Effects of High-intensity Inspiratory Muscle Training as a Pre-cardiac Rehabilitation Intervention on Cardiovascular Functions in Patients With Heart Disease
Phase: NA
Conditions: Coronary Artery Bypass Graft, CABG
Sponsor: University of Illinois at Chicago

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 1 of 27 
Revised: December 10, 2021 
PROTOCOL TITLE: 
Effects of high-intensity inspiratory muscle training as a pre-cardiac rehabilitation 
intervention on cardiovascular functions in patients with heart disease  
PRINCIPAL INVESTIGATOR: 
Cemal Ozemek, PhD. 
UIC Department of Physical Therapy 
312-355-3996,  
ozemek@uic.edu 
 
VERSION NUMBER/DATE:  
Version: 2  
Date: 12/12/2023 
 
REVISION HISTORY 
 
Revision 
# 
Version Date 
Summary of Changes 
Consent 
Change? 
1 
12/1/2023 
1. Changed title to Effects of high-intensity 
muscle training as a pre-cardiac rehabilitation 
intervention on cardiovascular function in 
patients with heart disease 
 
2. Expand participant population to include 
those with a history of percutaneous coronary 
interventions, heart failure, and/or myocardial 
infarction. 
Yes 
 
 
 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
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Revised: December 10, 2021 
Table of Contents 
1.0 
Study Summary ........................................................................................................ 3 
2.0 
Objectives* .............................................................................................................. 3 
3.0 
Background* ............................................................................................................ 3 
4.0 
Study Endpoints* ..................................................................................................... 4 
5.0 
Study Intervention/Investigational Agent ................................................................ 4 
6.0 
Study Timelines* ..................................................................................................... 5 
7.0 
Inclusion and Exclusion Criteria* ............................................................................ 6 
8.0 
Vulnerable Populations* .......................................................................................... 6 
9.0 
Number of Subjects.................................................................................................. 7 
10.0 Recruitment Methods ............................................................................................... 7 
11.0 Procedures Involved*............................................................................................... 7 
12.0 Data and Specimen Banking* ................................................................................ 11 
13.0 Sharing of Results with Subjects* ......................................................................... 11 
14.0 Withdrawal of Subjects* ........................................................................................ 11 
15.0 Risks to Subjects* ................................................................................................ 122 
16.0 Potential Benefits to Subjects* ............................................................................ 122 
17.0 Data Management* and Confidentiality .............................................................. 112 
18.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* ...................... 144 
19.0 Provisions to Protect the Privacy Interests of Subjects .......................................... 15 
20.0 Compensation for Research-Related Injury ........................................................... 15 
21.0 Economic Burden to Subjects ................................................................................ 15 
22.0 Consent Process ..................................................................................................... 15 
23.0 Process to Document Consent in Writing .............................................................. 17 
24.0 Setting .................................................................................................................... 18 
25.0 Resources Available............................................................................................... 18 
26.0 Multi-Site Research* ............................................................................................. 18 
27.0 References ............................................................... Error! Bookmark not defined. 
 
 
 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 3 of 27 
Revised: December 10, 2021 
1.0 
Study Summary 
Background / aim: Endothelial function is closely associated with coronary artery health 
among individuals being treated for heart disease. An impairement in endothelial function 
promotes arterial stiffening that directoy contributes to elevated systolic blood pressure as 
a result of increased vascular resistance. Inspiratory muscle training is simply a form of 
training consisting of repeated inspirations against a resistance. Inspiratory muscle training 
has also been applied to patients with chronic disease or as an additional therapy for cardiac 
rehabilitation and it has proven to be safe in these groups. Few studies in the literature 
examined the effects of high intensity inspiratory muscle training in this population, 
however, these studies did not examine the direct effects of inspiratory muscle training on 
vascular function. To the best of our knowledge, the effects of inspiratory muscle training 
in patients with heart disease on endothelial function and arterial stiffness prior to starting 
cardiac rehabilitation have not been investigated.  
 
Methods: The study was designed as a randomized controlled trial. The demographic and 
clinical characteristics of the patients will be recorded after consent is obtained from the 
volunteer patients who meet the inclusion criteria. Subsequently, patients will be randomly 
divided with into two groups (22 subjects in each group) for inspiratory muscle training 
(IMT) with 60% of maximum inspiratory pressure (MIP) or sham inspiratory muscle 
training (Sham-control), for 4 weeks. In both groups, before and after 4-week-training, 
resting blood pressure (systolic/diastolic), resting heart rate, endothelial function, arterial 
stiffness, functional exercise capacity, the severity of dyspnea and inspiratory muscle 
functions will be measured.  
 
 
2.0 
Objectives* 
2.1 
Objectives: The aim of this study is to investigate and interpret 
whether high-intensity inspiratory muscle training, beyond the usual care of 
heart disease, improves endothelial function and arterial stiffness. 
2.2 
Hypotheses: High-intensity inspiratory muscle training will 
improve endothelial function and arterial stiffness beyond the usual care of 
patients with heart disease. 
 
