of dehydration 
including headache, confusion, tachycardia, significantly increased respiratory rate, and 
changes in skin elasticity.  
 
After providing written informed consent, each participant will be asked to provide clinical 
provider contact information. In the event of an emergency, study personnel will call 9-1-1, 
according to the protocol of the AHWC and outpatient clinics on the AMC. AEDs are 
available throughout the AHWC. The PI will contact the designated clinical provider if an 
emergency arises (after first responders are summoned) or a participant exhibits or reports 
exacerbation of symptoms. In the case of a medical emergency, the participant must be 
cleared for exercise by their clinical provider before resuming exercise training or testing.  
 
The BfitBwell Program has emergency protocols established for virtually supervised 
exercise sessions: 
- 
Prior to each exercise session the physical address of where the participant is located 
will be collected/confirmed and the name and contact information of a close by 
individual will be collected and confirmed (local support person). 
- 
Non-emergent event protocol: In response to a non-emergent event (e.g. non-life 
threatening injury in which the participant remains conscious and is able to 
communicate) study personnel will stay online with the participant and contact the 
local support person. A plan of action will be created and executed, with periodic 
follow up by study personnel. 
- 
Emergent event protocol: In response to an emergent event (e.g. participant loses 
consciousness or shows signs of a serious health event [heart attack or stroke]) study 
personnel will call 911 and provide the physical address of the participant. If 
possible, personnel will then contact the local support person. Personnel will stay in 
touch with all involved until emergency support arrives at the participant’s location. 
Study personnel will then follow up with the participant or local support person. 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 18 
CF-146, Effective 7/10/11 
 
  
 
Risks of IMST - While performing spirometry and breathing maximally, it is possible that 
participants may begin to feel light-headed or dizzy, or experience a brief headache or 
momentary shortness of breath. To minimize the likelihood of these events participants 
will be allowed recovery time between each task and will be instructed to perform training 
while seated in a safe location. Participants will be warned of these risks and told to report 
any experiences of these risks. 
 
The risks of the venipuncture (molecular markers) are momentary discomfort from the 
needle stick, excessive bleeding, light-headedness with insertion of needle, and infection or 
hematoma at the site of the blood draw. The risks of hematoma and infection will be 
minimized by having trained clinical personnel perform the procedures using sterile 
techniques at the CTRC. 
 
Risks of Tasso+ blood sample collection: The Tasso+ device sticks to the skin with a light 
adhesive. When the button is pressed, a vacuum forms and a lancet pricks the surface of 
the skin. The vacuum draws blood out of the capillaries and into a tube attached to the 
bottom of the device. There is a slight risk of an allergic reaction to the adhesive, which 
will be monitored for and the device removed immediately if this occurs. There is risk of 
bruising or soreness at the site where blood is drawn. There is also a slight possibility of 
infection, and a rare risk of fainting. These risks are minimized by having trained personnel 
perform the sample collection. The area of collection will be cleaned with alcohol prior 
placement of the device. The Tasso+ is an FDA approved Class I device, presenting 
minimal potential harm to the user. 
 
Risk of data collection and confidentiality: The primary risk of data collection in the study 
is a breach of confidentiality and privacy. Overall, no stigmatizing information is collected 
in the study, minimizing risk. This risk will be explained to participants prior to enrolling 
in the study. Study data will be stored on University servers and/or REDCap, a secure, 
university approved data collection tool. Only study personnel will be given access to the 
REDCap project. 
8.2 Potential Benefits 
All participants, whether in the IMST or sham group, will receive free participation in the 
BfitBwell Cancer Exercise Program. The benefits of exercise in cancer survivors are 
numerous and well documented, including improved quality of life, reduced fatigue, 
improved physical fitness and function, and potential reductions in risk of recurrence.  
 
The outcomes and results of this investigation will not be utilized to inform the exercise 
prescription in the study and will not impart any direct benefit to the participant.  

