PROactive Evaluation of Function to Avoid CardioToxicity
Phase: PHASE2
Conditions: Cardiotoxicity, Breast Cancer, Lymphoma, Sarcoma, Leukemia, Myeloma, Lung Cancer
Sponsor: Washington University School of Medicine

Protocol Title:   
PROactive evaluation of function to Avoid CardioToxicity 
(PROACT) 
 
Protocol ID#:  
 
201809177 
 
NCT#:  
 
 
NCT03862131 
 
Protocol Version Date: 
09/27/2021 
 

 
 
Version 6.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version Date: 09.27.2021 
PROACT 
PROactive evaluation of function to Avoid CardioToxicity 
 
Washington University School of Medicine 
660 South Euclid Avenue, Campus Box 8086 
St. Louis, MO 63110 
 
Protocol: VAL-1020P(A) 
Version: 6.0 
Version Date: September 27, 2021 
 
Principal Investigator:                Sponsor Name: 
Joshua Mitchell, MD, MSCI, FACC, FICOS       Myocardial Solutions, Inc. 
Assistant Professor of Medicine            3000 RDU Center Drive, Suite 117 
Cardiovascular Division                Morrisville, NC 27560 USA 
Interim Director, Cardio-Oncology Center of Excellence  
Phone: +1 (314) 362-1291              Sponsor Contact: 
Email: jdmitchell@wustl.edu              James G. Whayne 
                          Chief Clinical Officer 
                          Phone: +1 (919) 740-3051 
                          Email: jim.whayne@myocardialsolutions.com  
 
Co-Investigators: 
Lindsay Peterson, MD, MSCR            Brian Van Tine, MD, PhD 
Assistant Professor of Medicine            Associate Professor of Medicine 
Division of Medical Oncology – Breast Cancer      Division of Medical Oncology – Sarcomas 
Phone: +1 (314) 273-1473              Phone: +1 (314) 362-7997  
Email: llpeterson@wustl.edu             Email: bvantine@wustl.edu 
                         
Neha Mehta-Shah, MD                 Keith Stockerl-Goldstein, MD         
Assistant Professor of Medicine            Associate Professor of Medicine 
Division of Medical Oncology – Lymphoma       Division of Medical Oncology – BMT and Leukemia 
Phone: +1 (314) 362-5654              Phone: +1 (314) 454-8304 
Email: mehta-n@wustl.edu               Email: ksgoldstein@wustl.edu 
 
Shahed Badiyan, MD                Clifford Robinson, MD    
Assistant Professor of Medicine            Associate Professor of Medicine 
Division of Radiation Oncology             Division of Radiation Oncology 
Phone: +1 (314) 273-2931              Chief of Service, SBRT 
Email: sbadiyan@wustl.edu               Direction, Clinical Trials and Clinical Informatics 
                          Phone: +1 (314) 362-8567 
Pamela Woodard, MD                 Email: clifford.robinson@wustl.edu 
Sr. Vice Chair, Radiology Research Facilities  
Professor of Radiology and Biomedical Engineering 
Director, Center for Clinical Imaging Research 
Head, Advanced Cardiac Imaging (CT/MR) 
Director, Research Residency Program 
Phone: +1 (314) 747-3386 
Email: woodardp@mir.wustl.edu 
 
 
Participating Site lnvestigator:          Institution:            Modality: 
Vlad Zaha, MD, PhD, FACC, FASE, FHFSA     University of Texas Southwestern  Cardiology 
Lauren Baldassarre, MD, FACC, FSCMR, FSCCT  Yale               Cardiology 
Vijay Rao, MD, PhD, FACC, FASE, FHFSA     Franciscan St. Francis Health    Cardiology 
 
 
Data and Safety Monitoring Committee:     Institution:            Modality: 
Edward Geltman, MD               Washington University       Cardiology 
Nusayba Bagegni, MD              Washington University       Medical Oncology 
Elena Deych                   Washington University       Cardiology Statistician 
 
This submission contains CONFIDENTIAL material and information and should be restricted in its distribution.    
Do not copy without the permission of the Sponsor. 
This protocol was co-written by Daniel J. Lenihan, MD, FACC and Susan F. Dent, MD, FRCPC, Medical Oncologist at Ottawa 
Hospital Cancer Center. 
 

VAL-1020P 
PROactive evaluation of function to Avoid CardioToxicity 
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Version 6.0 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version Date: 09.27.2021 
PROACT 
PROactive evaluation of function to Avoid CardioToxicity 
 
 
Protocol Revision History 
 
 
Initial Approval Version                             08/24/2018 
 
Amendment 1: Version 2.0                           05/13/2019 
Summary of Changes 
Protocol v1.0 
Protocol v2.0 
 
Page 1 
Co-Investigators 
Addition of the following co-investigators: 
Keith Stockerl-Goldstein, MD 
Shahed Badiyan, MD 
Clifford Robinson, MD 
Page 8 
1.3 Study Design 
Original: 
Breast cancer, lymphoma, and sarcoma patients scheduled to receive anti-
cancer therapy, who are previously enrolled in the SURVIVE Registry, will be 
screened for study participation. 
Page 8 
1.3 Study Design 
Modified: 
Breast cancer, lymphoma, and sarcoma, leukemia, myeloma, and lung cancer 
patients scheduled to receive anti-cancer therapy, who are previously enrolled 
in the SURVIVE Registry, will be screened for study participation. 
Page 8 
1.6 Inclusion Criteria 
Original: 
3) Histological diagnosis of early or metastatic breast cancer, lymphoma, or 
sarcoma (patients with treated and clinically stable brain metastasis are 
acceptable) 
Page 8 
1.6 Inclusion Criteria 
Modified: 
3) Histological diagnosis of early or metastatic breast cancer, lymphoma, or 
sarcoma, leukemia, myeloma, or lung cancer (patients with treated and 
clinically stable brain metastasis are acceptable) 
Page 17 
5.1 Summary Protocol 
Original: 
Breast cancer, lymphoma, or sarcoma patients scheduled to receive anti-
cancer therapy with or without concomitant radiotherapy and enrolled in the 
SURVIVE Registry will be evaluated based on baseline MyoStrain® segmental 
dysfunction risk profile. 
Page 17 
5.1 Summary Protocol 
Modified: 
Breast cancer, lymphoma, or sarcoma, leukemia, myeloma, or lung cancer 
patients scheduled to receive anti-cancer therapy with or without concomitant 
radiotherapy and enrolled in the SURVIVE Registry will be evaluated based on 
baseline MyoStrain® segmental dysfunction risk profile. 
 
Page 18 
Figure 2 – Study Flow Diagram 
Modified to reflect addition of leukemia, myeloma, and lung cancer and to 
update the secondary inclusion criteria as listed in the context of the protocol. 
Page 20 
5.3 Study Population 
Original: 
Subjects enrolled in the SURVIVE Registry and scheduled to undergo 
chemotherapy or targeting treatment as well as clinically indicated cardiac MRI 
will be will be consented for possible inclusion in PROACT. 
Page 20 
5.3 Study Population 
Modified: 
Subjects enrolled in the SURVIVE Registry and scheduled to undergo 
chemotherapy or targeteding treatment as well as clinically indicated cardiac 
MRI will be will be consented for possible inclusion in PROACT. 
Page 20 
5.4 Inclusion Criteria 
Original: 
3) Histological diagnosis of early or metastatic breast cancer, lymphoma, or 
sarcoma (patients with treated and clinically stable brain metastasis are 
acceptable) 
Page 20 
5.4 Inclusion Criteria 
Modified: 
3) Histological diagnosis of early or metastatic breast cancer, lymphoma, or 
sarcoma, leukemia, myeloma, or lung cancer (patients with treated and 
clinically stable brain metastasis are acceptable) 
 
 
Amendment 2: Version 3.0                           09/05/2019 
Summary of Changes 
Protocol v2.0 
Protocol v3.0 
Page 17 
5.1 Summary Protocol 
Original: 
Eligible patients will be randomized 1:1 into the MyoStrain® guided treatment 
arm versus the Myostrain® blinded observational arm, as shown in Figure 2.  
The treatment arm will guide patient management by augmenting standard of 
care with serial MyoStrain® monitoring of the impact of cancer therapy on 
myocardial function.  The observational arm will provide investigators with 
LVEF and LVEDV/LVESV measurements, which are clinical.  The standard of 
care assessments by cardiac MRI, will not include MyoStrain® assessments. 
Page 17 
5.1 Summary Protocol 
Modified: 
Eligible patients will then be randomized 1:1 into the MyoStrain® guided 
treatment arm versus the Myostrain® blinded observational arm, as shown in 
Figure 2.  The treatment arm will guide patient management by augmenting 
standard of care with serial MyoStrain® monitoring of the impact of cancer 
therapy on myocardial function by providing physicians with MyoStrain® values, 
in addition to LVEF, LVEDV, and LVESV.  In tThe observational arm, 
physicians will only be provided investigators with LVEF, LVEDV, and /LVESV, 
which are clinical measurements.  The standard of care assessments by 
cardiac MRI, will not include MyoStrain® assessments.  
 
 

 
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Page 17 
5.1 Summary Protocol 
Added: 
In order to obtain the MyoStrain® values, MRI images obtained will be 
uploaded de-identified to Myocardial Solutions, Inc.  After the baseline scan, 
Myocardial Solutions, Inc. will inform research staff whether the patient met 
criteria for continued follow up in the study.  At that time, the patient will be 
randomized to one of the two arms, as previously described, and Myocardial 
Solutions, Inc. will be made aware of the randomization result.  If randomized 
to the blinded observational arm, no results from any cardiac MRI obtained for 
the study will be provided to physicians from Myocardial Solutions, Inc. If 
randomized to the MyoStrain® guided treatment arm, MyoStrain® results and 
LVEF, LVEDV, and LVESV will be provided for all cardiac MRI’s obtained in 
the study to the physicians.  Sites will also send Myocardial Solutions, Inc. de-
identified information about the patients’ medical history (i.e. comorbidities, 
past/current medications, etc.). 
 
In addition to Myocardial Solutions, Inc. reviewing the cardiac MRI images, due 
to the multi-departmental nature of this study, sites may also choose to obtain 
a clinical read on the research cardiac MR images obtained on the short axis, 
which are the same images that would be obtained in a clinical MRI, and 
provide only the LVEF, LVEDV, and LVESV for all subjects, regardless of 
randomization arm, and those values may be uploaded to the patients’ medical 
record, if permitted.  Doing so would then allow patients’ oncology team access 
to this information in lieu of obtaining additional testing (i.e. clinical cardiac 
MRI’s, echocardiograms, etc.) to obtain this same information. 
 
Page 18 
Figure 2 
Clarified: 
Clarified randomization pathway vs. screen failure pathway after the second 
inclusion criteria is met. 
Page 22 
Section 8 
Original: 
The following steps must be taken before registering patients to this study: 
1. 
Registration of patient in the Siteman Cancer Center OnCore 
database 
2. 
Confirmation of patient eligibility by Washington University 
 
Page 22 
Section 8 
Modified: 
The following steps must be taken in order to before registering patients to this 
study: 
1. Confirmation of patient eligibility by site PI 
2. Consent of patient to PROACT study 
3. Confirmation of patient eligibility by Washington University 
4. Assignment of Participant ID 
5. Registration of patient participant in the Siteman Cancer Center OnCore 
database 
 
Added: 
Once the patient has been entered into the Siteman Cancer Center OnCore 
database, the coordinating center’s coordinator will forward verification of 
enrollment and the subject ID. 
Page 23 
Section 8.1 
Original: 
Section 8.2 
Confirm patient eligibility by collecting the information listed below and 
scanning and emailing it to the coordinating center’s coordinator at least one 
business day prior to randomizing the patient: 
1. 
Your name and contact information (telephone number, fax 
number, and email address) 
2. 
Your site PI’s name, the registering investigator’s name, and your 
institution name 
3. 
Patient’s race, sex, and DOB 
4. 
Three letters (or two letters and dash) for the patient’s initials 
5. 
Currently approved protocol version date 
6. 
Copy of signed consent form (patient name may be blacked out) 
7. 
Completed eligibility checklist, signed and dated by a member of 
the study team 
8. 
Copy of appropriate source documentation confirming patient 
eligibility 
 
The coordinating center will email the participating site with verification of 
eligibility of the patient within 1 business day.  Once verification of eligibility has 
been received, the patient can be randomized. 
Page 23 
Section 8.1 
Modified: 
Moved to Section 8.1 
Confirm patient eligibility by collecting the information listed below and 
scanning and emailing it to the coordinating center’s coordinator at least one 
business day prior to the patient’s baseline MRI scan: 
1. 
Your name and contact information (telephone number, fax 
number, and email address) 
2. 
Your site PI’s name, the registering investigator’s name, and your 
institution name 
3. 
Patient’s race, sex, and DOB 
4. 
Three letters (or two letters and dash) for the patient’s initials 
5. 
Currently approved protocol version date 
6. 
Copy of signed consent form 
7. 
Completed eligibility checklist, signed and dated by a member of 
the study team 
8. 
Copy of appropriate source documentation confirming patient 
eligibility 
 
The coordinating center will email the participating site with verification of 
eligibility of the patient within 1 business day.  Once verification of eligibility has 
been received, the patient can be randomized will be registered into OnCore 
and the patient may undergo the baseline MRI scan. 
Page 23 
Section 8.2 
Original: 
Section 8.1 
Registrations may be submitted Monday through Friday between 8am and 5pm 
CST.  Urgent late afternoon or early morning enrollments should be planned in 
advance and coordinated with the Washington University research coordinator.  
Registration will be confirmed by the research coordinator or his/her delegate 
by email within 1 business day. 
Page 23 
Section 8.2 
Modified: 
Moved to Section 8.2 
Registrations may be submitted Monday through Friday between 8am and 5pm 
CST.  Urgent late afternoon or early morning enrollments should be planned in 
advance and coordinated with the Washington University research coordinator.  
Registration will be confirmed by the research coordinator or his/her delegate 

 
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All patients at all sites must be registered after the patient has been consented, 
prior to the baseline MRI scan. 
by email within 1 business day.  Verification of eligibility and registration should 
be retained in the participant’s study chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center 
OnCore database at Washington University after the patient has been 
consented, prior to the baseline MRI scan. 
 