3.0 
Background* 
Cardiovascular diseases (CVD) remains a leading cause of morbidity and mortality 
in both men and women in developed and developing societies (Joseph et al., 2017). Some 
degree of pulmonary dysfunction is highly likely in patients with heart disease compared 
to those without(Calles et al., 2016; Cahalin and Arena, 2015). This can affect pulmonary 
function, gas exchange, as well as decrease maximum inspiratory and expiratory pressures 
(MIP and MEP, respectively)(Dos Santos et al., 2019; Haeffener et al., 2008; Roncada et 
al., 2015; Cahalin and Arena, 2015).  

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 4 of 27 
Revised: December 10, 2021 
Inspiratory muscle training has been shown to be an effective form of training that 
enhances lung function. It consists of repetitive breath cycles where one inspires against 
resistance placed by a device and expires against no resistance.   Studies that have applied 
this form of training in patients with heart disease have found significant improvements in 
MIP-MEP, tidal volume, vital capacity, and 6-minute walking distance. Few studies have 
examined the effects of high-intensity (between 50-80% of MIP) inspiratory muscle 
training in patients with heart disease (Dos Santos et al., 2019; Dos Santos et al., 2021; 
Laoutaris et al., 2007; Miozzo et al., 2018; Sadek et al., 2022). This level of training has 
been associated with greater improvements in the aferomentioned outcomes of interest, 
however, no study has explored the effects of high-intensity inspiratory muscle training in 
patients with heart disease on measures of cardiovascular function. 
This study will therefore examine the effects of high-intensity inspiratory muscle 
training in patients with heart disease  on cardiovascular function. 
 
4.0 
Study Endpoints* 
4.1 Primary endpoints; inspiratory muscle function, endothelial function, 
arterial stiffness.  
4.2 Secondary endpoints; dyspnea, functional exercise capacity. 
 
5.0 
Study Intervention/Investigational Agent 
 
5.1 
Description of the study intervention: Based on the findings of a 
systematic review (Z. Sadek et al., 2018), it has been determined that to achieve 
significant improvements in inspiratory muscle strength, the threshold pressure for 
inspiratory muscle training (IMT) should be set at 60% of the maximal inspiratory 
mouth pressure (MIP). Consequently, the intervention protocol for IMT involves 
using a threshold-loaded IMT device (Threshold IMT Philips® Respironics, Inc). 
In the IMT group, the initial intensity of the inspiratory threshold will be set at 60% 
of each patient's initial maximal MIP, which is then readjusted after 2 weeks of 
training to maintain the 60% of MIP throughout the 4-week period. Rates of 
perceived inspiratory effort on a modified Borg scale will also be used to determine 
the highest tolerable load for each patient (at the 4-6 level of 10) (Borg, 1982; 
Wilson and Jones, 1989). Patients will perform IMT for 2 sets of 30 repetitions, 
with one-minute intervals between each set (McConnell, 2013; Z. Sadek et al., 
2018). Throughout the training sessions, patients will be instructed to maintain 
diaphragmatic breathing. On the other hand, the Sham-control group will follow 
the same training program using the same device, but without any inspiratory load. 
Both groups will perform the training program twice a day, five days a week, for a 
total of 4 weeks, under the supervision of a physiotherapist (McConnell, 2013). The 
supervision will be conducted remotely through telerehabilitation, utilizing video 
calls to connect with the patients without requiring them to physically visit the 
healthcare facility. To familiarize the participants with the training procedure, both 
the IMT and Sham-control groups will undergo a session without any load on the 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 5 of 27 
Revised: December 10, 2021 
day of the baseline assessments. Throughout the study, all participants will visit the 
healthcare facility for baseline assessments, final assessments, and an additional 
brief assessment session at the end of the second week of training to measure MIP 
and readjust the loading value. The assessment to be made at the end of the 2nd 
week of the 4-week training seasons will only include the assessment of inspiratory 
muscle function described in 11.1.5. 
 
5.2 
Device Handling: The Threshold IMT Philips products will be obtained by 
researchers and provided to patients without any cost. The Threshold IMT Philips 
products is a legally marketed device when used in accordance with its labeling. 
There are no expected adverse events based on the product label. They will be used 
only on subjects and be used only by authorized investigators. On the other hand, a 
patient who loses the product before the study ends will be notified that he or she 
will be excluded from the study. 
 
 
6.0 
Study Timelines* 
• The duration of an individual subject’s participation in the study will 
be 4 weeks. 
• The duration anticipated to enroll all study subjects is 9 months. 
• The estimated duration for the investigators to complete this study is 
10 months.  
• The estimated date for the investigators to complete this study is June 
14, 2024. 
 