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 19 
CF-146, Effective 7/10/11 
 
8.3 Assessment of Potential Risks and Benefits  
The risks to participants are reasonable in relation to the anticipated benefits to participants 
and/or society, and in relation to the importance of the knowledge that may reasonably be 
expected to result, thereby falling in favor of performing the study: 
- 
To Participant: Minimal risks with possible significant benefit. The risks of 
exercise, IMST, fitness assessment, and blood sample collection are minimal for 
these standard procedures and activities. The potential benefit of exercise and 
IMST in the participant can be substantial, though individual results are variable. 
- 
To Society: As the number of cancer survivors continues to grow, effective 
supportive care programs, such as exercise programs will grow. This investigation 
will inform adaptations and modifications of these programs to improve exercise 
prescription to maximize potential benefits of exercise in each individual patient.   
- 
Justify the importance of the knowledge gained: IMST is a novel, accessible, and 
potentially effective tool to reduce CVD risk in cancer survivors instead of or 
alongside a personalized exercise program. Increased knowledge of this 
intervention and its mechanisms are necessary to maximize its benefit in each 
individual cancer survivor. 
9 STUDY DISCONTINUATION  
9.1 Discontinuation of Study  
The investigative team has the right to terminate this study at any time. Reasons for 
terminating the study may include, but are not limited to, the following: 
- 
The incidence or severity of AEs in this or other studies indicates a potential health 
hazard to patients. 
- 
Patient enrollment is unsatisfactory, despite efforts to increase enrollment. 
10 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM 
STUDY 
Participants are free to withdraw from participation in the study at any time upon 
request. In addition, the investigator has the right to withdraw a patient from the study at 
any time. Reasons for withdrawal from the study may include, but are not limited to, the 
following: 
- 
Patient withdrawal of consent at any time 
- 
Any medical condition that the Sponsor-Investigator determines may jeopardize the 
patient’s safety if he or she continues in the study. 
- 
Sponsor-Investigator determines it is in the best interest of the patient 
- 
Patient non-compliance 
Every effort should be made to obtain information on patients who withdraw from 
the study. The primary reason for withdrawal from the study should be documented on the 
appropriate case report form.  

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 20 
CF-146, Effective 7/10/11 
 
11 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS  
11.1 Definition of Adverse Events (AE) 
Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related. 
11.2 Definition of Serious Adverse Events (SAE) 
An AE or suspected adverse reaction is considered “serious” if, in the view of 
either the PI or investigative team, it results in any of the following outcomes: death, a life-
threatening AE, inpatient hospitalization or prolongation of existing hospitalization, a 
persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or a congenital anomaly/ birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious 
when, based upon appropriate medical judgment, they may jeopardize the patient or 
subject and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition.  
11.3 Classification of an Adverse Event 
11.3.1 Severity of event  
For AEs, the following guidelines will be used to describe severity. 
- 
Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
- 
Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
- 
Severe – Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually potentially life-
threatening or incapacitating. 
11.3.2 Relationship to study intervention 
Only AEs directly related to study intervention will be recorded.  
11.3.3 Expectedness  
Expectedness will only be documented for SAEs. The study PI and MD will be 
responsible for determining whether an SAE is expected or unexpected. An SAE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent 
with the risk information previously described for the study intervention. 
11.3.4 Time period and frequency for event assessment and follow-up  
The occurrence of an AE or SAE may come to the attention of study personnel 
during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. All AEs including local and systemic reactions not 
meeting the criteria for SAEs will be captured on the appropriate case report form. 
Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, (if applicable) relationship to study intervention (assessed only by 
those with the training and authority to make a diagnosis), and time of resolution/ 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 21 
CF-146, Effective 7/10/11 
 
