HCMR Re-Imaging Study
Conditions: Hypertrophic Cardiomyopathy (HCM)
Sponsor: Christopher Kramer

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Version 2.000
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HCMR Re-Imaging Study 
Unique Protocol Identification Number:  
National Clinical Trial (NCT) Identified Number:  
Principal Investigator: Christopher Kramer 
IND/IDE Sponsor:  
Funded by: Cytokinetics 
Version Number: 2.000 
12 February 2025 
 
 
Summary of Changes from Previous Version: 
 
Affected Section(s) Summary of Revisions Made 
Rationale 
  
  
  
  
  
  
 
 
Table of Contents 
Statement of Compliance ............................................................................................................................. 4 
1 Protocol Summary...................................................................................................................................... 5 
1.1 Synopsis ............................................................................................................................................... 5 
1.2 Schema ................................................................................................................................................ 6 
1.3 Schedule of Activities (SoA) ................................................................................................................. 7 
2 Introduction ............................................................................................................................................... 8 
2.1 Study Rationale ................................................................................................................................... 8 
2.2 Background .......................................................................................................................................... 8 
2.3 Risk/Benefit Assessment ..................................................................................................................... 9 
2.3.1 Known Potential Risks................................................................................................................... 9 
2.3.2 Known Potential Benefits ........................................................................................................... 10 
2.3.3 Assessment of Potential Risks and Benefits ............................................................................... 10 
3 Objectives and Endpoints ........................................................................................................................ 11 
4 Study Design ............................................................................................................................................. 12 
4.1 Overall Design .................................................................................................................................... 12 
4.2 Scientific Rationale for Study Design ................................................................................................. 12 
4.3 Justification for Dose ......................................................................................................................... 12 
4.4 End of Study Definition...................................................................................................................... 12 
5 Study Population ...................................................................................................................................... 13 

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5.1 Inclusion Criteria ................................................................................................................................ 13 
5.2 Exclusion Criteria ............................................................................................................................... 13 
5.3 Lifestyle Considerations .................................................................................................................... 14 
5.4 Screen Failures .................................................................................................................................. 14 
5.5 Strategies for Recruitment and Retention ........................................................................................ 14 
6 Study Intervention ................................................................................................................................... 15 
6.1 Study Intervention(s) Administration ................................................................................................ 15 
6.1.1 Study Intervention Description ................................................................................................... 15 
6.1.2 Dosing and Administration ......................................................................................................... 15 
6.2 Preparation/Handling/Storage/Accountability ................................................................................. 15 
6.2.1 Acquisition and accountability.................................................................................................... 15 
6.2.2 Formulation, Appearance, Packaging, and Labeling ................................................................... 15 
6.2.3 Product Storage and Stability ..................................................................................................... 16 
6.2.4 Preparation ................................................................................................................................. 16 
6.3 Measures to Minimize Bias: Randomization and Blinding ................................................................ 16 
6.4 Study Intervention Compliance ......................................................................................................... 16 
6.5 Concomitant Therapy ........................................................................................................................ 16 
6.5.1 Rescue Medicine ......................................................................................................................... 16 
7 Study Intervention Discontinuation and Participant Discontinuation/Withdrawal ................................ 17 
7.1 Discontinuation of Study Intervention .............................................................................................. 17 
7.2 Participant Discontinuation/Withdrawal from the Study ................................................................. 17 
7.3 Lost to Follow-Up .............................................................................................................................. 17 
8 Study Assessments and Procedures ......................................................................................................... 18 
8.1 Efficacy Assessments ......................................................................................................................... 18 
8.2 Safety and Other Assessments .......................................................................................................... 18 
8.3 Adverse Events and Serious Adverse Events ..................................................................................... 18 
8.3.1 Definition of Adverse Events (AE) ............................................................................................... 18 
8.3.2 Definition of Serious Adverse Events (SAE) ................................................................................ 18 
8.3.3 Classification of an Adverse Event .............................................................................................. 18 
8.3.4 Time Period and Frequency for Event Assessment and Follow-Up ............................................ 19 
8.3.5 Adverse Event Reporting ............................................................................................................ 19 
8.3.6 Serious Adverse Event Reporting ............................................................................................... 19 
8.3.7 Reporting Events to Participants ................................................................................................ 19 
8.3.8 Events of Special Interest ........................................................................................................... 19 
8.3.9 Reporting of Pregnancy .............................................................................................................. 19 
8.4 Unanticipated Problems .................................................................................................................... 19 
8.4.1 Definition of Unanticipated Problems (UP) ................................................................................ 19 
8.4.2 Unanticipated Problem Reporting .............................................................................................. 19 
8.4.3 Reporting Unanticipated Problems to Participants .................................................................... 19 
9 Statistical Considerations ......................................................................................................................... 20 
9.1 Statistical Hypotheses ....................................................................................................................... 20 
9.2 Sample Size Determination ............................................................................................................... 20 