7.0 
Inclusion and Exclusion Criteria* 
7.1 
Inclusion criteria as follows;  
• Aged >18 years old 
• Be able to walk independently. 
• Had coronary artery bypass graft (CABG) surgery, history of 
percutaneous 
coronary 
interventions, 
heart 
failure, 
and/or 
myocardial infarction. 
• Sufficient English language comprehension and cognitive ability to 
understand the study protocol, give informed consent and follow 
instructions. 
 
7.2 
Exclusion criteria as follows; 
• <18 years of age 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 6 of 27 
Revised: December 10, 2021 
• Being a current smoker (or tobacco). 
• Having a diagnosed chronic disease such as inflammatory bowel 
disease/irritable bowel syndrome, cerebrovascular diseases, COPD,  
chronic kidney disease requiring dialysis, neurological disorders, or 
diseases that may affect motor/cognitive function [multiple 
sclerosis, Parkinson's disease, polio, Alzheimer's disease, dementia, 
or other brain diseases of ageing]) 
• Getting a score below 24 on the Standardized Mini Mental Test 
• Using antipsychotic medications commonly used to treat 
schizophrenia or schizoaffective disorders (i.e., haloperidol) 
• Having had any other previous thoracic operation except CABG 
(e.g. Pneumonectomy, lobectomy, etc.) 
• Having a history of unstable-angina 
• Having had pneumonia in the last 3 months 
8.0 
Vulnerable Populations* 
8.1 The research not involves individuals who are vulnerable to coercion 
or undue influence. 
• 
The research not involves pregnant women. 
• 
The research not involves neonates of uncertain viability or non-
viable neonates. 
• 
The research not involves prisoners. 
• 
The research not involves persons who have not attained the 
legal age for consent (“children”). 
• 
The research not involves cognitively impaired adults. 
 
9.0 
Number of Subjects 
9.1 
For the required sample size; on the basis of prior studies (Hermes 
et al., 2015; Dos Santos et al., 2019; Dos Santos et al., 2021), the sample 
size was calculated as 20 subjects per group (n = 40 in total) for a 
significance level of 5%, a statistical power of 90%, and a difference in 
maximum inspiratory pressure (MIP) of at least 23 cmH2O between groups. 
However, to optimize the results, the required sample size was calculated 
as 44 participants, n=22 participants per group, with consideration of a 10% 
loss at follow-up. Separately, after ethical approval, the ClinicalTrials.gov 
study registration will be done before the study starts. 
 
10.0 Recruitment Methods 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 7 of 27 
Revised: December 10, 2021 
For research purposes only, we propose to recruit patients that have undergone 
CABG surgery, history of percutaneous coronary interventions, heart failure, 
and/or myocardial infarction. Potential participants may be recruited at University 
of Illinois Health (UIH) clinics including Division of Cardiology (Dr. Ziccardi). 
Potential participants may actively be recruited from the Outpatient UIH Heart 
Center, and the Cardiac Rehabilitation (Dr. Ozemek) and Exercise Testing 
(Hannah Ozemek) Programs via clinician referral during patient’s routine visit. 
  
Patients may be identified via clinician referral during routine in person visits or 
phone calls used to schedule a cardiac rehabilitation orientation visit. Dr. Ziccardi 
and their staff may also notify Dr. Ozemek about whether and when any patients 
who meet the study criteria are scheduled to be seen in the clinic during the day or 
the following day. Patients that have received a referral to cardiac rehabilitation 
will be given the opportunity to take part in the study as long as the study 
requirements can be completed prior to their cardiac rehabilitation start date. 
Cardiac rehabilitation will not be delayed for the sole purpose of taking part in the 
study. Patients will not be able to do both study and cardiac rehabilitation at the 
same time as exercise is known to improve cardiovascular function. 
The informed consent will be obtained from volunteer patients who meet 
the inclusion criteria. Patients will then be randomly assigned to a study or 
control group. The randomization sequence will generate from the 
www.randomizer.org website by an investigator not otherwise involved in 
the study, using a table of random numbers uniformly distributed and 
divided into 2 groups. No names or personal identification will be given out. 
 
11.0 Procedures Involved* 
This research will take place in the Physical Therapy Faculty Practice 
located at 1640 W. Roosevelt Road in Chicago, IL. It will be an 
interventional randomized controlled study. The data will be collected  for 
research purposes only. We will ensure to participants that no new 
information (i.e., results from any study procedures) will be entered into or 
collected from patient’s medical records. After eligibility is determined, 
those who agree to participate (provide oral consent) will be required to 
provide written informed consent statement before proceeding to 
subsequent data collection. All participants, both control and intervention, 
will be assessed with the following assessments. 
Baseline Clinical Data collected will include demographics, level of 
educational attainment and past-medical history. Anthropometrics, Body 
Mass (kg) and height (m) will be assessed. (visit #1) 
 