stabilization of the event. All AEs occurring while on study must be documented 
appropriately. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened 
will be considered as baseline and not reported as an AE. However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as an 
AE. Unanticipated problems (UAPs) will be recorded in the data collection system 
throughout the study. 
Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed. AEs characterized as 
intermittent require documentation of onset and duration of each episode. 
The PI will record all reportable events with start dates occurring any time after 
informed consent is obtained until 30 days after the last day of study treatment or until 
initiation of new treatment, whichever comes first. SAEs will be followed until resolution 
or stabilization. At each study visit, the investigator will inquire about the occurrence of 
AE/ SAEs since the last visit.  
11.3.5 Adverse event reporting  
The investigator will record non-serious adverse events in a case report form. Adverse 
events will be reported to COMIRB according to their policy. 
11.3.6 Serious adverse event reporting  
The PI will record all SAEs and report to COMIRB within five days, in accordance 
with their policy. All deaths and immediately life-threatening events, (if applicable, 
whether related or unrelated) will be recorded on a SAE Form and submitted to COMIRB 
within 24 hours of site awareness. SAE will also be reported to the University of Colorado 
Cancer Center Data Safety Monitoring Committee within five business days.  
12 UNANTICIPATED PROBLEMS  
12.1 Definition of Unanticipated Problems (UAPs) 
This study will use the COMIRB definition of UAP. An UAP is any event or 
information that was unforeseen and indicates that the research procedures caused harm 
(including physical, psychological, economic, or social harm) to participants or others or 
indicates that participants or others are at increased risk of harm than was previously 
known or recognized.  
12.2 Reporting of Unanticipated Problems  
This study will follow COMIRB’s guidance for UAP reporting. AEs, 
noncompliance and protocol violations will be recorded and reported as required either 
promptly (within 5 business days of PI’s knowledge) or at the time of the study’s 
continuing review. It is the responsibility of the PI to report incidents or events that meet 
the criteria for UAPs reporting to COMIRB using COMIRB’s standard UAP form.  
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 22 
CF-146, Effective 7/10/11 
 
13 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
13.1 Informed Consent Process 
13.1.1 Consent/assent and other informational documents provided to participants 
Consent forms describing in detail the study agent, study procedures, and risks will be 
given to the participant and written documentation of informed consent is required prior to 
starting the study.  
13.1.2 Consent procedures and documentation 
Informed consent process will be initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation. 
Extensive discussion of risks and possible benefits of participation will be provided to the 
participants and - if applicable - their families.  
Consent forms will be approved by COMIRB and the participant will be asked to 
read and review the document. The investigator will explain the research study to the 
participant and answer any questions that may arise. All participants will receive a verbal 
explanation in terms suited to their comprehension of the purposes, procedures, and 
potential risks of the study and of their rights as research participants. Participants will 
have the opportunity to carefully review the written consent form and ask questions prior 
to signing. The participants will have the opportunity to discuss the study with their 
surrogates or think about it prior to agreeing to participate. The participant will sign the 
informed consent document prior to any procedures being done specifically for the study.  
The participants may withdraw consent at any time throughout the course of the 
trial. A copy of the informed consent document will be given to the participants for their 
records. The rights and welfare of the participants will be protected by emphasizing to 
them that the quality of their medical care will not be adversely affected if they decline to 
participate in this study. 
13.2 Confidentiality and Privacy 
Participant confidentiality is strictly held in trust by the participating investigators 
and staff. This confidentiality is extended to cover testing of biological samples and 
genetic tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in 
strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the PI. 
The study monitor, other authorized representatives of the sponsor-investigator, or 
representatives of COMIRB may inspect all documents and records required to be 
maintained by the investigator, including but not limited to, medical records (office, clinic, 
or hospital) for the participants in this study. The clinical study site will permit access to 
such records. 
Hard or digital copies of the study participant’s contact information will be 
securely stored at the Anschutz Health and Wellness Center or on REDCap for internal use 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 23 
CF-146, Effective 7/10/11 
 
during the study. At the end of the study, all records will continue to be kept in a secure 
location for as long a period as dictated by local IRB and Institutional regulations. 
Study participant research data, which is for purposes of statistical analysis and 
scientific reporting, will be transmitted to and stored through REDCap (Research 
Electronic Data Capture), which is a secure, HIPAA-compliant web-based application 
designed for data collection for research studies. REDCap is secured and password 
protected; login will be limited to members of the study team.  
13.3 Future Use of Stored Specimens or Data 
Intended Use: Data collected under this protocol may be used to investigate molecular 
responses to exercise and IMST in cancer survivors.  
Storage: Data will be stored using codes assigned by the investigators. Data will be kept in 
password-protected computers or secure laboratories. Only study investigators will have 
access to the data and specimens. 
Tracking: Data and specimen location and status will be tracked using REDCap. 
Disposition at completion of the study: Study participants who request destruction of 
data will be notified of compliance with such request and all supporting details will be 
maintained for tracking. 
13.4 Data Safety Monitoring   
 