Page 23 
Section 8.3 
Added: 
Each patient will be identified with a unique Participant ID for this study.  The 
Participant ID will be based on the patient’s Participant ID in the SURVIVE 
Registry, as well as the patient’s enrollment number in the PROACT study.  All 
data will be recorded with this Participant ID on the appropriate CRFs. 
Page 26 
Section 9.4.3 
Original: 
The research team at a participating site is responsible for following its site’s 
guidelines for reporting applicable events to its site’s IRB according to its own 
institutional guidelines.   
Page 26 
Section 9.4.3 
Modified: 
The research team at a participating site is responsible for following its site’s 
guidelines for reporting applicable events to its site’s IRB according to its own 
institutional guidelines.  Since sites will be relying on Washington University’s 
IRB, any reportable event will also be submitted to Washington University’s 
IRB for review. 
Page 27 
Section 10.1.2 
 
 
 
 
 
 
 
 
 
 
 
 
Original: 
Data monitoring will be conducted by the coordinating center and will consist of 
data checks, both electronic and manual. Every 6 months, data entered into 
the REDCap database will be reviewed for accuracy by designated study staff 
at the coordinating center.  Uploaded source documentation by participating 
sites will also be reviewed for inconsistent data, if applicable.  If there are 
inconsistencies or missing values, queries will be issued to the participating 
sites and they will refer to the subject’s records to correct the aberration. 
Participating sites are expected to enter data into REDCap within 14 business 
days of a study visit.  Sites that appear to have significant delays between the 
time of enrollment/study visits and data entry will be contacted by the 
coordinating center.  Participating sites are also expected to respond to any 
REDCap queries within 1 month of issuance. Sites that appear to have a 
significant amount of REDCap queries will be contacted by the coordinating 
center.  At each interval, the coordinating center will note the number of 
participants accrued to date as well as the number of participants accrued for 
that 6 months interval.  
 
Page 27 
Section 10.1.2 
Added: 
Data and regulatory documents from all participating sites will be reviewed by 
the Washington University Quality Assurance and Safety Monitoring 
Committee (QASMC) every 6 months.  For participating sites added on after 
study initiation, the first review for that site will take place during the next 
scheduled QASMC review, which may occur prior to 6 months after site 
initiation.  Because all monitoring will take place remotely, uploads of source 
documentation, including consent forms with signatures, either to REDCap 
and/or WUSTL Box will be mandatory for participating sites.  In addition, 
QASMC may request access to participating sites’ electronic medical record, if 
the site’s institution allows such access. 
 
Modified: 
Data and regulatory document monitoring will also be conducted by the 
coordinating center’s research coordinators and will consist of data checks, 
both electronic and manual. Every 6 months prior to QASMC review, data 
entered into the REDCap database will be reviewed for accuracy by 
designated study staff at the coordinating center.  As with QASMC audits, for 
participating sites added on after study initiation, the first review for that site will 
take place during the next scheduled data review.  Uploaded source 
documentation, including consent forms with signatures, by participating sites 
will also be reviewed for inconsistent data, if applicable.  If there are 
inconsistencies or missing values, queries will be issued to the participating 
sites and they will refer to the subject’s records to correct the aberration. 
Participating sites are expected to enter data into REDCap within 14 business 
days of a study visit.  Sites that appear to have significant delays between the 
time of enrollment/study visits and data entry will be contacted by the 
coordinating center.  Participating sites are also expected to respond to any 
REDCap queries within 1 month of issuance. Sites that appear to have a 
significant amount of REDCap queries will be contacted by the coordinating 
center.  At each interval, the coordinating center will note the number of 
participants accrued to date as well as the number of participants accrued for 
that 6 months interval.  
Page 27 
Section 10.1.3 
Original: 
In compliance with the Washington University Institutional Data and Safety 
Monitoring Plan, the Data and Safety Monitoring Committee (DSMC) will meet 
to review data semi-annually beginning six months after accrual has begun.  
The report will include: 
• 
HRPO protocol number, protocol title, Principal Investigator name, 
and research coordinator name 
• 
Date of initial HRPO approval, date of most recent HRPO 
approval/revision of consent, date of HRPO expiration, and study 
status 
• 
History of study including summary of substantive amendments; 
summary of accrual suspensions including start/stop dates and 
reason 
• 
Study-wide target accrual and study-wide actual accrual 
• 
Protocol activation date 
• 
Average rate of accrual observed in Year 1, Year 2, and 
subsequent years 
• 
Expected accrual end date 
• 
Objectives of protocol with supporting data and list of the number 
of participants who have met each objective 
• 
Measures of efficacy 
Page 27 
Section 10.1.3 
Modified: 
In compliance with the Washington University Institutional Data and Safety 
Monitoring Plan, the Principal Investigator will provide a Data and Safety 
Monitoring Committee (DSMC) report to the Washington University Quality 
Assurance and Safety Monitoring Committee (QASAMC) will meet to review 
data semi-annually beginning six months after accrual has opened (if at least 5 
patients have been enrolled) or 1 year after accrual has opened (if fewer than 5 
patients have been enrolled at the 6 month mark) begun.   
 
The Principal Investigator will review all patient data at least every 6 months, 
and provide a semi-annual report to QASMC.  The report will include: 
• 
HRPO protocol number, protocol title, Principal Investigator name, 
and research coordinator name 
• 
Date of initial HRPO approval, date of most recent HRPO 
approval/revision of consent, date of HRPO expiration, date of 
most recent QA audit, and study status, and phase of study 
• 
History of study including summary of substantive amendments; 
summary of accrual suspensions including start/stop dates and 
reason; and summary of protocol exceptions, error, or breach of 
confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual 
• 
Protocol activation date 

 
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• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or 
ethics of the study 
• 
Average rate of accrual observed in Year 1, Year 2, and 
subsequent years 
• 
Expected accrual end date 
• 
Objectives of protocol with supporting data and list of the number 
of participants who have met each objective 
• 
Measures of efficacy 
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or 
ethics of the study 
 
Amendment 3: Version 4.0                           01/24/2020 
Summary of Changes 
Protocol v3.0 
Protocol v4.0 
Page 1 
Data and Safety Monitoring Committee 
Original: 
Gregory Ewald, MD, FACC     Washington University     Cardiology 
Edward Geltman, MD              Washington University     Cardiology 
Justin Vader, MD                     Washington University     Cardiology 
Page 1 
Data and Safety Monitoring Committee 
Modified: 
Gregory Ewald, MD, FACC   Washington University    Cardiology 
Edward Geltman, MD            Washington University    Cardiology 
Manik Amin, MD                    Washington University    Cardiology 
Elena Deych                          Washington University    Cardiology Statistician 
Justin Vader, MD                   Washington University    Cardiology 
Page 9 
1.3 Study Design 
Original: 
Breast cancer, lymphoma, sarcoma, leukemia, myeloma, and lung cancer 
patients scheduled to receive anti-cancer therapy, who are previously enrolled 
in the SURVIVE Registry, will be screened for study participation. 
 
 
1.5 Endpoints 
Original: 
The primary efficacy endpoint is the sensitivity of detection of patients with 
myocardial dysfunction using MyoStrain® compared to standard assessments 
of cardiac function: left ventricular ejection fraction (LVEF), as well as end-
systolic (LVESV) and end-diastolic (LVEDV) volumes.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page 10 
1.3 Study Design 
Modified: 
Breast cancer, lymphoma, sarcoma, leukemia, myeloma, or lung cancer 
patients Patients with any type of cancer scheduled to receive anti-cancer 
therapy, who are previously enrolled in the SURVIVE Registry, will be 
screened for study participation. 
 
1.5 Endpoints  
Modified: 
The primary efficacy endpoint is the sensitivity and accuracy of detection of 
patients with myocardial dysfunction using MyoStrain® compared to standard 
assessments of cardiac function: left ventricular ejection fraction (LVEF), as 
well as end-systolic (LVESV), and end-diastolic (LVEDV), and stroke (LVSV) 
volumes indexed to body surface area.   
 
Changes in function based on clinical presentation, standard assessments, 
and all available metrics will be used to define the cardiotoxicity status of the 
patient.  A clinical committee organized and chaired by the principal 
investigator will be used to classify each exam in both unblinded and blinded 
arms according to professional knowledge and derived from the ASE Expert 
Consensus Position Paper, the ESC Position Paper, and the ESMO Clinical 
Practice Guidelines.  [1] [2] [3] 
 
• 
Clinical cardiac dysfunction is defined as an absolute change in 
LVEF > 10% from baseline to below 53% combined with heart 
failure symptoms or abnormal cardiac biomarkers (troponin, BNP, 
or NT pro BNP).   
• 
Subclinical CTX was defined as an asymptomatic patient with a 
greater than 15% decrease in LVEF that remains >= 53%, 
worsening GLS more than 15% from baseline, or abnormal 
cardiac biomarkers (troponin, BNP, or NT pro BNP). 
If no baseline information is available to compare metrics for categorizing 
cardiotoxicity status, considering most patients in the PROACT sub-study of 
the Survive Registry will have metastatic cancer with prior treatments including 
chemotherapy, physician discretion and patient presentation will provide the 
final decision on cardiotoxicity category.  All available metrics will be used to 
classify patients at each assessment time point. 
Page 9 
1.6 Inclusion Criteria 
Original: 
3) Histological diagnosis of early or metastatic breast cancer, lymphoma, 
sarcoma, leukemia, myeloma, or lung cancer (patients with treated and 
clinically stable brain metastasis are acceptable) 
Page 11 
1.6 Inclusion Criteria 
Modified: 
3) Histological diagnosis of early or metastatic breast cancer, lymphoma, 
sarcoma, leukemia, myeloma, or lung any cancer type (patients with treated 
and clinically stable brain metastasis are acceptable) 
 
1.7 Exclusion Criteria 
Added/Clarified: 
Note: If a patient develops a temporary contraindication (e.g. temporary tissue 
expanders in breast cancer patients) after the baseline MRI, follow up MRIs will 
be discontinued for safety for the duration in which the patient has the 
contraindication.  However, once the patient is no longer contraindicated to 
receiving MRIs, the study schedule may resume with their next scheduled MRI 
time point from the date of enrollment.  Therefore, some time points may be 
skipped during the patient’s enrollment in the study. 
 
Also, if a patient needs a repeat MRI at any time point for any reason (i.e. 
panic attack during the MRI causing them to not be able to continue, 

 
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unreadable images, etc.), we may repeat the MRI as long as the patient is 
willing. 
Page 18 
5.1 Summary Protocol 
Original: 
Breast cancer, lymphoma, sarcoma, leukemia, myeloma, or lung cancer 
patients scheduled to receive anti-cancer therapy with or without concomitant 
radiotherapy and enrolled in the SURVIVE Registry will be evaluated based on 
baseline MyoStrain segmental dysfunction risk profile. 
Page 19 
5.1 Summary Protocol 
Original: 
Breast cancer, lymphoma, sarcoma, leukemia, myeloma, or lung cancer 
patients Patients with any type of cancer scheduled to receive anti-cancer 
therapy with or without concomitant radiotherapy and enrolled in the SURVIVE 
Registry will be evaluated based on baseline MyoStrain segmental dysfunction 
risk profile. 
Page 21 
5.4 Inclusion Criteria 
3) Histological diagnosis of early or metastatic breast cancer, lymphoma, 
sarcoma, leukemia, myeloma, or lung cancer (patients with treated and 
clinically stable brain metastasis are acceptable) 
 
 
 
Page 23 
5.4 Inclusion Criteria 
3) Histological diagnosis of early or metastatic breast cancer, lymphoma, 
sarcoma, leukemia, myeloma, or lung any cancer type (patients with treated 
and clinically stable brain metastasis are acceptable) 
 
5.5 Exclusion Criteria 
Added/Clarified: 
Note: If a patient develops a temporary contraindication (e.g. temporary tissue 
expanders in breast cancer patients) after the baseline MRI, follow up MRIs will 
be discontinued for safety for the duration in which the patient has the 
contraindication.  However, once the patient is no longer contraindicated to 
receiving MRIs, the study schedule may resume with their next scheduled MRI 
time point from the date of enrollment.  Therefore, some time points may be 
skipped during the patient’s enrollment in the study. 
 