11.1 Assessments 
11.1.1 Evaluation of mental state (visit #1) 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 8 of 27 
Revised: December 10, 2021 
A standardized Mini Mental Test (SMMT) will be used to evaluate the 
mental state. SMMT is a test with high sensitivity levels for moderate to 
severe cognitive impairment, as well as satisfactory reliability, internal 
consistency, and test-retest reliability, first developed by (Folstein et al., 
1975) (Tombaugh & McIntyre, 1992). The test, which is one of the most 
widely used screening criteria for evaluating neuropsychological functions, 
is used in many patient groups, including heart diseases. SMMT is a scale 
that evaluates cognitive functions in orientation, registration, attention and 
calculation, recall and language sub-categories with a total of 30 points. 
Low scores indicate poor performance, while the cut-off point of the test is 
24 for most patient populations (Nussmeier et al., 2010; Tombaugh and 
McIntyre, 1992). In our study, individuals who score below 24 in SMMT 
will be excluded from the study. The SMMT attached end of this document. 
 
11.1.2 Questioning alcohol use (visit #1) 
The alcohol use status of the participants will be evaluated by the American 
Psychiatric Association, Diagnostic and Statistical Manual of Mental 
Disorders (DSM-5) (American Psychiatric Association, 2013). The DSM-5 
evaluates an individual's alcohol use in the last 12 months with 11 items. 
Under the DSM-5, individuals who meet any 2 of 11 criteria within the last 
12 months are diagnosed with alcohol dependence. The severity of the 
addiction (mild, moderate, or severe) depends on the number of criteria met. 
Participants meeting 2 or more of the 11 criteria defined in the DSM-5 in 
our study will be excluded from the study. The DSM-5 attached end of this 
document. Alcohol consumption is known to affect vascular function. 
 
11.1.3 Dyspnea Evaluation (visit #1, 4-week visit) 
The modified Medical Research Council (mMRC) dyspnea scale used in 
the evaluation of general dyspnea is a simple, valid and reliable five-item 
scale based on various physical activities that cause dyspnea. With this 
scale, patients are asked to mark the activity level that causes dyspnea 
(Bestall et al., 1999). There are many studies indicating that this scale is 
associated with dyspnea, arterial blood gases, health status, and lung 
function tests (Bausewein et al., 2007; Bestall et al., 1999; Wilson and 
Jones, 1989). The mMRC dyspnea scale attached end of this document. 
 
11.1.4 Evaluation of Functional Exercise Capacity (visit #1, 4-week 
visit) 
Submaximal functional exercise capacity will be evaluated with the 6-
minute walking test (6MWT). 6MWT is a test that is frequently used in the 
evaluation of submaximal functional exercise capacity, has a low cost, 
provides important clinical results and is recommended by the guidelines 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 9 of 27 
Revised: December 10, 2021 
(ATS, 2002). As the standard protocol of the test, the person is asked to 
walk as fast as possible for six minutes in a continuous 30-meter corridor. 
Peripheral oxygen saturation, heart rate, perceived severity of dyspnea and 
leg fatigue (range 0-10) with the modified Borg scale are recorded before 
and after the test (ATS 2002; Borg, 1982). At the end of the test, the total 
distance walked is recorded in meters (Enright and Sherrill, 1998).  
 
11.1.5 Inspiratory Muscle Function Evaluation (visit #1, 2-week visit, 
4-week visit) 
Inspiratory muscle function testing will be obtained from the PrO2Fit 
device (PrO2 Health Incorporated, Rhode Island, NE, USA) in which the 
maximal inspiratory pressure (MIP), total breath power and Fatigue Index 
Test (FIT) can be seen (McCreery et al., 2021). The PrO2Fit device 
incorporates a 2 mm leak to avoid glottal closure during maximal 
inspiration. The MIP is the highest pressure measured during inspiration 
and measured at residual volume (RV), with the unit of measure centimetres 
of water (cm H2O). 
 
11.1.6 Endothelial Function Assessment (visit #1, 4-week visit) 
A standard non-invasive method will be used to assess endothelial function. 
For this, flow-mediated dilation (FMD) ultrasound measurements of 
brachial artery flow-mediated dilatation will be performed according to 
standard methods with ultrasonography (ProSound α7; Aloka, Tokyo, 
Japan) using a multifrequency linear array transducer as previously 
described (Ozemek et al., 2020; Thijssen et al., 2011). Briefly, a cuff will 
be placed on the upper forearm and brachial artery images will be taken ~3–
6 cm above the antecubital fossa. After taking simultaneous measurements 
of 1-min baseline brachial artery diameter and blood flow velocity, forearm 
occlusion will be produced by inflating the cuff to 250 mmHg for 5 minutes 
and then rapidly deflating it. After the release of the artery occlusion, 
Doppler blood flow velocity will be obtained and B-mode ultrasound 
brachial artery diameter images will be measured continuously for 3 
minutes. Brachial artery diameter and blood flow velocity will be analyzed 
using an available software package (QUIPU SRL, Cardiovascular Suite 
4.5.0, Italy). All procedures will be performed following published 
guidelines for the assessment of FMD in human participants (Corretti et al., 
2002; Thijssen et al., 2011).  
 