The principal investigator will be responsible for the conduct of this study, 
overseeing participant safety, executing the data and safety monitoring (DSM) plan, and 
complying with all reporting requirements to local and federal authorities. This oversight 
will be accomplished through additional oversight from the Data and Safety Monitoring 
Committee (DSMC) at the University of Colorado Cancer Center (CU Cancer Center). The 
DSMC is responsible for ensuring data quality and study participant safety for all trials at 
the CU Cancer Center. A summary of the DSMC’s activities is as follows:  
 
• Conduct of internal audits  
• Ongoing review of all serious adverse events (SAEs) and unanticipated problems (UAPs)  
• May submit recommendations for corrective actions to the CU Cancer Center’s 
Executive Committee  
 
Per the CU Cancer Center Institutional DSM Plan, SAEs and UAPs are reported to 
the DSMC, IRB and the principal investigator per protocol. All SAEs and UAPs are to be 
reported to the DSMC within 7 (for fatal or life-threatening events) or 15 (non-life-
threatening events) calendar days of the principal investigator receiving notification of the 
occurrence. 
Study audits conducted by the DSMC will consist of a review of the regulatory 
documents, consent forms, and source data verification. Documentation of the audit 
conducted by the DSMC will then need to be submitted to the IRB of record at the time of 
the IRB’s continuing review of this trial. 
 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 24 
CF-146, Effective 7/10/11 
 
13.5 Quality Assurance and Quality Control 
Quality Control (QC) procedures will be implemented beginning with the data entry system 
and data QC checks that will be run on the database will be generated. Any missing data or 
data anomalies will be communicated to the site(s) for clarification/ resolution. 
 
Following written SOPs, the PI will verify that the clinical trial is conducted and data are 
generated, documented (recorded), and reported in compliance with the protocol, GCP, and 
the applicable regulatory requirements. 
 
The investigational site will provide direct access to all trial-related sites, source data/ 
documents, and reports for the purpose of auditing by the DSMC audit team, and inspection 
by local and regulatory authorities. 
13.6 Data Handling and Record Keeping 
13.6.1 Data collection and management responsibilities 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. The PI is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure 
accurate interpretation of data. When making changes or corrections, cross out the original 
entry with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, 
OR USE CORRECTION FLUID OR TAPE ON THE ORIGINAL. 
Copies of the electronic case report form will be provided for use as source 
documents and maintained for recording data for each participant enrolled in the study. 
Data reported in the electronic case report form derived from source documents should be 
consistent with the source documents or the discrepancies should be explained and 
captured in a progress note and maintained in the participant’s official electronic study 
record. 
Clinical data (including AEs, concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into REDCap. The data system 
includes password protection and internal quality checks, such as automatic range checks, 
to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
13.6.2 Study records retention 
Study documents should be retained for a minimum of 7 years per HIPAA 
regulations. These documents should be retained for a longer period, however, if required 
by local regulations or institutional policies. No records will be destroyed without the 
written consent of the sponsor-investigator.  
13.6 Protocol Deviations 
A protocol deviation is any noncompliance with the clinical trial protocol or good 
clinical practice. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 25 
CF-146, Effective 7/10/11 
 
developed by the site and implemented promptly. These practices are consistent with 
International Council for Harmonization of Technical Requirements for Pharmaceuticals 
for Human Use E6, sections: 
- 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3. 
- 
5.1 Quality Assurance and Quality Control, section 5.1.1. 
- 
5.20 Noncompliance, sections 5.20.1 and 5.20.2. 
All deviations will be addressed in study source documents and reported to COMIRB, 
per their guidelines. The PI and study staff is responsible for knowing and adhering to 
COMIRB requirements.  
13.7 Publication and Data Sharing Policy 
This study will ensure that the public has access to the published results of this research 
upon request.  
13.8 Conflict of Interest Policy 
Independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical. Any actual conflict of interest of persons who have a 
role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed.by the University of Colorado Denver’s Office of Regulatory 
Compliance Conflict of Interest and Commitment Management program. Persons with a 
perceived conflict of interest will have such conflicts managed in a way that is appropriate 
to their participation in the trial. Conflict of Interest management plans are project-specific 
and are reviewed at least annually. University of Colorado Denver has integrated the 
institutional conflict of interest management program with its existing program. 
14 REFERENCES 
 