Also, if a patient needs a repeat MRI at any time point for any reason (i.e. 
panic attack during the MRI causing them to not be able to continue, 
unreadable images, etc.), we may repeat the MRI as long as the patient is 
willing. 
Page 27 
Statistical Considerations 
Original: 
…Furthermore, we will use decision trees for identifying the importance of 
MyoStrain cardiac features compared to cardiac toxicity risk prediction based 
on standard assessment of variables LVEF, LVESV, and LVEDV… 
 
 
 
 
 
 
 
 
Original: 
The sensitivity, specificity, and diagnostic accuracy of each reader to detect 
changes in myocardial function will be determined for quantitative SENC-CMR. 
Cutoff-values used to calculate sensitivity and specificity of the quantitative 
SENC parameters will be determined using data previously published.  
McNemar’s test with continuity correction will be used to compare the 
diagnostic performance of each of the SENC-CMR cutoff parameters. 
Additionally, Receiver Operating Characteristic curves will be generated to 
calculate and compare the area under the curves to determine the diagnostic 
performance of changes in various strain parameters. Inter- and intra-observer 
variability will also be determined for each of the above parameters using 
intraclass correlation. 
Page 30 
Statistical Considerations 
Modified: 
…Furthermore, we will use decision trees for identifying the importance of 
MyoStrain cardiac features compared to cardiac toxicity risk prediction based 
on standard assessment of variables LVEF, LVESV, and LVEDV, and LV 
Stroke Volume Index (LVSVi). Endpoints will be evaluated based on discrete 
variables of MyoStrain values versus standard assessments.  Considering 
many patients will have a complex management of cardioactive medications as 
well as cancer treatment regimen, the classification of cardiotoxicity status will 
be based on a clinical committee to designate whether the patient experienced 
no cardiotoxicity, functional decline without cardiotoxicity, subclinical 
cardiotoxicity, or clinical cardiac dysfunction at each exam time point… 
 
Modified: 
The sensitivity, specificity, and diagnostic accuracy of each reader to detect 
changes in myocardial function will be determined for quantitative SENC-CMR. 
Cutoff-values used to calculate sensitivity and specificity of the quantitative 
SENC parameters will be were determined using data previously published. 
The cutoff for the % of MyoStrain segments <= -17% (based on 37 left 
ventricular segments) in detecting subclinical cardiotoxicity in the PREFECT50 
planned interim analysis was 68% and the cutoff for detecting clinical cardiac 
dysfunction was 49%; a cutoff of 80% differentiates normal cardiac function 
from patients experiencing functional decline.  McNemar’s test with continuity 
correction will be used to compare the diagnostic performance of each of the 
SENC-CMR cutoff parameters. Additionally, Receiver Operating Characteristic 
curves as well as Precision Recall curves will be generated to calculate and 
compare the area under the curves to determine the diagnostic performance of 
changes in various strain parameters and standard assessments. Inter- and 
intra-observer variability will also be determined for each of the above 
parameters using intraclass correlation. 
 
Amendment 4: Version 5.0                           04/13/2020 
Summary of Changes 
Protocol v4.0 
Protocol v5.0 
Page 20 
5.1 Summary Protocol 
Original: 
Patient’s will continue to undergo MyoStrain® MRI testing, regardless of study 
arm, at 1 month (+ 1 week), 3 months (+ 1 week), 6 months (+ 1 week), 12 
months (+ 30 days), 24 months (+ 30 days), and 36 months (+ 30 days) after 
the baseline visit.   
Page 20 
5.1 Summary Protocol 
Modified: 
Patient’s will continue to undergo MyoStrain® MRI testing, regardless of study 
arm, at 1 month (+ 2 weeks 1 week), 3 months (+ 2 weeks 1 week), 6 months 
(+ 2 weeks 1 week), 12 months (+ 30 days), 24 months (+ 30 days), and 36 
months (+ 30 days) after the baseline visit.   
Page 22 
5.1 Summary Protocol 
 
Page 22 
5.1 Summary Protocol 
Modified: 
Changed time point windows for 1 month, 3 month, and 6 month time points in 
the PROACT Schedule of Events chart from + 1 week to + 2 weeks. 
 
 

 
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Amendment 5: Version 6.0                           09/27/2021 
Summary of Changes 
Protocol v5.0 
Protocol v6.0 
Page 1 
Principal Investigator: 
Original: 
Daniel J. Lenihan, MD, FACC 
Professor of Medicine 
Cardiovascular Division 
Director, Cardio-Oncology Center of Excellence 
Advanced Heart Failure 
Clinical Research 
Phone: +1 (314) 362-1291 
Email: djlenihan@wustl.edu  
 
Data and Safety Monitoring Committee: 
Original: 
Manik Amin, MD 
 
Original: 
This protocol was co-written by Susan F. Dent, MD, FRCPC, Medical 
Oncologist at Ottawa Hospital Cancer Center. 
Page 1 
Principal Investigator: 
Modified: 
Daniel J. Lenihan, MD, FACC Joshua Mitchell, MD, MSCI, FACC, FICOS 
Assistant Professor of Medicine 
Cardiovascular Division 
Interim Director, Cardio-Oncology Center of Excellence 
Advanced Heart Failure 
Clinical Research 
Phone: +1 (314) 362-1291 
Email: djlenihan@wustl.edu jdmitchell@wustl.edu  
 
Data and Safety Monitoring Committee: 
Modified: 
Manik Amin, MD Nusayba Bagegni, MD 
 
Modified: 
This protocol was co-written by Daniel J. Lenihan, MD, FACC and Susan F. 
Dent, MD, FRCPC, Medical Oncologist at Ottawa Hospital Cancer Center. 
Page 7 
Investigator’s Signature Page: 
Original: 
Name: Daniel J. Lenihan, MD, FACC 
Name: Vlad Zaha, MD, PhD, FACC, FASE, FHFSA 
Title: Clinical Site Investigator (University of Texas Southwestern) 
Name: Lauren Baldassarre, MD, FACC, FSCMR, FSCCT 
Title: Clinical Site Investigator (Yale) 
Name: Vijay Rao, MD, PhD, FACC, FASE, FHFSA 
Title: Clinical Site Investigator (Franciscan St. Francis Health) 
Page 8 
Investigator’s Signature Page: 
Modified: 
Name: Daniel J. Lenihan, MD, FACC Joshua Mitchell, MD, MSCI, FACC, 
FICOS 
Name: Vlad Zaha, MD, PhD, FACC, FASE, FHFSA 
Title: Clinical Site Investigator (University of Texas Southwestern) 
Name: Lauren Baldassarre, MD, FACC, FSCMR, FSCCT 
Title: Clinical Site Investigator (Yale) 
Name: Vijay Rao, MD, PhD, FACC, FASE, FHFSA 
Title: Clinical Site Investigator (Franciscan St. Francis Health) 
Page 11 
1.8 Expected Duration 
Original: 
Based on an enrollment of 102 eligible patients (a subset of the approximately 
700 SURVIVE Registry patients enrolled annually across all SURVIVE 
participating sites)… 
Page 12 
1.8 Expected Duration 
Modified: 
Based on an enrollment of 102 eligible 40 evaluable patients (a subset of the 
approximately 700 SURVIVE Registry patients enrolled annually across all 
SURVIVE participating sites)… 
Page 24 
5.6 Duration of the study for the subject 
Original: 
Based on an enrollment of 102 eligible patients (a subset of the approximately 
700 SURVIVE Registry patients enrolled annually across all SURVIVE 
participating sites)… 
 
5.7 Sample size 
Original: 
102 patients will be randomized 1:1 to the MyoStrain® imaging guided arm 
versus the standard of care arm. 
Page 25 
5.6 Duration of the study for the subject 
Modified: 
Based on an enrollment of 102 eligible 40 evaluable patients (a subset of the 
approximately 700 SURVIVE Registry patients enrolled annually across all 
SURVIVE participating sites)… 
 
5.7 Sample size 
Modified: 
102 40 evaluable patients will be randomized 1:1 to the MyoStrain® imaging 
guided arm versus the standard of care arm. 
 
 
 

 
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PROACT 
PROactive evaluation of function to Avoid CardioToxicity 
 
 
Principal Investigator’s Signature Page 
 
 
The study will be conducted in accordance with the International Conference on 
Harmonisation guidelines for Good Clinical Practice (ICH E6), the Code of Federal 
Regulations on the Protection of Human Subjects (45 CFR Part 46), and the NIDCR Clinical 
Terms of Award. All personnel involved in the conduct of this study have completed human 
subject’s protection training. 
The signature below constitutes the approval of this protocol and the attachments, and 
provides the necessary assurances that this trial will be conducted according to all 
stipulations of the protocol, including all statements regarding confidentiality, and according 
to local legal and regulatory requirements and applicable US federal regulations and ICH 
guidelines. 
Principal Investigator and Clinical Site Investigators: 
 
 
Signed: 
 
Date:  
 
Name: Joshua Mitchell, MD, MSCI, FACC, FICOS 
 
Title: 
Principal Investigator 
 

 
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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ................................................................................................................................9 
1. 
SUMMARY ......................................................................................................................................... 11 
1.1. Study Purpose................................................................................................................................. 11 
1.2. Study Device and Intended Use ...................................................................................................... 11 
1.3. Study Design ................................................................................................................................... 11 
1.4. Objectives ....................................................................................................................................... 11 
1.5. Endpoints ........................................................................................................................................ 11 
1.6. Inclusion Criteria ............................................................................................................................. 12 
1.7. Exclusion Criteria ............................................................................................................................ 12 
1.8. Expected Duration ........................................................................................................................... 12 
2. 
DEVICE DESCRIPTION...................................................................................................................... 12 
2.1. MyoStrain® SENC CMR Imaging System ......................................................................................... 12 
2.2. Background Clinical & Preclinical Testing ........................................................................................ 13 
2.3. PROACT Pilot Clinical Testing ......................................................................................................... 15 
2.4. Risk Analysis and Risk Assessment ................................................................................................ 20 
3. 
OBJECTIVES...................................................................................................................................... 20 
4. 
PROJECT DESCRIPTION .................................................................................................................. 20 
5. 
STUDY DESIGN ................................................................................................................................. 20 
5.1. Summary Protocol ........................................................................................................................... 20 
5.2. MyoStrain® Testing Methodology ..................................................................................................... 23 
5.3. Study Population ............................................................................................................................. 24 
5.4. Inclusion Criteria ............................................................................................................................. 24 
5.5. Exclusion Criteria ............................................................................................................................ 24 
5.6. Duration of the study for the subject ................................................................................................ 25 
5.7. Sample size .................................................................................................................................... 25 
5.8. Enrollment ....................................................................................................................................... 25 
6. 
INFORMED CONSENT ....................................................................................................................... 25 
6.1. Consent for Study Participation ....................................................................................................... 25 
6.2. Subject withdrawal .......................................................................................................................... 25 
7. 
RISK / BENEFIT ASSESSMENT ......................................................................................................... 25 
7.1. Risks ............................................................................................................................................... 25 
7.2. Benefits ........................................................................................................................................... 25 
8. 
ONCORE REGISTRATION PROCEDURES ....................................................................................... 26 
8.1. Confirmation of Patient Eligibility by WUSTL Prior to Registration .................................................... 26 
8.2. Patient Registration in the Siteman Cancer Center OnCore Database ............................................. 26 
8.3. Assignment of Participant ID ........................................................................................................... 26 
9. 
ADVERSE EVENTS AND REPORTING REQUIREMENTS ................................................................. 26 
9.1. Adverse Event Definitions................................................................................................................ 26 
9.2. Attribution, Anticipation, Expectedness, and Grading of AEs ............................................................ 27 
9.2.1. 
Attribution ............................................................................................................................ 27 
9.2.2. 
Anticipation .......................................................................................................................... 27 
9.2.3. 
Expectedness ...................................................................................................................... 27 
9.2.4. 
Grading................................................................................................................................ 28 
9.3. Noncompliance and Exceptions ....................................................................................................... 28 
9.4. Reporting Requirements .................................................................................................................. 28 
9.4.1. 
Reporting to the Human Research Protection Office (HRPO) at Washington University ........ 28 
9.4.2. 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at Washington 
University29 
9.4.3. 
Reporting Requirements for Participating Sites .................................................................... 29 
9.4.4. 
Reporting to Participating Sites ............................................................................................ 29 
9.4.5. 
Reporting to MyoCardial Solutions ....................................................................................... 29 
9.4.6. 
Timeframe for Reporting Required Events ............................................................................ 29 
10. DATA SAFETY AND MONITORING.................................................................................................... 30 
10.1.1. 
Data Monitoring by MyoCardial Solutions ............................................................................. 30 
10.1.2. 
Data Monitoring by Coordinating Sites ................................................................................. 30 
10.1.3. 
Data Safety and Monitoring Committee ................................................................................ 30 
11. STATISTICAL CONSIDERATIONS ..................................................................................................... 31 
12. DATA MANAGEMENT ........................................................................................................................ 32 
13. DEVICE ACCOUNTABILITY ............................................................................................................... 32 
14. STATEMENTS OF COMPLIANCE ...................................................................................................... 33 
15. INVESTIGATOR RESPONSIBILITIES AND OBLIGATIONS ................................................................ 33 
15.1. Investigator Responsibilities ............................................................................................................ 33 

 
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15.2. Investigator Records ....................................................................................................................... 33 
15.3. Investigator Reports ........................................................................................................................ 33 
15.4. Financial Disclosure by Clinical Investigators ................................................................................... 33 
16. REFERENCES ................................................................................................................................... 34 
17. APPENDICES ..................................................................................................................................... 36 
17.1. Patient Satisfaction Questionnaire ................................................................................................... 36 
 
 
 

 
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1. 
SUMMARY 
1.1. 
Study Purpose 
This study is intended to evaluate the ability of a new analysis package with cardiac MRI to assist in the early 
detection and management of cardiotoxicity from therapeutics used to treat cancer.   
1.2. 
Study Device and Intended Use 
Common Name:  Cardiac MRI Imaging Software 
 
Trade Name: 
  MyoStrain® 
 
Regulatory Status: The MyoStrain® SENC CMR Imaging System is limited to observational evaluation within 
the United States.  MyoStrain® has European approval with an EC Certificate according to 
Directive 93/42/EEC on Medical Devices, Annex II excluding Section 4 (CE 657862) in 
respect of: Design, development and manufacture of software for the quantification of 
cardiac MRI images. 
 