11.1.7 Evaluation of Arterial Stiffness (visit #1, 4-week visit) 
Arterial stiffness will be assessed by measuring pulse wave velocity with a 
dedicated system (Noninvasive hemodynamics (NIHem) workstation, 
Cardiovascular Engineering, Inc. Norwood, MA) according to the methods 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 10 of 27 
Revised: December 10, 2021 
previously described (Mitchell et al., 2010). Arterial tonometry of the 
brachial, radial, femoral and carotid artery will be performed with a custom 
transducer and waveforms were signal-averaged and gated to the ECG R-
wave (NIHem, Cardiovascular Engineering, Inc. Norwood, MA) as 
previously described (Mitchell et al., 2010). Measurements will be made 
after a four-hour fast and before any other exercise test to be performed on 
the same day (Scalzo et al., 2017; Mitchell et al., 2010).  
 
11.2 
Inspiratory Muscle Training Protocol: 
Based on the findings of a systematic review (Z. Sadek et al., 2018), it has 
been determined that to achieve significant improvements in inspiratory 
muscle strength, the threshold pressure for inspiratory muscle training 
(IMT) should be set at 60% of the maximal inspiratory mouth pressure 
(MIP). Consequently, the intervention protocol for IMT involves using a 
threshold-loaded IMT device (Threshold IMT Philips® Respironics, Inc). 
In the IMT group, the initial intensity of the inspiratory threshold will be set 
at 60% of each patient's initial maximal MIP, which is then readjusted after 
2 weeks of training to maintain the 60% of MIP throughout the 4-week 
period. Rates of perceived inspiratory effort on a modified Borg scale will 
also be used to determine the highest tolerable load for each patient (at the 
4-6 level of 10) (Borg, 1982; Wilson and Jones, 1989). Patients will perform 
IMT for 2 sets of 30 repetitions, with one-minute intervals between each set 
(McConnell, 2013; Z. Sadek et al., 2018). Throughout the training sessions, 
patients will be instructed to maintain diaphragmatic breathing. On the other 
hand, the Sham-control group will follow the same training program using 
the same device, but without any inspiratory load. Both groups will perform 
the training program twice a day, five days a week, for a total of 4 weeks, 
under the supervision of a physiotherapist (McConnell, 2013). The 
supervision will be conducted remotely through telerehabilitation, utilizing 
video calls to connect with the patients without requiring them to physically 
visit the healthcare facility. To familiarize the participants with the training 
procedure, both the IMT and Sham-control groups will undergo a session 
without any load on the day of the baseline assessments. Throughout the 
study, all participants will visit the healthcare facility for baseline 
assessments, final assessments, and an additional brief assessment session 
at the end of the second week of training to measure MIP and readjust the 
loading value. The assessment to be made at the end of the 2nd week of the 
4-week training seasons will only include the assessment of inspiratory 
muscle function described in 11.1.5. 
The Threshold IMT products will be obtained by researchers and 
provided to patients without any cost. A patient who loses the product 
before the study ends will be notified that he or she will be excluded from 
the study. The enrolled research subject is not responsible for returning the 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 11 of 27 
Revised: December 10, 2021 
Threshold IMT product upon completion of the research activities. There 
are no expected adverse events based on the product label. 
 
 
  
 
 
12.0 Data and Specimen Banking* 
12.1 
The data will be banked for future use by sharing with all researchers 
for 5 years at least without any personal information of patients. All written 
data collection forms and digital data will be hendled by principal 
investigator.. The principal investigator will be the person contacted and the 
authorizing authority in this regard. 
12.2 
The data to be stored: All written data collection forms, in addition 
to digital data that prepared for analysis. 
12.3 
The procedures to release data: Before using the data, those 
wishing to use it should contact the principal investigator via e-mail. In this 
e-mail, a state in general what the data will be used for and how it will be 
shared with whom. The principal investigator will be able to authorize the 
use of the data by providing a digitally signed pdf letter. Only academic 
researcher can obtain data.  
13.0 Sharing of Results with Subjects* 
13.1 Results (study results or individual subject results, such as results of 
investigational diagnostic tests, genetic tests, or incidental findings) 
will not be shared with subjects or others (e.g., the subject’s primary 
care physicians). Only the involved researchers will be informed.  
Patients will not be informed about the change in MIP values. 
14.0 Withdrawal of Subjects* 
14.1 
Subjects will be withdrawn from the research without their consent 
according to the rules as follows; 1. Not attending more than 20% of 
supervised intervention sessions. 2. Not perform the measurements after the 
intervention (at the end of the 4th week). 3. Losing the product (Philips 
IMT) before the study ends. 4. Consent in writing that who wishes to end 
the study at any stage of the study. 
14.2 
For patients meeting any of 14.1 (one of the above), the principal 
investigator will be notified. The principal investigator will notify that 
he/she has been terminated from the study by obtaining verbal consent from 
the relevant patient. 
14.3 Should the subject choose to withdraw, the health information 
already collected will continue to be used for research, however, no 
further health information will be collected.  All health information 
and collected data will be stored coded on paper, electronically on 
UIC Health Data Box Folder. Only the PI and Co-Is will have access 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 12 of 27 
Revised: December 10, 2021 
to the key to the code that links coded data with the identity of the 
subject (which will be password protected). 
 