1. 
de Moor JS, Mariotto AB, Parry C, et al. Cancer survivors in the United States: prevalence 
across the survivorship trajectory and implications for care. Cancer Epidemiol Biomarkers 
Prev. 2013;22(4):561-570. 
2. 
Mariotto AB, Yabroff KR, Shao Y, Feuer EJ, Brown ML. Projections of the cost of cancer 
care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103(2):117-128. 
3. 
DeSantis CE, Lin CC, Mariotto AB, et al. Cancer treatment and survivorship statistics, 
2014. CA Cancer J Clin. 2014;64(4):252-271. 
4. 
Demark-Wahnefried W, Rogers LQ, Alfano CM, et al. Practical clinical interventions for 
diet, physical activity, and weight control in cancer survivors. CA Cancer J Clin. 
2015;65(3):167-189. 
5. 
Marker RJ, Cox-Martin E, Jankowski CM, Purcell WT, Peters JC. Evaluation of the effects 
of a clinically implemented exercise program on physical fitness, fatigue, and depression in 
cancer survivors. Support Care Cancer. 2018;26(6):1861-1869. 
6. 
Marker RJ, Ostendorf DM, Leach HJ, Peters JC. Cancer-related fatigue mediates the 
relationships between physical fitness and attendance and quality of life after participation 
in a clinical exercise program for survivors of cancer. Quality of Life Research. 2022. 
7. 
Armenian SH, Xu L, Ky B, et al. Cardiovascular Disease Among Survivors of Adult-Onset 
Cancer: A Community-Based Retrospective Cohort Study. J Clin Oncol. 2016;34(10):1122-
1130. 
8. 
McGowan JV, Chung R, Maulik A, Piotrowska I, Walker JM, Yellon DM. Anthracycline 
Chemotherapy and Cardiotoxicity. Cardiovasc Drugs Ther. 2017;31(1):63-75. 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 26 
CF-146, Effective 7/10/11 
 