Intended Use: 
MyoStrain® SENC software receives image data from MRI storage archives and performs 
viewing, image manipulation, communication, printing, and quantification of images.  
Available measurements include longitudinal and circumferential strain to quantitatively 
describe the wall motion of the heart.  Tools are provided for display of regional motion 
properties of the heart. 
 
 
A report interface is provided.  Measurement tools provide information that can be output 
in standardized or specialized report formats.  This interface makes it possible to quickly 
and reliably fill out a complete clinical report of a cardiac imaging exam with strain.  The 
results of the measurement tools are interpreted by the physician and can be 
communicated to referring physicians to support the determination of a diagnosis. 
1.3. 
Study Design 
This is a prospective, multi-center, open label, randomized study.  The study will enroll patients who exhibit 
subclinical myocardial dysfunction at baseline as determined by MyoStrain® evaluation. 
 
Patients with any type of cancer scheduled to receive anti-cancer therapy, who are previously enrolled in the 
SURVIVE Registry, will be screened for study participation.   Consented subjects meeting all 
inclusion/exclusion criteria will be enrolled into the PROACT study.  Subjects will be randomized 1:1 between 
the MyoStrain® guided treatment arm and MyoStrain® observational arm.  Patients in both randomized study 
arms will be followed with MyoStrain® testing at baseline, 1, 3, 6, 12, 24 & 36 month follow-ups, as outlined in 
the protocol. 
1.4. 
Objectives 
The primary objectives of this study are:   
1. to robustly quantify myocardial function in cancer  patients scheduled to receive anti-cancer therapy    
2. to determine the ability of MyoStrain® testing to detect subclinical cardiac dysfunction compared to 
standard cardiac imaging 
3. to determine the impact of MyoStrain® imaging on medical management of cardiotoxicity through early 
detection of at risk patients 
1.5. 
Endpoints 
The primary efficacy endpoint is the sensitivity and accuracy of detection of patients with myocardial 
dysfunction using MyoStrain® compared to standard assessments of cardiac function: left ventricular ejection 
fraction (LVEF), as well as end-systolic (LVESV), end-diastolic (LVEDV), and stroke (LVSV) volumes indexed 
to body surface area.   
 
Changes in function based on clinical presentation, standard assessments, and all available metrics will be 
used to define the cardiotoxicity status of the patient.  A clinical committee organized and chaired by the 
principal investigator will be used to classify each exam in both unblinded and blinded arms according to 
professional knowledge and derived from the ASE Expert Consensus Position Paper, the ESC Position 
Paper, and the ESMO Clinical Practice Guidelines.  [1] [2] [3] 
 

 
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• 
Clinical cardiac dysfunction is defined as an absolute change in LVEF > 10% from baseline to below 
53% combined with heart failure symptoms or abnormal cardiac biomarkers (troponin, BNP, or NT pro 
BNP).   
• 
Subclinical CTX was defined as an asymptomatic patient with a greater than 15% decrease in LVEF 
that remains >= 53%, worsening GLS more than 15% from baseline, or abnormal cardiac biomarkers 
(troponin, BNP, or NT pro BNP). 
• 
If no baseline information is available to compare metrics for categorizing cardiotoxicity status, 
considering most patients in the PROACT sub-study of the Survive Registry will have metastatic 
cancer with prior treatments including chemotherapy, physician discretion and patient presentation will 
provide the final decision on cardiotoxicity category.  All available metrics will be used to classify 
patients at each assessment time point. 
1.6. 
Inclusion Criteria 
1) Participant in the SURVIVE registry 
2) Signed consent form for PROACT 
3) Histological diagnosis of any cancer type (patients with treated and clinically stable brain metastasis 
are acceptable) 
4) Scheduled to receive anti-cancer therapy (radiation therapy is permitted) 
1.7. 
Exclusion Criteria 
1) Contraindication to magnetic resonance imaging (MRI) 
2) Unable to comply with study investigations (in the judgment of the investigator) 
3) Life expectancy less than 1 year  
 
Note: If a patient develops a temporary contraindication (e.g. temporary tissue expanders in breast cancer 
patients) after the baseline MRI, follow up MRIs will be discontinued for safety for the duration in which the 
patient has a contraindication.  However, once the patient is no longer contraindicated to receiving MRIs, the 
study schedule may resume with their next scheduled MRI time point from date of enrollment.  Therefore, 
some time points may be skipped during the patient’s enrollment in the study.  
 
Also, if a patient needs a repeat MRI at any time point for any reason (i.e. panic attack during the MRI causing 
them to not be able to continue, unreadable images, etc.), we may repeat the MRI as long as the patient is 
willing. 
1.8. 
Expected Duration 
Based on an enrollment of 40 evaluable patients (a subset of the approximately 700 SURVIVE Registry 
patients enrolled annually across all SURVIVE participating sites) who demonstrate moderate to high risk of 
cardiotoxic effects during cardio-oncology treatment due to observed segmental dysfunction on baseline 
MyoStrain® evaluation, it is anticipated that all subjects will be enrolled within 12 months after study initiation.  
The study will end when the last enrolled subject completes the 36-month follow-up, data is analyzed and 
reports are written.  Therefore, study duration is anticipated to be approximately 54 months. 
 
 
2. 
DEVICE DESCRIPTION 
For all patients undergoing a cardiac MRI, a standard non-contrast protocol will be used to acquire a full 
cardiac volume for chamber sizes and LVEF in the short axis as the initial scan. 
2.1. 
MyoStrain® SENC CMR Imaging System 
The MyoStrain® SENC CMR Imaging System is limited to observational evaluation within the United States.  
MyoStrain® has been approved with an EC Certificate according to Directive 93/42/EEC on Medical Devices, 
Annex II excluding Section 4 (CE 657862) in respect of: Design, development and manufacture of software for 
the quantification of cardiac MRI images. 
 
Strain Encoding (SENC) MRI technology is a fast MRI scanning diagnostic test that measures the contraction 
of the heart muscle in one heartbeat per image plane. This means that patients can be scanned very fast 
while breathing, and a complete view of the ventricles’ health can be obtained in less than 6 seconds. 
Quantitative assessment of the strength of the heart muscle can have many clinical applications, but its 
highest value is in the two largest heart disease populations: those patients with heart failure and coronary 
artery disease.       
 

 
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SENC is an MRI Pulse Sequence for Strain Encoding 
• 
A pulse sequence is an algorithm that instructs the MRI scanner to acquire certain types of images.  
Any MRI scanner has a large number of pulse sequences for general and specialized imaging of 
different parts of the body.  They produce images that show different anatomies, physiologies, or 
pathologies of the different tissues of the body.   For imaging the heart, there is a group of specialized 
pulse sequences that can show different aspects of the heart, including, but not limited to, the 
structure of the heart, the motion of the heart, the tissue characterization of the muscle, the flow of the 
blood, the structure of the vessels, and more. 
• 
The Strain Encoding (SENC) pulse sequence is a specialized pulse sequence that produces images 
of the heart muscle that reveal the underlying contraction of the muscle of a healthy heart and 
associated weaknesses in case of disease.  The measurements of the deformations of regions within 
the heart muscle (“myocardium”) associated by contraction and relaxation during a single heartbeat is 
measured by the mechanical quantity called “strain.” 
• 
Myocardial Solutions, Inc. software measures tissue deformation or “strain” from the pulse sequence 
images.  Quantitatively, “strain” is a mechanical property of deforming objects and measured as the 
percentile change in spacing between two points on a deforming object.  For example, when muscle 
contracts, the muscle length is shortened.  For example, a 30% shortening of the muscle is measured 
as strain of negative 30%.   
• 
Measuring the shortening of the Heart Muscle results in two parameters that SENC quantifies: 
circumferential and longitudinal strain.  Strain measurement depends on “direction” of measuring.   
For measuring the contraction of the heart muscle, there are two main directions that are typically 
used:  1) longitudinal strain, which describes the contraction of the myocardium that contributes to the 
base-to-apex contraction of the heart chambers; 2) circumferential strain, which describes the 
contraction of heart muscle fibers around the circumference of the chambers of the heart. 
• 
Using SENC, segmental circumferential and longitudinal strain values in 37 regions are measured in 6 
seconds. 
 
The Intended Use of the MyoStrain® SENC MRI acquisition is:   
• 
MyoStrain® SENC software receives image data from MRI storage archives and performs viewing, 
image manipulation, communication, printing, and quantification of images.  Available measurements 
include longitudinal and circumferential strain to quantitatively describe the wall motion of the heart.  
Tools are provided for display of regional motion properties of the heart. 
• 
A report interface is provided.  Measurement tools provide information that can be output in 
standardized or specialized report formats.  This interface makes it possible to quickly and reliably fill 
out a complete clinical report of a cardiac imaging exam with strain.  The results of the measurement 
tools are interpreted by the physician and can be communicated to referring physicians to support the 
determination of a diagnosis. 
2.2. 
Background Clinical & Preclinical Testing 
Myocardial Solutions, Inc. (MSI) MyoStrain® Software was implemented with SENC MRI acquisition using 
source codes that were developed at Johns Hopkins University.  Both Diagnosoft, before, and MSI, today, 
continue to use the original SENC strain source code. SENC pulse sequence patches, derived from the SENC 
source code, designed for Philips MRI Scanners, have been validated with extensive clinical and preclinical 
testing.   
 
The MSI software leverages prior SENC image acquisition and processing functions that have been 
extensively studied on volunteers, phantoms studies, and clinical applications. The Fast SENC software 
processes images obtained with the well-studied SENC pulse sequence patch, which has supported several 
publications demonstrating the utility of strain imaging for various clinical applications. 
 
Implementation of the SENC MRI acquisition in the Myocardial Solutions SENC Software has been validated 
as evidenced by literature across three separate comparisons:  Comparisons with 1) Diagnosoft HARP, a 
510k FDA certified software for measuring strain from tagged MR images; 2) EchoPAC STE, a certified 
software from GE Vingmed for measuring strain using speckle tracking methods; and 3) various physiological 
and pathological indicators. 
 
Validation of MyoStrain® SENC relative to Diagnosoft HARP 
1. 
Diagnosoft HARP is a 510k certified software for the analysis of MR Tagging images of the heart and 
measuring the strain that reveals the deformation of the myocardium as the heart muscle contracts 
and relaxes.   Diagnosoft HARP is considered to be the gold standard for measuring regional strain 
and there are over 100 peer-reviewed published studies on the use of strain from HARP.   
2. 
Published Comparisons: SENC versus Diagnosoft HARP compared the strain measurements from 
SENC to strain calculated by MR Tagging and Diagnosoft HARP software. [4] [5] [6]  The comparisons 

 
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showed strong correlation in measurements of strain, both regional and global, and also the different 
strain measurements, such as longitudinal and circumferential strain; the correlation between SENC 
and tagged MRI was significant with R=0.90. 
3. 
The published literature demonstrates that SENC strain measurements are comparable to those 
obtained used MR Tagging and HARP software, which is considered to be the gold standard method 
for measuring strain. SENC strain software has advantages over HARP software by providing the 
comparable strain results with faster acquisition and analysis. The SENC strain test takes as little as 
10 minutes including analysis, which can be performed by a technologist, while HARP would require 
much longer testing and more specialized expertise to analyze. SENC strain is much more patient- 
and user-friendly requiring only a single heartbeat for image acquisition, eliminating the need for 
patient breath holding.  
 
Comparison of SENC to EchoPAC, GE Vingmed STE 
4. 
EchoPAC is a 510k and CE Mark certified package form GE Vingmed for the processing of 
echocardiographic images and films.  It can measure the deformation and strain of tissue using 
speckle tracking echocardiography (STE), which is an image post-processing algorithm. 
5. 
Published Comparisons: SENC versus EchoPAC STE compares the strain measurements from 
SENC to the strain calculated using Tissue Strain Echocardiography (STE). [7]  STE was calculated 
using EchoPAC software from GE.  
6. 
Cardiac MRI measurements of strain using SENC and MR tagging are considered to be equivalent to 
STE or better due to the excellent image of cardiac tissue by MRI and creation of actual physical 
markers inside the tissue to measure strain.  STE is an image processing method that tries to extract 
motion and strain from conventional echocardiographic movies with their known image quality 
limitations. 
7. 
The published comparisons showed a correlation between strain measurements obtained by SENC 
and those calculated by STE.  It is important to point out that MRI, as a gold standard method, was 
used as the reference for measuring strain. STE post-processing calculations were expected to be 
inherently inferior as it inherits some of the suboptimal image qualities of echocardiography (relative to 
MRI). 
 