15.0 Risks to Subjects* 
15.1 Confidentiality and privacy: A risk of this research is a loss of privacy 
or confidentiality. To minimize this risk and protect the participant’s 
identity, we will store health information coded, using a subject ID # 
instead of the participant’s name. Coding and locking of data will 
minimize the risk of confidentiality loss. All data collected during 
visits linking study and health information will also be coded and 
stored in the PI’s laboratory. Only the PI and limited research 
personnel will have access to the key to the code that links coded data 
with the identity of the participant (which will be password protected) 
and this key will be stored in the PI’s locked office (Rm 308A). 
15.2 Questionnaires: Participants may feel uncomfortable providing any 
personal information to questions. Subject will be advised to skip any 
questions they do not wish to answer. 
15.3 Cardiovascular function: There are no known risks associated with the 
process of measuring endothelial function or arterial stiffness. 
Subjects may however feel uncomfortable when the blood pressure 
cuffs are inflated. 
15.4 Lung/Respiratory Muscle Function and Inspiratory Muscle Training: 
There is risk of dizziness, coughing, and/or feeling short of breath 
during the tests. 
15.5 Functional Status: Participants may experience muscle tightness, 
muscle soreness and fatigue, shortness of breath, and lightheadedness. 
A research staff member will stand an arm’s length away while you 
are performing the balancing portion of the test for precautionary 
measures. 
 
16.0 Potential Benefits to Subjects* 
16.1 
Individual subjects who take part in this research may or may not 
experience improvements in pulmonary and/or physical functions. 
Information acquired during this study will contribute to the literature that 
seeks to determine the efficacy of this form of training. 
 
17.0 Data Management* and Confidentiality 
17.1 
All statistical analyses will be performed using SPSS 21.0 (SPSS, 
Chicago, Illinois). The Shapiro–Wilk test will be used to evaluate the 
normality of the data distribution for each variable, and the natural 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 13 of 27 
Revised: December 10, 2021 
logarithmic transformation will be applied when necessary. The continuous 
variables will be reported as a mean (standard deviation) and 95% 
confidence interval (95% CI), and the categorical variables will be 
presented in absolute frequencies and percentages. Nominal data will be 
compared using a chi-square test. An independent T-test will be used to 
compare groups for baseline characteristics. The treatment effect will be  
assessed using analysis of covariance (ANCOVA) with baseline values 
entered as covariates. The estimated marginal means will be saved from the 
ANCOVA model and will compare main effects with Bonferroni correction 
(Van Breukelen G. J., 2006) The significance level was set at 5% for all 
analyses. The necessary sample size based on Praveen et al. study 
examining the effects of inspiratory muscle training performed after CABG 
(Praveen et al., 2009), was calculated to be 14 participants per group (total 
n=28), with a significance level of 5%, statistical power of 80%, and a 
minimum difference of 54 m in 6-minute walking distance (6MWD), taking 
into account the change in maximum inspiratory pressure (MIP) after 
training. However, to optimize the results, a 20% loss was anticipated 
during follow-up, resulting Erdfelder et al., 1996). 
 
17.2 
To ensure the confidentiality, integrity, and availability of the data 
collected during the study, the following steps will be taken: 
o Authorization of Access: Access to the data will be limited to 
authorized personnel only, such as the study coordinator and 
principal investigator. The study participants' data will be 
anonymized, and any identifiable information will be stored 
separately from the study data. 
o Password Protection: All electronic data will be password-protected, 
with access restricted to authorized personnel only. Passwords will 
be required to access electronic files and folders containing the data. 
o Encryption: All electronic data collected during the study will be 
encrypted to ensure its security during transmission and storage. 
Data will be transmitted securely using encrypted methods and 
stored on secure hard drives. 
o Physical Controls: All physical documents and materials containing 
patient data will be stored in locked cabinets or rooms with access 
restricted to authorized personnel only. 
o Separation of Identifiers and Data: Identifiers, such as names and, 
will be stored separately from study data to ensure the privacy and 
confidentiality of participants. Identifiers will only be used to link 
study data to the participants, and they will be removed once the 
data analysis is complete. 
 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 14 of 27 
Revised: December 10, 2021 
17.3 
The data will be handled study-wide as follows: All written data 
collection forms and electronic data will be handled and stored by principal 
investigator. The written data collection forms will be stored in  PI’s locked 
office in a locked filing cabinet. The research electronic data will be stored 
using the UIC Health Box Data Folder electronic database.  
Authorized research personnel will maintain a master sheet which has the 
subject's name linked to their code. This sheet will be maintained within the 
UIC Health Box Data Folder designated for the study. All personal 
identifiable data will be destroyed 10 years after study completion. Results 
published will not include names of subjects. Some personal health 
information will be collected during the screening process, including name, 
contact information, and for individuals who meet the inclusion and 
exclusion criteria, dates of birth and CABG.  
  