9. 
Yeh ET, Tong AT, Lenihan DJ, et al. Cardiovascular complications of cancer therapy: 
diagnosis, pathogenesis, and management. Circulation. 2004;109(25):3122-3131. 
10. 
Lenihan DJ, Cardinale DM. Late cardiac effects of cancer treatment. J Clin Oncol. 
2012;30(30):3657-3664. 
11. 
Accordino MK, Neugut AI, Hershman DL. Cardiac effects of anticancer therapy in the 
elderly. J Clin Oncol. 2014;32(24):2654-2661. 
12. 
Lakatta EG, Levy D. Arterial and cardiac aging: major shareholders in cardiovascular 
disease enterprises: Part I: aging arteries: a "set up" for vascular disease. Circulation. 
2003;107(1):139-146. 
13. 
Pierce GL, Donato AJ, LaRocca TJ, Eskurza I, Silver AE, Seals DR. Habitually exercising 
older men do not demonstrate age-associated vascular endothelial oxidative stress. Aging 
Cell. 2011;10(6):1032-1037. 
14. 
Forstermann U, Sessa WC. Nitric oxide synthases: regulation and function. Eur Heart J. 
2012;33(7):829-837, 837a-837d. 
15. 
Arem H, Mama SK, Duan X, Rowland JH, Bellizzi KM, Ehlers DK. Prevalence of Healthy 
Behaviors among Cancer Survivors in the United States: How Far Have We Come? 
Cancer Epidemiol Biomarkers Prev. 2020;29(6):1179-1187. 
16. 
Piercy KL, Troiano RP, Ballard RM, et al. The Physical Activity Guidelines for Americans. 
JAMA. 2018;320(19):2020-2028. 
17. 
Schoenborn CA, Stommel M. Adherence to the 2008 adult physical activity guidelines and 
mortality risk. Am J Prev Med. 2011;40(5):514-521. 
18. 
Craighead DH, Freeberg KA, McCarty NP, Seals DR. Time-efficient, high-resistance 
inspiratory muscle strength training for cardiovascular aging. Exp Gerontol. 
2021;154:111515. 
19. 
Craighead DH, Heinbockel TC, Freeberg KA, et al. Time‐Efficient Inspiratory Muscle 
Strength Training Lowers Blood Pressure and Improves Endothelial Function, NO 
Bioavailability, and Oxidative Stress in Midlife/Older Adults With Above‐Normal Blood 
Pressure. Journal of the American Heart Association. 2021;10(13). 
20. 
Nemkov T, Skinner SC, Nader E, et al. Acute Cycling Exercise Induces Changes in Red 
Blood Cell Deformability and Membrane Lipid Remodeling. International Journal of 
Molecular Sciences. 2021;22(2):896. 
21. 
Whelton PK, Carey RM, Aronow WS, et al. 2017 
ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the 
Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A 
Report of the American College of Cardiology/American Heart Association Task Force on 
Clinical Pr. Hypertension. 2018;71(6):e13-e115. 
22. 
Hughes AD, Chaturvedi N. Estimation of Maximal Oxygen Consumption and Heart Rate 
Recovery Using the Tecumseh Sub-Maximal Step Test and their Relationship to 
Cardiovascular Risk Factors. Artery Res. 2017;18:29-35. 
23. 
Hanssens S, Luyten R, Watthy C, et al. Evaluation of a comprehensive rehabilitation 
program for post-treatment patients with cancer. Oncol Nurs Forum. 2011;38(6):E418-424. 
24. 
Lee MK, Kim NK, Jeon JY. Effect of the 6-week home-based exercise program on physical 
activity level and physical fitness in colorectal cancer survivors: A randomized controlled 
pilot study. PLoS One. 2018;13(4):e0196220. 
25. 
Hong SH, Yang HI, Kim DI, Gonzales TI, Brage S, Jeon JY. Validation of Submaximal Step 
Tests and the 6-Min Walk Test for Predicting Maximal Oxygen Consumption in Young and 
Healthy Participants. Int J Environ Res Public Health. 2019;16(23). 
26. 
Catala A, Culp-Hill R, Nemkov T, D’Alessandro A. Quantitative metabolomics comparison 
of traditional blood draws and TAP capillary blood collection. Metabolomics. 2018;14(7). 
27. 
Leach HJ, Marker RJ, Scorsone JJ, Peters JC, Purcell WT. Predictors of attendance during 
an exercise program for cancer survivors. Support Care Cancer. 2021;29(7):3425-3428. 
28. 
Czajkowski SM, Powell LH, Adler N, et al. From ideas to efficacy: The ORBIT model for 
developing behavioral treatments for chronic diseases. Health Psychol. 2015;34(10):971-
982. 

PI:   Ryan Marker, PT, PhD 
Protocol #:  22-1216 
Version Date:  8.28.24 
Protocol Template 
Page 27 
CF-146, Effective 7/10/11 
 
29. 
Denlinger CS, Ligibel JA, Are M, et al. Survivorship: healthy lifestyles, version 2.2014. J 
Natl Compr Canc Netw. 2014;12(9):1222-1237. 
30. 
Campbell KL, Winters-Stone KM, Wiskemann J, et al. Exercise Guidelines for Cancer 
Survivors: Consensus Statement from International Multidisciplinary Roundtable. Med Sci 
Sports Exerc. 2019;51(11):2375-2390. 
31. 
Marker RJ, Kittelson AJ, Jankowski CM, Scorsone JJ, Peters JC, Purcell WT. 
Development of a Reference Chart for Monitoring Cancer-Related Fatigue Throughout a 
Supervised Exercise Program. Rehab Oncol. 2022;40:82-88. 
32. 
Curran-Everett D. Explorations in statistics: permutation methods. Adv Physiol Educ. 
2012;36(3):181-187. 
33. 
Schmitz KH, Holtzman J, Courneya KS, Masse LC, Duval S, Kane R. Controlled physical 
activity trials in cancer survivors: a systematic review and meta-analysis. Cancer Epidemiol 
Biomarkers Prev. 2005;14(7):1588-1595.