Validation of MyoStrain® SENC Based on Clinical Physiological and Pathological Indicators 
8. 
SENC strain was directly compared to different physiological and pathological indicators to 
understand the mechanics of the heart muscle and alterations due to underlying disease and 
pathology.  This includes the understanding of the contraction of the left and right ventricles, changes 
in strain in the case of myocardial infarction as determined using delayed enhancement methods, and 
detection of ischemia in patients by utilizing stress testing. 
9. 
Published Comparisons: SENC Strain for Physiological and Pathological Indicators.  Different studies 
were done using SENC to understand the mechanics of the heart wall muscle and the changes that 
accompany certain diseases.  In the case of coronary artery diseases, the studies showed changes in 
strain because of acute coronary artery syndrome that results in myocardial infarction.  
10. 
Stress testing for ischemia, performed on patients with suspected or known ischemic heart disease, 
demonstrated that measured strain was more sensitive in detecting stenosis in the coronary arteries 
compared to 1) conventional cine movies with qualitative assessment of abnormal wall motion under 
stress, and 2) the outcomes of revascularization of positively diagnosed patients. [8] [9] [10] [11] [12] 
11. 
Myocardial infarction studies show the value of strain measurements in assessing, with high accuracy, 
changes in regional function associated with damage from myocardial infarction. [13] [14] [15] [16]  
Quantification of changes in contraction is more accurate (more sensitive and specific) in associating 
with the depth of damage vis-à-vis subjective wall motion assessment.  Figure 1 shows the composite 
strain scale based on comparison to late gadolinium enhancement analysis to differentiate segmental 
myocardial function into healthy with normal contraction (defined as normokinesia and hyperkinesia), 
at risk with abnormal contraction (hypokinesia), and impaired viability (akinesia and dyskinesia). 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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Figure 1 – MyoStrain® Segmental Scale of Myocardial Health 
 
12. 
Cardiac mechanics studies illustrated other applications of SENC strain measurements in 
understanding the mechanics of the heart, especially the left and right ventricles. [17] [18] [19] [20] [21] 
These healthy subjects studies demonstrated, with high accuracy and precision, the ability to detect 
subtle variations in regional contraction.  Also, quantification revealed variations in contractility as a 
result of diseases affecting the right ventricle, which is very hard to assess using echocardiography 
because of the position of the right ventricle close to the ribs and the sternum and its geometry. 
2.3. 
PROACT Pilot Clinical Testing 
A single center, pilot study was performed to evaluate the ability of the MyoStrain® MRI software system to 
identify cardiotoxicity during cardio-oncology treatment of breast cancer and lymphoma patients.  An interim 
analysis of 15 subjects from the PROACT Pilot study (VAL-1005P) is included below to provide additional 
clinical evidence that the MyoStrain® software is able to detect progression of myocardial dysfunction resulting 
from cardiotoxicity.  The pilot study was performed by Principal Investigator Hr. Priv.-Doz. Dr. Henning Steen 
(Facharzt für Innere Medizin, Kardiotogie PD DR) at Marien Krankenhaus GmbH (Hamburg, Germany). 
 
• 
Patient Demographics 
 
Demographic 
Average ± St Dev 
Age (years) 
52.2 ± 11.5 
Body Surface Area (m2) 
1.8 ± 0.2 
Body Mass Index (kg/m2) 
25.7 ± 4.7 
History of Cancer (months) 
1.4 ± 0.8 
Charlson Comorbidity Index 
1.4 ± 1.0 
 
• 
Baseline CMR Information 
 
Baseline CMR Information 
Average ± St Dev 
LVEF (%) 
58.8 ± 5.3 
LVEDV Index (ml/m2) 
77.6 ± 13.4 
LVESV Index (ml/m2) 
32.1 ± 8.0 
Stroke Volume Index (ml/m2) 
45.5 ± 7.8 
T1 Value Pre-Contrast (msec) 
1052.4 ± 44.6 
T1 St Dev Pre-Contrast (msec) 
52.4 ± 11.8 
Global Longitudinal Strain (%) 
-20.8 ± 1.9 
Global Circumferential Strain (%) 
-19.0 ± 1.8 
Healthy 
High-Risk 
Heart Failure 
MyoStrain Metric Scale 

 
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# Segments > -10% 
1.7 ± 1.5 
# Segments > -17% 
8.5 ± 4.7 
 
• 
Baseline Risk Assessment of Developing Cardiotoxicity by Segmental MyoStrain®.   
Patients were stratified as to their risk by the number of dysfunctional (> -10%) and abnormal 
segments (> -17%).  These thresholds have been validated as previously described in Figure 1 
above. 
 
Cardiotoxicity 
Risk Level 
Segmental MyoStrain® Criteria 
Incidence 
Low 
≤ 1 Segment > -10% & < 9 Segments > -17% 
46% (7/15) 
Moderate 
2-3 Segments > -10% or 9+ Segments > -17% 
27% (4/15) 
High 
3+ Segments > -10% & 10+ Segments > -17% 
27% (4/15) 
 
• 
Baseline Echocardiography Data 
 
Baseline Echocardiography Data 
Average ± St Dev 
LVEF (%) 
63.9 ± 5.8 
LVEDV Index (ml/m2) 
47.7 ± 10.1 
LVESV Index (ml/m2) 
17.3 ± 6.4 
Stroke Volume Index (ml/m2) 
30.3 ± 5.1 
GLS (%) 
-26.5 ± 14.6 
E/E’ 
8.8 ± 2.0 
# Pts with Poor Acoustic Window:  4/14 (29%) 
 
• 
Interim Results of Segmental Dysfunction and Global Measures Throughout Follow-up 
 
 
 
 
 
 
 
 
 
 

 
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• 
Interim Results of Global Strain Evolution Throughout Follow-up 
 
 
• 
Example of Low Risk Patient Not Experiencing Cardiotoxicity.    
A 50 year female with breast cancer did not show substantial dysfunction after 360 mg/m2 of 
epirubicin at a follow-up of 128 days.  The patient had LVEF of 57% at baseline and 61% after 128 
days of chemotherapy.  The GLS and GCS did not decrease significantly from baseline to follow-up 
(GLS:-22% vs -20% and GCS: -20% vs -19%).  Segmental dysfunction also did not substantially 
change throughout follow-up representing adequate myocardial health during cancer treatment.  
 
 
 
Baseline MyoStrain®  
 
 
 
Follow-Up MyoStrain® (128 days) 
     
 
 
• 
Example of Low Risk patient showing progressive decline thereby increasing risk of 
developing cardiotoxicity during continued treatment. 
A 46 year female treated for breast cancer observed progressive decline throughout 89 days of follow-
up with a total of 360 mg/m2 epirubicin and 160 mg/m2 Paclitaxel.  The patients LVEF fluctuated but 

 
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remained in the normal range at baseline, 56 days, and 89 days of follow-up (68%, 56%, and 66%).  
GLS and GCS showed gradual decline throughout follow-up (GLS -22% vs -19% vs -17% and GCS: -
20% vs -21% vs -19%).  Segmental dysfunction showed progressive worsening throughout follow-up 
indicating the reduced ability of the heart to compensate for gradual myocardial damage due to 
cardiotoxic effects of chemotherapy. 
 
      Baseline MyoStrain®     Follow-Up #1 (56 days)   Follow-Up #2 (89 days) 
    
      
  
 
 
 
• 
Example of a Medium Risk patient observing cardiotoxic effects and showing non-compliance 
with preventative therapy.   
A 66 year female treated for lymphoma observed substantial segmental myocardial dysfunction after 
administration of 150 mg/m2 doxorubicin at a follow-up of 19 days.  The patient was not compliant with 
the prescribed Heart Failure therapy and observed continued progression of myocardial dysfunction at 
89 days and cumulative dose of 300 mg/m2 of doxorubicin and 375 mg/m2 of rituximab.  
Subsequently, the patient was urged to maintain compliance to address the cardiotoxic effects of 
chemotherapy.  The patient’s LVEF reduced well after segmental dysfunction identified the risk and 
worsening of myocardial health, measuring 64% at baseline, 60% at 19 days when MyoStrain® 
detected worsening dysfunction, and finally reducing to 45% at 89 days since the patient was not 
compliant with heart failure therapy.  However, GLS and GCS continued to decrease significantly from 
baseline throughout follow-up (GLS:-22.8% vs -16.9% vs -16.3% and GCS: -17.9% vs -16.3% vs -
12.3%).  Segmental dysfunction demonstrated worsening function throughout follow-up providing a 
sensitive measure to non-compliance of HF therapy. 
 
Baseline  MyoStrain®  
 
 
 
Cardiotoxic Effects (19 days)  
Non-Compliance to HF therapy (89 days) 
 
 
 
  

 
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• 
Example of a High Risk patient observing reversible cardiotoxic effects.   
A 59 year female treated for Hodgkin lymphoma with doxorubicin observed substantial segmental 
myocardial dysfunction after administration of 70 mg/m2 at a follow-up of 51 days.  The patient was 
treated with angiotensin converting enzyme inhibitors (ACE-I)and beta blockers that improved function 
while maintaining chemotherapy with a cumulative dose of 140 mg/m2 (follow-up of 106 days).  The 
patient maintained an LVEF around 58% throughout 106 days of chemotherapy.  However, GLS and 
GCS decreased significantly from baseline to first follow-up before improving upon prescription of 
preventative heart failure therapy (GLS:-20.5% vs -15.1% vs -17.7% and GCS: -18.3% vs -14.9% vs -
16.6%).  Segmental dysfunction also demonstrated worsening function until heart failure therapy was 
employed at which time heart function improved. 
 
Baseline MyoStrain®  
 
 
 
 
 
Cardiotoxic Effects (51 days)  
Impact of HF Therapy (106 days) 
 
 
  
 
• 
Summary 
The PROACT Pilot study showed the ability of MyoStrain® to quantify the progressive changes in 
segmental and global myocardial health during cancer treatment to detect subclinical cardiotoxic 
effects of chemotherapy and/or targeted treatment.  In this pilot study, serial MyoStrain® scans also 
enabled patient management to identify patients in need of proactive cardiac protection therapy while 
monitoring the impact including compliance of such therapy.  The ability to define risk assessment 
based on segmental dysfunction allows identification of patients at risk of developing cardiotoxicity to 
monitor those predisposed to developing new or worsening heart failure.  The findings in this pilot 
study provide further evidence for the inclusion criteria and performance criteria of the PROACT 
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2.4. 
Risk Analysis and Risk Assessment 
The MSI SENC MyoStrain® software has been tested and approved following ISO 14971 (Medical Devices – 
Application of Risk Management to Medical Devices).  
 
Detailed risk assessments have been done by Myocardial Solutions, Inc. throughout the software 
development.   The company routinely performs management review that include analysis of device 
performance, change control (design, process, labeling), and corrective and preventative action for the 
product.   
 
Myocardial Solutions’ risk assessment has been completed and clinical risks have been reduced as far as 
possible by device design, labeling, and training protocols for intended users.  There are no unacceptable 
residual clinical risks based on the risk/benefit reviews. 
 
3. 
OBJECTIVES  
The primary objectives of this study are:   
1. to robustly quantify myocardial function in cancer  patients scheduled to receive anti-cancer therapy    
2. to determine the ability of MyoStrain® testing to detect subclinical cardiac dysfunction compared to 
standard cardiac imaging 
3. to determine the impact of MyoStrain® imaging on medical management of cardiotoxicity through early 
detection of at risk patients. 
 
4. 
PROJECT DESCRIPTION 
This study evaluates the impact of medical management of cardiotoxicity through early detection of at risk 
patients and management of with heart failure therapy to restore myocardial function.   
 
SENC MyoStrain® testing will quantify changes in myocardial function at pre-defined intervals to detect the 
progression of cardiotoxic effects of chemotherapy and/or targeted treatment.  Cancer treatment regimens 
such as anthracyclines, trastuzumab, taxanes, other agents, or combination of drugs, with or without 
concomitant Radiotherapy, have been shown to cause cardiotoxicity leading to heart failure. [22] [23] 
 
MRI strain testing (SENC or HARP) has been shown to detect cardiotoxicity before systemic changes occur. 
MRI strain has been shown to detect abnormal myocardial function in cancer patients treated with high-dose 
anthracycline chemotherapy despite normal systolic function by traditional measures. [24] [25]  Clinical utility 
of SENC strain testing is to evaluate risk of heart failure, immediate or delayed, for chemotherapy to reduce 
adverse cardiac events in cancer patients treated with anthracyclines or other drug therapy known to cause 
cardiotoxicity. 
 
 
5. 
STUDY DESIGN  
5.1. 
Summary Protocol 
Patients with any type of cancer scheduled to receive anti-cancer therapy with or without concomitant 
radiotherapy and enrolled in the SURVIVE Registry will be evaluated based on baseline MyoStrain® 
segmental dysfunction risk profile.  After consenting to the PROACT study, patients will undergo a baseline 
MRI to determine their risk stratification for the study.  This baseline MyoStrain® MRI must demonstrate 2 or 
more segments measuring >-10% or 9 or more segments >-17% for entrance into the study. 
 
Eligible patients will then be randomized 1:1 into the MyoStrain® guided treatment arm versus the Myostrain® 
blinded observational arm, as shown in Figure 2.  The treatment arm will guide patient management by 
augmenting standard of care with serial MyoStrain® monitoring of the impact of cancer therapy on myocardial 
function by providing physicians with MyoStrain® values, in addition to LVEF, LVEDV, and LVESV.  In the 

 
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observational arm, physicians will only be provided with LVEF, LVEDV, and LVESV, which are clinical 
measurements.  The standard of care assessments by cardiac MRI, will not include MyoStrain® assessments.   
 