 
18.0 Provisions to Monitor the Data to Ensure the Safety of Subjects* 
 The principal investigator will be primarily responsible for monitoring the 
safety of participants, and the safety and confidentiality of data. This will 
be done by following the best practices to ensure that we strictly adhere to 
the inclusion and exclusion criteria, and protections against risks outlines. 
The safety of each participant will be assessed on an individual basis 
throughout their involvement with the study. Any decline in function or 
participant responses that indicates a potential adverse effect will be 
reviewed individually and events will be reported to the IRB per UIC policy 
in a timely manner. 
A member of the study personnel will be available to each participant 
throughout testing and will be monitoring participant safety. Participants 
will be instructed to immediately inform study personnel if any adverse 
effects of treatment are experienced. We will ask the participant to provide 
us with a phone number of a caregiver (or friend or family member) to 
contact in case of emergency. Any adverse events or unanticipated 
problems will be recorded and communicated to all study personnel as soon 
as possible. Study personnel will be trained to identify and manage adverse 
events or unanticipated problems involving risks to subjects or others. The 
PI will be notified immediately. Serious adverse events, study-related 
adverse events, and unanticipated problems will be reported within 24 hours 
to the UIC IRB. Participants will be removed from the study if the study 
procedures threaten the participants’ safety or study procedures are 
unbearable. Any adverse events will be noted within the subject file. 
In the event of injury related to this research, treatment will be available. 
However, the subject or his/her third party payer, if any, will be responsible 
for payment of this treatment. In the unlikely event that the subject requires 
emergency medical care during a study visit, 911 will be called 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 15 of 27 
Revised: December 10, 2021 
immediately. There is no compensation and/or payment for such medical 
treatment for such injury except as may be required by law. 
 
 
19.0 Provisions to Protect the Privacy Interests of Subjects 
Confidentiality and privacy: A risk of this research is a loss of 
privacy or confidentiality. To minimize this risk and protect the 
participant’s identity, we will store health information coded, using a 
subject ID # instead of the participant’s name. Coding and locking of 
data will minimize the risk of confidentiality loss. All data collected 
during visits linking study and health information will also be coded 
and stored in the PI’s laboratory, in addition to a UIC Health Box Data 
Folder. Only the PI and limited research personnel will have access to 
the key to the code that links coded data with the identity of the 
participant (which will be password protected) and this key will be 
stored in a UIC Health Box Data Folder. 
 
20.0 Compensation for Research-Related Injury 
Compensation for research-related injury is not available. 
 
21.0 Economic Burden to Subjects 
Participants will only be invited to the institution where the study will be 
conducted for measurement at the beginning, middle and end of the study. 
In total, each patient will have come 3 times. Participants will cover their 
own travel expenses. It is not foreseen that there will be any other expenses. 
This information will be stated in the consent form, and patients who 
volunteered to participate in this study must have accepted it. 
22.0 Consent Process 
Informed consent will be obtained from the participant by the PI and/or research 
personnel according to UIC policy at the screening. 
Proper informed consent will be given according to previous training in responsible 
conduct of research, protection of human research participants, and good clinical 
practice. Participants will be be given a sufficient amount of time to review the 
consent document and ask any questions that they may have prior to providing their 
consent for participation. 
 
• Informed consent and authorization will be obtained after eligibility screening 
has been confirmed, either during the routine patient visit at the outpatient 
Exercise Testing or Cardiac Rehabilitation Programs.  
 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 16 of 27 
Revised: December 10, 2021 
o Subjects expressing interest in participating in the study will 
communicate to key research personnel conducting the screening 
and consenting process. During the routine visit, oral consent will 
be obtained so that eligibility screening. 
o An alteration of consent and a waiver of documentation of consent 
will be obtained for the eligibility screening.  
 
• All investigators/study personnel carrying out recruitment will follow a detailed 
informed consent process that will include a careful review study requirements 
and explanation of the study protocol  
• PI, and Key Research Personnel (research assistants) will obtain consent. 
Beside the PI and Co-Is, study staff thoroughly trained by the PI in the 
consenting process, and who have completed their CITI and HIPPA training 
may also obtain consent from subjects. 
 