In order to obtain the MyoStrain® values, MRI images obtained will be uploaded de-identified to Myocardial 
Solutions, Inc.  After the baseline scan, Myocardial Solutions, Inc. will inform research staff whether the 
patient met criteria for continued follow up in the study.  At that time, the patient will be randomized to one of 
the two arms, as previously described, and Myocardial Solutions, Inc. will be made aware of the 
randomization result.  If randomized to the blinded observational arm, no results from any cardiac MRI 
obtained for the study will be provided to physicians from Myocardial Solutions, Inc. If randomized to the 
MyoStrain® guided treatment arm, MyoStrain® results and LVEF, LVEDV, and LVESV will be provided for all 
cardiac MRI’s obtained in the study to the physicians.  Sites will also send Myocardial Solutions, Inc. de-
identified information about the patients’ medical history (i.e. comorbidities, past/current medications, etc.). 
 
Patient’s will continue to undergo MyoStrain® MRI testing, regardless of study arm, at 1 month (+ 2 weeks), 3 
months (+ 2 weeks), 6 months (+ 2 weeks), 12 months (+ 30 days), 24 months (+ 30 days), and 36 months (+ 
30 days) after the baseline visit.  In addition to the MyoStrain® testing, patients will also be asked to complete 
a brief patient satisfaction questionnaire at each PROACT time point.  Patient’s will already be completing the 
EQ-5D Questionnaire and the Cardiovascular Risk Assessment Questionnaire as part of the SURVIVE 
Registry protocol at the baseline, 6 month, 12 month, 24 month, and 36 month time points. 
 
In addition to Myocardial Solutions, Inc. reviewing the cardiac MRI images, due to the multi-departmental 
nature of this study, sites may also choose to obtain a clinical read on the research cardiac MR images 
obtained on the short axis, which are the same images that would be obtained in a clinical MRI, and provide 
only the LVEF, LVEDV, and LVESV for all subjects, regardless of randomization arm, and those values may 
be uploaded to the patients’ medical record, if permitted.  Doing so would then allow patients’ oncology team 
access to this information in lieu of obtaining additional testing (i.e. clinical cardiac MRI’s, echocardiograms, 
etc.) to obtain this same information. 
 
 
 
 

 
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EXAMPLE OF GENERAL PRINCIPLES FOR CLINICAL DECISIONS 
WITH MYOSTRAIN® RESULTS: 
• 
Worsening segment abnormalities, consider cardio-protective therapies. 
• 
Advise oncology about developing toxicities. 
• 
Enhance patient education (symptom awareness). 
 
Figure 2 – Study Flow Diagram 
 
 
 
 
 
 
Patients Enrolled in SURVIVE Registry
Signed Informed Consent for SURVIVE Registry
Signed PROACT Informed Consent Form
Inclusion Criteria
- Diagnosed with any cancer type
- Scheduled to receive anti-cancer therapy with or without concomitant radiotherapy
If patient meets 
inclusion criteria...
Baseline 
MyoStrain®  MRI 
Testing
Inclusion Criteria
- Baseline MyoStrain® demonstrating 2 or more segments measuring >-10% or 9 or more segments >-17%
High Risk Group
Meets baseline inclusion criteria
Randomize
MyoStrain®  Blinded
Standard of Care Arm
Standard of 
Care Testing
MyoStrain® 
Testing 1, 3, 6, 
12, 24, 36 mo
Manage Patients 
Based on Standard 
of Care Only
MyoStrain®  Guided
Treatment Arm
Standard of 
Care Testing
MyoStrain® 
Testing 1, 3, 6, 
12, 24, 36 mo
Manage Patients Based on 
Standard of Care and 
MyoStrain®  Results
Doesn't meet baseline inclusion 
criteria
Screen Failure
If patient doesn't meet 
inclusion criteria...
Screen Failure

 
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PROACT Schedule of Events 
Baseline 
1 Month 
(+2 weeks) 
3 Month 
(+2 weeks) 
6 Month 
(+2 weeks) 
12 month 
(+30 days) 
24 month 
(+30 days) 
36 month 
(+30 days) 
PROACT Informed Consent 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Confirmation 
 
 
 
 
 
 
 
MyoStrain® MRI Testing 
 
 
 
 
 
 
 
Randomization 
 
 
 
 
 
 
 
Patient Satisfaction Questionnaire 
 
 
 
 
 
 
 
 
5.2. 
MyoStrain® Testing Methodology  
System setup and testing methodology will follow the Myocardial Solutions SENC User’s Manual 4.1.  The 
SENC MyoStrain® Test procedure is a quick and simple analysis which will require only one series of images.  
The importation of the images from the scanner and organization of these images is mostly automated and 
requires very minimal interaction to function correctly. The workflow of the SENC MyoStrain® test requires 
only one scan and analysis phase allowing the complete scan to be completed with 6 heartbeats after imaging 
planning without breath-holds. 
 
1. Use Preview mode for discovery and planning 
• 
Before the actual analysis begins, the operator will use Preview mode to perform image planning and 
ensure the scanner is looking in the correct location and the myocardium is being imaged properly. 
• 
After using Preview mode, the operator will switch the mode to Strain before acquiring more images 
or beginning the exam by clicking the Strain button found above the Report section 
 
2. Select one slice from the Image List 
 
3. Identify view and locate end-systole 
 
4. Draw epicardial and endocardial contours on the myocardium 
• 
To ensure accurate analysis of any view of the heart, the operator will draw a contoured mesh around 
the heart tissue. The mesh will quantify the entire LV of the current view and automatically segment 
the heart using the standard AHA model. This is done by drawing a contour on both the epicardial and 
endocardial edges of the left ventricle.  The mesh application should be performed on each slice/view 
available. 
• 
NOTE: When computing the strain after segmenting the heart with a mesh, the strain measurements 
are restricted within the mesh. 
 
5. Repeat steps 2-4 for each image in Image List 
 
6. After all images have been analyzed, complete the report and Export to PDF 
• 
The Report Page automatically composes a report from the various sources of information that are 
obtained during the analysis. This report can then be uploaded, exported as a PDF document, or 
printed out for review. 
 
During the SENC MyoStrain® Test analysis, each mesh applied to the dataset will populate the 
appropriate model in the Measures section.   The color legend in Figure 3 provides a basic guide to the 
meaning of each color.  The coloring shown demarcates specific regions validated in published literature 
based on levels of myocardial function. Normokinetic defines strain < -17% while Akinetic defines strain > 
-10%.  The numeric strain values for each segment and global measurements will also be displayed on 
the report.  Alternative coloring schemes may be utilized depending on operator preference.   
 
Figure 3: Color Legend for Strain Test 
 
The Measures section SENC MyoStrain® exams will display resting strain, as well as global 
circumferential and longitudinal strain as shown in Figure 4. 

 
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Figure 4: Example Strain exam with 6 views quantified 
5.3. 
Study Population 
Subjects enrolled in the SURVIVE Registry and scheduled to undergo chemotherapy or targeted cancer 
treatment will be consented for possible inclusion in PROACT.  Then the patient will be evaluated with a 
baseline MyoStrain® test to determine whether the patient exhibits moderate or high risk of developing 
cardiotoxicity.  As a minimum, the inclusion and exclusion criteria listed below will apply. 
5.4. 
Inclusion Criteria 
1) Participant in the SURVIVE registry 
2) Signed consent form for PROACT 
3) Histological diagnosis of any cancer type (patients with treated and clinically stable brain metastasis 
are acceptable) 
4) Scheduled to receive anti-cancer therapy (radiation therapy is permitted) 
5.5. 
Exclusion Criteria 
5) Contraindication to magnetic resonance imaging (MRI) 
6) Unable to comply with study investigations (in the judgment of the investigator) 
7) Life expectancy less than 1 year  
 
Note: If a patient develops a temporary contraindication (e.g. temporary tissue expanders in breast cancer 
patients) after the baseline MRI, follow up MRIs will be discontinued for safety for the duration in which the 
patient has a contraindication.  However, once the patient is no longer contraindicated to receiving MRIs, the 
study schedule may resume with their next scheduled MRI time point from date of enrollment.  Therefore, 
some time points may be skipped during the patient’s enrollment in the study.  
 
Also, if a patient needs a repeat MRI at any time point for any reason (i.e. panic attack during the MRI causing 
them to not be able to continue, unreadable images, etc.), we may repeat the MRI as long as the patient is 
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5.6. 
Duration of the study for the subject 
Based on an enrollment of 40 evaluable patients (a subset of the approximately 700 SURVIVE Registry 
patients enrolled annually across all SURVIVE participating sites) who demonstrate moderate to high risk of 
cardiotoxic effects during cardio-oncology treatment due to observed segmental dysfunction at baseline, it is 
anticipated that all subjects will be enrolled within 12 months after study initiation.  The study will end when 
the last enrolled subject completes the 36-month follow-up, data is analyzed and reports are written.  
Therefore, study duration is anticipated to be approximately 54 months. 
5.7. 
Sample size 
40 evaluable patients will be randomized 1:1 to the MyoStrain® imaging guided arm versus the standard of 
care arm. 
5.8. 
Enrollment  
Subjects are considered to be enrolled in the study after they have signed the IRB approved PROACT 
informed consent form. No investigational tests will be performed before this moment. 
 
 
6. 
INFORMED CONSENT 
6.1. 
Consent for Study Participation  
All subjects recruited for study participation must meet all study enrollment inclusion/exclusion criteria prior to 
being enrolled in the study.  Once compliance with study inclusion/exclusion criteria is confirmed and the 
Investigator has determined that a subject is potentially eligible for study participation, the subject may be 
asked to participate in the study. Informed consent must be obtained from all subjects prior to study 
participation. The Informed Consent must be approved by the Institutional Review Board (IRB)/Ethics 
Committee (EC) overseeing the conduct of this study. Each original signed informed consent will be retained 
in the subject’s study records and a copy of the consent should be provided to the subject. 
6.2. 
Subject withdrawal 
Subjects can withdraw informed consent at any time during the study. Subjects who withdraw informed 
consent will not be replaced and the data will not be analyzed (per protocol analysis, see section “statistical 
considerations”).  Subjects discontinuing participation in the study upon written notification before completion 
of the predefined follow-up will have their data (baseline and interim follow-up intervals) imputed from 
analysis.  
 
 
7. 
RISK / BENEFIT ASSESSMENT 
7.1. 
Risks 
The SENC MyoStrain® software with the associated pulse sequence patch is a noninvasive imaging 
technology.  There is minimal direct physical risk for imaged subjects as it is an MRI procedure that does not 
require any invasive intervention or injections.  As such the risks are limited to those typical for conventional 
MRI exams.  Subjects will be evaluated for potential contraindications to MRI imaging.  Considering image 
acquisition is very fast (< 5 min) reducing time within the magnetic bore and patients do not need to hold their 
breath during image acquisition, risks of claustrophobia or anxiety may actually be reduced compared to 
traditional MRI tests.   
7.2. 
Benefits 
The results of the strain analysis provide quantitative assessment of regional function.  These measurements 
will be utilized as observational analysis.  Physicians will make clinical decisions using all available clinical 
information and cardiac test results that are available. 
 
 

 
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8. 
ONCORE REGISTRATION PROCEDURES 
Patients must not start any protocol intervention prior to registration through the Siteman Cancer Center. 
 
The following steps must be taken in order to register patients to this study: 
1. Confirmation of patient eligibility by site PI 
2. Consent of patient to PROACT study 
3. Confirmation of patient eligibility by Washington University 
4. Assignment of Participant ID 
5. Registration of participant in the Siteman Cancer Center OnCore database 
 
Once the patient has been entered into the Siteman Cancer Center OnCore database, the coordinating 
center’s coordinator will forward verification of enrollment and the subject ID. 
8.1. 
Confirmation of Patient Eligibility by WUSTL Prior to Registration 
Confirm patient eligibility by collecting the information listed below and scanning and emailing it to the 
coordinating center’s coordinator at least one business day prior to the patient’s baseline MRI scan: 
1. 
Your name and contact information (telephone number, fax number, and email address) 
2. 
Your site PI’s name, the registering investigator’s name, and your institution name 
3. 
Patient’s race, sex, and DOB 
4. 
Three letters (or two letters and dash) for the patient’s initials 
5. 
Currently approved protocol version date 
6. 
Copy of signed consent form 
7. 
Completed eligibility checklist, signed and dated by a member of the study team 
8. 
Copy of appropriate source documentation confirming patient eligibility 
 
The coordinating center will email the participating site with verification of eligibility of the patient within 1 
business day.  Once verification of eligibility has been received, the patient will be registered into OnCore and 
the patient may undergo the baseline MRI scan. 
8.2. 
Patient Registration in the Siteman Cancer Center OnCore Database 
Registrations may be submitted Monday through Friday between 8am and 5pm CST.  Urgent late afternoon or 
early morning enrollments should be planned in advance and coordinated with the Washington University 
research coordinator.  Registration will be confirmed by the research coordinator or his/her delegate by email 
within 1 business day.  Verification of eligibility and registration should be retained in the participant’s study 
chart. 
 
All patients at all sites must be registered through the Siteman Cancer Center OnCore database at 
Washington University after the patient has been consented, prior to the baseline MRI scan. 
8.3. 
Assignment of Participant ID 
Each patient will be identified with a unique Participant ID for this study.  The Participant ID will be based on 
the patient’s Participant ID in the SURVIVE Registry, as well as the patient’s enrollment number in the 
PROACT study.  All data will be recorded with this Participant ID on the appropriate CRFs. 
 
 
9. 
ADVERSE EVENTS AND REPORTING REQUIREMENTS 
Only adverse events in relation to the study procedures will be documented and reported.  These include 
adverse events occurring from the MRI scanner, SENC MyoStrain® Testing Software, or breach of 
confidentiality.  Adverse events in relation to cancer diagnosis will not be recorded or reported.  Recording of 
adverse events must be documented by the Participating Sites and entered into REDCap on a continuous 
basis. 
9.1. 
Adverse Event Definitions 
Term 
Definition 
Adverse Event (AE) 
An unfavorable medical occurrence in a human subject including any 
abnormal sign, symptom, or disease. 
Serious Adverse Event (SAE) 
An adverse experience occurring that results in any of the following 
outcomes: 
a. Death 
b. A life-threatening adverse experience 

 
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c. Inpatient hospitalization or prolongation of existing hospitalization 
d. A persistent or significant disability/incapacity (i.e. a substantial 
disruption of a person’s ability to conduct normal life functions) 
e. A congenital anomaly/birth defect 
f. 
Any other experience which, based upon appropriate medical 
judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
Life-Threatening 
An adverse experience that places the subject (in the view of the 
investigator) at immediate risk of death from the reaction as it occurred, i.e. 
it does not include a reaction that, had I occurred in a more severe form, 
might have caused death. 
9.2. 
Attribution, Anticipation, Expectedness, and Grading of AEs 
The terms for attribution, expectedness, and severity are defined as follows: 
9.2.1. 
Attribution  
Classification 
Description 
Definitely Related 
The adverse event, incident, experience or outcome was definitely caused 
by the procedures involved in the research. 
Probably Related 
There is a reasonable probability that the adverse event, incident, 
experience or outcome may have been caused by the procedures involved 
in the research. 
Possibly Related  
There is a reasonable possibility that the adverse event, incident, 
experience or outcome may have been caused by the procedures involved 
in the research. 
Unlikely Related 
The adverse event, incident, experience or outcome was unlikely caused 
by the procedures involved in the research. 
Unrelated 
The adverse event, incident, experience or outcome was unrelated to the 
procedures involved in the research. 
9.2.2. 
Anticipation 
Classification 
Description 
Anticipated 
Any incident, experience, or outcome that is anticipated to occur due to the 
research (i.e. procedures, investigational medication, etc.). 
Unanticipated 
Any incident, experience, or outcome that meets all of the following criteria: 
a. unexpected (in terms of nature, severity, or frequency) given (a) 
the research procedures that are described in the protocol-related 
documents, such as the IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the 
subject population being studied; 
b. related or possibly related to a subject’s participation in the 
research; and 
c. suggests that the research places subjects or others at a greater 
risk of harm (including physical, psychological, economic, or social 
harm) related to the research than was previously known or 
recognized. 
9.2.3. 
Expectedness 
Classification 
Description 
Expected 
Any adverse event that is a known or foreseeable risk associated with the 
procedures involved in the research or is an expected natural progression 
of any underlying disease, disorder, or condition. 
Unexpected 
Any adverse event occurring in one or more subjects in a research 
protocol, the nature, severity, or frequency of which is not consistent with 
either: 
a. the known or foreseeable risk of adverse events associated with 
the procedures involved in the research that are described in (a) 
the protocol–related documents, such as the IRB-approved 
research protocol, any applicable investigator brochure, and the 
current IRB-approved informed consent document, and (b) other 
relevant sources of information, such as product labeling and 
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b. the expected natural progression of any underlying disease, 
disorder, or condition of the subject(s) experiencing the adverse 
event and the subject’s predisposing risk factor profile for the 
adverse event. 
9.2.4. 
Grading 
Grading refers to the severity of the adverse event.  All adverse events will be graded using the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The CTCAE 
displays grades 1 through 5 with unique clinical descriptions of severity for each AE based on this 
general guideline: 
Classification 
Description 
Grade 1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations 
only; intervention not indicated. 
Grade 2 
Moderate; minimal, local or noninvasive intervention indicated; limiting age-
appropriate instrumental ADL (preparing meals, shopping for groceries or 
clothes, using the telephone, managing money, etc.). 
Grade 3 
Severe or medically significant but not immediately life-threatening; 
hospitalization or prolongation of hospitalization indicated; disabling; 
limiting self-care ADL (bathing, dressing and undressing, feeding self, 
using the toilet, taking medications, and not bedridden). 
Grade 4 
Life-threatening consequences; urgent intervention indicated. 
Grade 5 
Death related to AE. 
 
For AE specific grading, please visit the following website to download a copy of the CTCAE version 
5.0: 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/CTCAE_v5_Quick_Referen
ce_8.5x11.pdf 
9.3. 
Noncompliance and Exceptions 
Term 
Definition 
Noncompliance 
Failure to follow an applicable regulation or institutional policies that govern 
human subjects research or failure to follow the determinations of the IRB.  
Noncompliance may occur due to lack of knowledge or due to deliberate 
choice to ignore regulations, institutional policiers, or determinations of the 
IRB. 
Serious Noncompliance 
Noncompliance that materially increases risks, that results in substantial 
harm to subjects or others, or that materially comprises the rights or 
welfare of participants. 
Protocol Exceptions 
A planned deviation from the approved protocol that are under the 
research team’s control.  Exceptions apply only to a single participant or a 
singular situation. 
 
Washington University central IRB pre-approval of all protocol exceptions 
must be obtained prior to the event for both the coordinating center and all 
participating sites.  Participating sites must also follow their local IRB’s 
guidelines for any submission that needs to be made to their local IRB. 
9.4. 
Reporting Requirements 
The entities providing oversight of safety and compliance with the protocol require reporting as outlined below.  
The Washington University Human Research Protection Office (HRPO) requires that all events meeting the 
definition of unanticipated problem or serious noncompliance be reported as outlined. 
9.4.1. 
Reporting to the Human Research Protection Office (HRPO) at Washington 
University 
The PI is required to promptly notify the IRB of the following events: 
• 
Any unanticipated problems involving risks to participants or others which occur at WU or any 
BJH or SLCH institution that impacts participants or the conduct of the study. 
• 
Noncompliance with federal regulations or the requirements or determinations of the IRB. 
• 
Receipt of new information that may impact the willingness of participants to participate or 
continue participation in the research study. 
 

 
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These events must be reported to the IRB within 10 working days of the occurrence of the event or 
notification to the PI of the event.  The death of a research participant that qualifies as a reportable event 
should be reported within 1 working day of the occurrence of the event or notification to the PI of the event. 
9.4.2. 
Reporting to the Quality Assurance and Safety Monitoring Committee (QASMC) at 
Washington University 
The PI is required to notify the QASMC of any unanticipated problem occurring at WU or any BJH or SLCH 
institution that has been reported to and acknowledged by HRPO as reportable.  Unanticipated problems 
reported to HRPO and withdrawn during the review process need not be reported to QASMC. 
 
QASMC must be notified within 10 days of receipt of IRB acknowledgement via email to a QASMC auditor. 
9.4.3. 
Reporting Requirements for Participating Sites 
The research team at each participating site is required to promptly notify the Washington University PI and 
research coordinator of all reportable events within 1 working day of the occurrence of the event or 
notification of the participating site’s PI of the event.  This notification may take place via email if there is not 
yet enough information for a formal written report.  A formal written report must be sent to the Washington 
University PI and research coordinator within 10 working days of the occurrence of the event or notification 
of the secondary site’s PI of the event.  The death of a research participant that qualifies as a reportable event 
should be reported within 1 working day of the occurrence of the event or notification of the participating 
site’s PI of the event. 
 
The research team at a participating site is responsible for following its site’s guidelines for reporting 
applicable events to its site’s IRB according to its own institutional guidelines.  Since sites will be relying on 
Washington University’s IRB, any reportable event will also be submitted to Washington University’s IRB for 
review. 
9.4.4. 
Reporting to Participating Sites 
The Washington University PI (or designee) will notify the research team at each participating site of all 
reportable events that have occurred at other sites within 10 working days of the occurrence of the event or 
notification of the PI of the event.  This includes events that take place both at Washington University and at 
other participating sites, if applicable. 
9.4.5. 
Reporting to MyoCardial Solutions 
The following adverse events will be reported to MyoCardial Solutions within 10 working days of the 
occurrence of the event or notification of the PI of the event at either Washington University or any 
participating site unless the event occurs in a death, in which case it will be reported within 1 working day: 
Term 
Description 
Device Related Adverse 
Event (DRAE) 
An adverse event will be considered to be related to the device if it results 
from the use or presence of the MRI Scanner, or the performance of any 
component of the MRI Scanner.   
Unanticipated Adverse 
Device Effect (UADE) 
A device or procedure related adverse effect will be considered 
unanticipated if it is not identified in the MRI Scanner or SENC MyoStrain® 
Testing Software operator manuals or instructions for use. 
9.4.6. 
Timeframe for Reporting Required Events 
Adverse events will be tracked from time of consent to the last study visit.  For the purposes of this protocol, 
adverse events collected and documented on CRFs include adverse events occurring from the MRI scanner, 
SENC MyoStrain® Testing Software, or breach of confidentiality. 
 
All incidences of noncompliance and protocol exceptions will be tracked from the time of IRB approval, at the 
coordinating center, or site initiation at the participating centers, until the close of the study.  
 
 
For more information on adverse event definitions and classifications and reporting requirements, please visit:  
https://www.hhs.gov/ohrp/regulations-and-policy/guidance/reviewing-unanticipated-problems/index.html 
 
 

 
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10. 
DATA SAFETY AND MONITORING 
10.1.1. Data Monitoring by MyoCardial Solutions 
Monitoring of the research is the responsibility of the Principal Investigator at each participating site. The 
participating sites and Myocardial Solutions will meet on regular basis to discuss the progress of the research 
and the efficiency of the PROACT study. 
10.1.2. Data Monitoring by Coordinating Sites 
The data consist of information obtained from MyoCardial Solutions, Inc. MyoStrain® software. Data will be 
stored in two places: 1) a WUSTL REDCap database and 2) all original paper copies will be stored in a locked 
cabinet behind a locked door at each participating site. Moreover, only the Research Coordinator or 
designated study staff will have keys to the locked cabinet. Only the designated study staff will have access to 
any resources with identifying information in REDCap. An important REDCap feature to note is that the 
access to study data is limited to those assigned access (i.e. Key Study Personnel [KSP]).  
 
Data and regulatory documents from all participating sites will be reviewed by the Washington University 
Quality Assurance and Safety Monitoring Committee (QASMC) every 6 months.  For participating sites added 
on after study initiation, the first review for that site will take place during the next scheduled QASMC review, 
which may occur prior to 6 months after site initiation.  Because all monitoring will take place remotely, 
uploads of source documentation, including consent forms with signatures, either to REDCap and/or WUSTL 
Box will be mandatory for participating sites.  In addition, QASMC may request access to participating sites’ 
electronic medical record, if the site’s institution allows such access. 
 
Data and regulatory document monitoring will also be conducted by the coordinating center’s research 
coordinators and will consist of data checks, both electronic and manual. Every 6 months prior to QASMC 
review, data entered into the REDCap database will be reviewed for accuracy by designated study staff at the 
coordinating center.  As with QASMC audits, for participating sites added on after study initiation, the first 
review for that site will take place during the next scheduled data review.  Uploaded source documentation, 
including consent forms with signatures, by participating sites will also be reviewed for inconsistent data.  If 
there are inconsistencies or missing values, queries will be issued to the participating sites and they will refer 
to the subject’s records to correct the aberration. Participating sites are expected to enter data into REDCap 
within 14 business days of a study visit.  Sites that appear to have significant delays between the time of 
enrollment/study visits and data entry will be contacted by the coordinating center.  Participating sites are also 
expected to respond to any REDCap queries within 1 month of issuance. Sites that appear to have a 
significant amount of REDCap queries will be contacted by the coordinating center.  At each interval, the 
coordinating center will note the number of participants accrued to date as well as the number of participants 
accrued for that 6 months interval.  
 
All study personnel will receive training on protocol procedures and data collection from the coordinating 
center. Only experienced personnel will take part in this study. Additionally, designated study staff will 
randomly monitor the consenting process pertinent to this study to maintain study protocol compliance, as well 
as ensure the minimization of measurement or information bias imposed by study personnel. 
10.1.3. Data Safety and Monitoring Committee 
In compliance with the Washington University Institutional Data and Safety Monitoring Plan, the Principal 
Investigator will provide a Data and Safety Monitoring (DSM) report to the Washington University Quality 
Assurance and Safety Monitoring Committee (QASAMC) semi-annually beginning six months after accrual 
has opened (if at least 5 patients have been enrolled) or 1 year after accrual has opened (if fewer than 5 
patients have been enrolled at the 6 month mark).   
 
The Principal Investigator will review all patient data at least every 6 months, and provide a semi-annual 
report to QASMC.  The report will include: 
• 
HRPO protocol number, protocol title, Principal Investigator name, and research coordinator name 
• 
Date of initial HRPO approval, date of most recent HRPO approval/revision of consent, date of HRPO 
expiration, date of most recent QA audit, study status, and phase of study 
• 
History of study including summary of substantive amendments; summary of accrual suspensions 
including start/stop dates and reason; and summary of protocol exceptions, error, or breach of 
confidentiality including start/stop dates and reason 
• 
Study-wide target accrual and study-wide actual accrual 
• 
Protocol activation date 
• 
Average rate of accrual observed in Year 1, Year 2, and subsequent years 
• 
Expected accrual end date 

 
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• 
Objectives of protocol with supporting data and list of the number of participants who have met each 
objective 
• 
Abstract submissions/publications 
• 
Summary of any recent literature that may affect the safety or ethics of the study 
 
 
11. 
STATISTICAL CONSIDERATIONS 
The data of cardiac features measured will be stored in a WUSTL REDCap-supported database and 
transformed into a SAS, R, excel, and CSV dataset, so they can be analyzed by our team using SAS, R and 
PYTHON software packages. 
 