• The PI will keep the original signed consent form, and the subject will receive 
a copy.  
 
• All consent documents and tracking sheets will be stored in Dr. Ozemek’s 
locked office in a locked filing cabinet.   
 
• All data collected for the current research purposes will be stored coded. 
 
• Subjects who do not speak English will be excluded (please see our inclusion 
and exclusion criteria for details). The process of recruitment, enrollment and 
obtaining written informed consent will only be in English. Lay language will 
be used to describe technical and medical terms 
 
*Non-English Speaking Subjects 
• 
Subjects who do not speak English will not be enrolled (please 
see our inclusion and exclusion criteria for details).  
 
*Request for Waiver or Alteration of Consent Process (If you 
will not obtain written consent, required information will not be 
disclosed, or the research involves deception) 
• Written consent will be obtain 
 
*Subjects who are not yet adults (infants, children, teenagers) 
• NA 
 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 17 of 27 
Revised: December 10, 2021 
*Cognitively Impaired Adults 
• 
The Standardized Mini-Mental Test will be applied to the 
patients as in the heading 11.1.1 and anyone with a score below 
24 will be excluded from the study. 
 
*Adults Unable to Consent 
• 
Adults Unable to Consent will not be involved in study. 
 
23.0 Process to Document Consent in Writing 
Informed consent will be obtained from the participant by the PI and/or research 
personnel according to UIC policy at the screening. 
Proper informed consent will be given according to previous training in responsible 
conduct of research, protection of human research participants, and good clinical 
practice. 
 
• Informed consent and authorization will be obtained after eligibility screening 
has been confirmed, either during the routine patient visit at the outpatient HF, 
Exercise Testing or Cardiac Rehabilitation Programs.  
 
o Subjects expressing interest in participating in the study will 
communicate to key research personnel conducting the screening 
and consenting process. During the routine visit, oral consent will 
be obtained so that eligibility screening. 
o An alteration of consent and a waiver of documentation of consent 
will be obtained for the eligibility screening.  
 
• All investigators/study personnel carrying out recruitment will follow a detailed 
informed consent process that will include a careful review study requirements 
and explanation of the study protocol  
• PI, and Key Research Personnel (research assistants) will obtain consent. 
Beside the PI and Co-Is, study staff thoroughly trained by the PI in the 
consenting process, and who have completed their CITI and HIPPA training 
may also obtain consent from subjects. 
 
• The PI will keep the original signed consent form, and the subject will receive 
a copy.  
 
• All consent documents and tracking sheets will be stored in Dr. Ozemek’s 
locked laboratory in a locked filing cabinet in Room 422 within the Applied 
Health Sciences Building.   
 
• All data collected for the current research purposes will be stored coded. 

PROTOCOL TITLE: Effects of high-intensity inspiratory muscle training as a pre-cardiac 
rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
Page 18 of 27 
Revised: December 10, 2021 
 
• Subjects who do not speak English will be excluded (please see our inclusion 
and exclusion criteria for details). The process of recruitment, enrollment and 
obtaining written informed consent will only be in English. Lay language will 
be used to describe technical and medical terms 
 
24.0 Setting 
This research will take place in the Physical Therapy Faculty Practice located at 
1640 W. Roosevelt Road in Chicago. 
Informed consent and authorization will be obtained after eligibility screening has 
been confirmed, either during the routine patient visit at the outpatient  Exercise 
Testing or Cardiac Rehabilitation Programs. 
Subjects expressing interest in participating in the study will communicate to key 
research personnel conducting the screening and consenting process. During the 
routine visit, oral consent will be obtained so that eligibility screening. 
An alteration of consent and a waiver of documentation of consent will be obtained 
for the eligibility screening.  
All investigators/study personnel carrying out recruitment will follow a detailed 
informed consent process that will include a careful review study requirements and 
explanation of the study protocol  
PI, and Key Research Personnel (research assistants) will obtain consent. Beside 
the PI and Co-Is, study staff thoroughly trained by the PI in the consenting process, 
and who have completed their CITI and HIPPA training may also obtain consent 
from subjects. 
After consent obtaining the first appointment for baseline measurements will be 
determined and research procedures detailed in section 11.0 will be carried out. 
 
25.0 Resources Available 
25.1 Dr. Ozemek runs UIC’s Cardiac Rehabilitation program and sees 
patients undergoing CABG, history of percutaneous coronary 
interventions, heart failure, and/or myocardial infarction on a daily 
basis. This service line will provide the volume of participants to 
complete the study. Dr. Ridvan Aktan is a visiting international 
scholar that has 100% of his time dedicated to this study and will 
therefore be able to oversee study visits and collect data.  
 
26.0 Multi-Site Research* 
This is a single site study. 
 

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rehabilitation intervention on cardiovascular functions in patients with heart disease  
 
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