At baseline and any other visit, the standard descriptive statistics will be used to summarize numeric 
variables, including the number of observed values, mean, standard deviation, median, minimum and 
maximum values.  Summaries of categorical variables will include the number and percentage of observed 
values, at each level of the categorical variable.  Baseline and demographic information will be summarized 
with standard descriptive statistics. 
 
There will be more than 60 cardiac 3D features measured for each patient (subjects’ n=102) resulting from 
use of MyoStrain SENC software, as shown in the schematic Figure 5. The results will be stratified based on 
the patient’s segmental strain (longitudinal and circumferential) profile with -10% or -17% as the threshold to 
determine segmental dysfunction and the number of dysfunctional segments delineating patient risk. The 
patients will be selected at baseline for high cardiovascular risk, which will be important in cancer patients in 
responding to cardiotoxicity.  
 
Patients will be separated by randomization into two groups. Those of whom the cardiac care will be served 
with prior knowledge of MyoStrain SENC data as measured in each visit, while the other half, with exception 
of 4 cardiac measures, they and their doctor will not have knowledge for the full cardiac features, but we will 
have access to these data also, only at the end of the study. 
 
Figure 5: A schematic of measurements and statistical methods to be used for inferring for cardiotoxicity from 
results of baseline and also at 1, 3, 6, 12, 24 and 36 months’ follow-up. 
 
The longitudinal data will be compared for each individual with his/her baseline, to learn and guide each 
individual’s care and to infer the level of cardiotoxicity. The same group’s data will be analyzed with the 
intention in identifying what trends exist among those in the group of MyoStrain SENC software guided 
treatment. The full cardiac measures for the other group: the observational arm will be available to us at the 
end of the trial. At that time, we will analyze also the longitudinal cardiac 3D features for this group at the 
individual levels compared to baseline. In addition, we will analyze the longitudinal data to identify trends for 
each group, as well as we will compare trends of two groups toward cardiac response to chemotherapy and / 
or radiology. We will test the cardiotoxicity development i.e. myocardial dysfunction by comparing the efficacy 
of detecting cardiac dysfunction using standard assessments LVEF, LVESV and LVEDV in time against 
analyzing all cardiac features collected via MyoStrain (more than 60 of them, Figure 5). Multivariate regression 
and logistic regression will be used with “stepwise” option to identify significant predictors at standard and 
guided care features for predicting cardiotoxicity. Furthermore, we will use decision trees for identifying the 
Impact of Cancer therapy on 
myocardial function
MRI-image
MyoStrain
SENC sofware
View
Image
manipulation
Image
quantification
Saving data
Prospective, multi-center, open label, randomized study
Visits: baseline & 1, 3, 6, 12, 24 and 36 months follow-up
Risk Decision: 
RANDOMIZATION
MyoStrain
guided
treatment
MyoStrain
observational
arm
Standard care
Cardiac 
structural 
features
Cardiac care 
guided by cancer 
treatment 
cardiotoxicity
No Patient Name
1
Accession #
MRN
1 Scan Data
8/1/2018
2 DOB
NA
3 Age
NA
4 Gender
NA
5 Height cm
158
6 Weight kg
70
7 BSA m2
1.72
8 LV Global Longitudinal Strain(GLS) %
-21.9
9 LV Global Circumferential Strain(GCS) %
-20.7
10 RV Global Longitudinal Strain(GLS) %
-20.7
11 RV Global Circumferential Strain(GCS) %
-17.8
12 Number of Dysfunctional Segments
1
13 Number of Segments > -17
6
14 LVEF %
67.6
15 LV Mass g
87.2
16 LV Mass Index g/m2
50.7
17 LVED Volume ml
156
18 LVED Volume Index ml/m2
90.7
19 LVES Volume ml
50.5
20 LVES Volume Index ml/m2
29.36
21 LV Stroke Volume ml
105.4
22 LV Stroke Volume Index ml/m2
61.28
23 Rest_LS01 Basal SA Anterior
-24.7
24 Rest_LS02 Basal SA Anteroseptal
-24.7
… …
…
Compare all follow-up 
measurements with 
baseline
Individually
Within group
Between two 
groups
Longitudinal 
analysis
Mixed model 
repeated 
measures
Features’ importance 
selection in identifying 
cardiac toxicity

 
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importance of MyoStrain cardiac features compared to cardiac toxicity risk prediction based on standard 
assessment of variables LVEF, LVESV, LVEDV, and LV Stroke Volume Index (LVSVi).  Endpoints will be 
evaluated based on discrete variables of MyoStrain values versus standard assessments.  Considering many 
patients will have a complex management of cardioactive medications as well as cancer treatment regimen, 
the classification of cardiotoxicity status will be based on a clinical committee to designate whether the patient 
experienced no cardiotoxicity, functional decline without cardiotoxicity, subclinical cardiotoxicity, or clinical 
cardiac dysfunction at each exam timepoint.  The last analysis will help to identify also any indication for 
interactions among variables studied. We will implement Intention-To-Treat-analysis, where the analyses of 
the two groups will be based on the initial treatment assignment in the two randomized groups. If in the follow-
up data-points may be missing, we will check if the missing data-points are random and if several covariates 
can help in imputation of missing. We plan to use MI procedure of SAS Institute for such imputations. The 
regression will be implemented via GLM, LOGISTIC and MIXED (for statistical analysis of repeated measures) 
procedures in SAS. For mixed models, a comparison of models will be done via likelihood ratio test and by 
using the Akaike Information Criterion (AIC) and Schwartz’s Bayesian Criterion (SBC). Graphical 
presentations will be implemented in R via LMER of LME4 mixed modelling build in functions, and specialized 
software GGPLOT2 in R. Decision (known also as partition) trees will be implemented with SAS-Data Mining 
software. We will use also PYTHON-scikit machine learning package for testing the performance of partition-
trees via random forest. A random forest is a meta estimator that fits a number of decision tree classifiers on 
various sub-samples of the dataset and use averaging to improve the predictive accuracy and control over-
fitting.  
 
Based on pilot data and utilizing only the moderate to high risk group (>2 segments of Myostrain determined 
segments >17%), the outcome expected would be 12.8 +/- 4.7 dysfunctional segments for the intervention 
group and 16.8 +/- 7.8 dysfunctional segments for the control group (and using average of 4.7 and 7.8 for the 
standard deviation for the overall outcome) at 6 months.  This same parameter will be followed at the other 
time points, including 1 year, 2 years, and 3 years, but the primary endpoint will be at 6 months. 
With these calculations,102 patients are required to have a 90% chance of detecting, as significant at the 5% 
level, a decrease in the primary outcome measure from 16.8 in the control group to 12.8 in the experimental 
group (number of dysfunctional segments (>17%)). 
 
The sensitivity, specificity, and diagnostic accuracy of each reader to detect changes in myocardial function 
will be determined for quantitative SENC-CMR. Cutoff-values used to calculate sensitivity and specificity of the 
quantitative SENC parameters were determined using data previously published. The cutoff for the % of 
MyoStrain segments <= -17% (based on 37 left ventricular segments) in detecting subclinical cardiotoxicity in 
the PREFECT50 planned interim analysis was 68% and the cutoff for detecting clinical cardiac dysfunction 
was 49%; a cutoff of 80% differentiates normal cardiac function from patients experiencing functional decline.  
McNemar’s test with continuity correction will be used to compare the diagnostic performance of each of the 
SENC-CMR cutoff parameters. Additionally, Receiver Operating Characteristic curves as well as Precision 
Recall curves will be generated to calculate and compare the area under the curves to determine the 
diagnostic performance of changes in strain parameters and standard assessments. Inter- and intra-observer 
variability will also be determined for each of the above parameters using intraclass correlation. 
 
 
12. 
DATA MANAGEMENT 
The coordinating center and primary investigator are responsible for data management. The 
investigator/clinical coordinator at each participating site will be responsible for completion and timely input of 
the study data into the WUSTL REDCap database.  Data entered will be reviewed to identify inconsistent or 
missing data and Adverse Events. The Investigator at each participating site is to maintain all source 
documents as required by the protocol, including SENC MyoStrain® results, supporting medical records, and 
Informed Consents. 
 
Confidentiality of data shall be observed by all parties involved during the research. The privacy of each 
subject and confidentiality of his/her information shall be preserved in reports and when publishing any data. 
 
 
13. 
DEVICE ACCOUNTABILITY 
Records shall be kept to document when the SENC software and pulse sequence patch is received, returned, 
uninstalled or disposed at the participating sites.  
 
 

 
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14. 
STATEMENTS OF COMPLIANCE 
This study will be conducted according to good clinical practice guidelines, the Declaration of Helsinki, and the 
ANSI ISO 14155: clinical investigation for human subjects. Written informed consent for the study will be 
received from all participants. 
 
 
15. 
INVESTIGATOR RESPONSIBILITIES AND OBLIGATIONS 
15.1. 
Investigator Responsibilities 
The investigator is responsible for obtaining the initial and continuing review and approval from the authorized 
IRB/Ethics Committee for the participating site at which the proposed clinical investigation is to be conducted.  
The Investigator is responsible for ensuring that informed consent is obtained from each study subject prior to 
the initiation of any study procedures. 
15.2. 
Investigator Records 
The Investigator will maintain complete, accurate and current study records, including the following materials: 
1) 
Study Subject Records, including Informed Consent forms, supporting source documents, and CMR 
image files including MyoStrain® reports; 
2) 
All relevant observations, including records concerning adverse device effects (whether anticipated or 
unanticipated); 
3) 
Current study protocol and protocol deviation log, with dates and details of any reason for deviations 
from the protocol that could affect the scientific quality of the study or the rights, safety, or welfare of 
the subjects; 
4) 
The approved blank Informed Consent form and Case Report Forms (CRFs); and 
5) 
Documentation that the Investigational Plan has been approved by all of the necessary approving 
authorities. 
15.3. 
Investigator Reports 
The Investigator will be responsible for the following reports: 
• 
Unanticipated Adverse Device Effect: The Investigator shall report all Unanticipated Adverse Device 
Effects to the Sponsor and to the reviewing IRB as soon as possible, but no later than 10 working days 
after the Investigator first learns of the effect.  All Unanticipated Adverse Device Effects should be 
documented by time of onset, a complete description of the event, severity, duration, actions taken and 
event outcome.   
• 
Withdrawal of IRB/EC Approval: The Investigator shall report to the Sponsor within 5 working days if, 
for any reason, the IRB/Ethics Committee withdraws approval to conduct the investigation.  The report 
will include a complete description of the reason(s) for which approval was withdrawn. 
• 
Deviations from the Investigational Plan: The Investigator shall notify the Sponsor and the reviewing 
IRB of any changes in, or deviations from, the Investigational Plan to protect the life or physical well-
being of the Subject in an emergency.  Such notice shall be given as soon as possible, but no later than 
5 working days after the emergency occurs.  
• 
Final Report: The Investigator will submit a final report to the Sponsor and to the IRB/EC within 3 
months of termination of the study or termination of that Investigator's participation in the study. 
15.4. 
Financial Disclosure by Clinical Investigators 
Pursuant to 21 CFR part 54 and prior to the initiation of the study, each investigator must disclose certain 
financial arrangements that may exist between that investigator and Myocardial Solutions. This information will 
be collected from each investigator, maintained in confidential files at Myocardial Solutions and will be available 
for review by regulatory agencies upon request.  
 
 
 
 

 
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16. 
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Kamishima, Y. M. Ito, H. Tsutsui, K. K. Tha, S. Terae and H. Shirato, "Identification and Further 
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[17] A. Youssef, E.-S. H. Ibrahim, G. Korosoglou, M. R. Abraham, R. G. Weiss and N. F. Osman, "Strain-
Encoding Cardiovascular Magnetic Resonance for Assessment of Right-Ventricular Regional Function," 
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[18] M. L. Shehata, T. A. Basha, W. H. Tantawy, J. A. Lima, J. Vogel-Claussen, D. A. Bluemke, P. M. 
Hassoun and N. F. Osman, "Real-Time Single-Heartbeat Fast Strain-Encoded Imaging of Right 
Ventricular Regional Function: Normal Versus Chronic Pulmonary Hypertension," Magnetic Resonance 
in Medicine, vol. 64, pp. 98-106, 2010.  
[19] A. Hamdan, T. Thouet, S. Kelle, I. Paetsch, R. Gebker, E. Wellnhofer, B. Schnackenburg, A. S. Fahmy, 
N. F. Osman and E. Fleck, "Regional Right Ventricular Function and Timing of Contraction in Healthy 
Volunteers Evaluated by Strain-Encoded MRI," Journal of Magnetic Resonance Imaging, vol. 28, no. 6, 
pp. 1379-1385, December 2008.  
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PROactive evaluation of function to Avoid CardioToxicity 
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Version: 6.0  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version Date: 09.27.2021 
17. 
APPENDICES 
17.1. 
Patient Satisfaction Questionnaire