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9.3 Populations for Analyses ................................................................................................................... 20 
9.4 Statistical Analyses ............................................................................................................................ 20 
9.4.1 General Approach ....................................................................................................................... 20 
9.4.2 Analysis of the Primary Efficacy Endpoint(s) .............................................................................. 20 
9.4.3 Analysis of the Secondary Endpoint(s) ....................................................................................... 20 
9.4.4 Safety Analyses ........................................................................................................................... 21 
9.4.5 Baseline Descriptive Statistics .................................................................................................... 21 
9.4.6 Planned Interim Analyses ........................................................................................................... 21 
9.4.7 Sub-Group Analyses .................................................................................................................... 21 
9.4.8 Tabulation of Individual Participant Data ................................................................................... 21 
9.4.9 Exploratory Analyses .................................................................................................................. 21 
10 Supporting Documentation and Operational Considerations ............................................................... 22 
10.1 Regulatory, Ethical, and Study Oversight Considerations ............................................................... 22 
10.1.1 Informed Consent Process ........................................................................................................ 22 
10.1.2 Study Discontinuation and Closure .......................................................................................... 22 
10.1.3 Confidentiality and Privacy ....................................................................................................... 22 
10.1.4 Future Use of Stored Specimens and Data ............................................................................... 22 
10.1.5 Key Roles and Study Governance ............................................................................................. 22 
10.1.6 Safety Oversight ........................................................................................................................ 23 
10.1.7 Clinical Monitoring .................................................................................................................... 23 
10.1.8 Quality Assurance and Quality Control..................................................................................... 23 
10.1.9 Data Handling and Record Keeping .......................................................................................... 23 
10.1.10 Protocol Deviations ................................................................................................................ 23 
10.1.11 Publication and Data Sharing Policy ....................................................................................... 24 
10.1.12 Conflict of Interest Policy ........................................................................................................ 24 
10.2 Additional Considerations ............................................................................................................... 24 
10.3 Abbreviations .................................................................................................................................. 24 
10.4 Protocol Amendment History ......................................................................................................... 25 
11 References ............................................................................................................................................. 28 
 
 
 

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STATEMENT OF COMPLIANCE 
Provide a statement that the trial will be conducted in compliance with the protocol, International 
Council on Harmonisation Good Clinical Practice (ICH GCP) and applicable state, local and federal 
regulatory requirements. Each engaged institution must have a current Federal-Wide Assurance (FWA) 
issued by the Office for Human Research Protections (OHRP) and must provide this protocol and the 
associated informed consent documents and recruitment materials for review and approval by an 
appropriate Institutional Review Board (IRB) or Ethics Committee (EC) registered with OHRP. Any 
amendments to the protocol or consent materials must also be approved before implementation. Select 
one of the two statements below. If the study is an intramural NIH study, use the second statement 
below: 
1. The trial will be carried out in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP) and the following: 
o 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 
CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and/or 21 CFR Part 812). 
National Institutes of Health (NIH)-funded investigators and clinical trial site staff who are 
responsible for the conduct, management, or oversight of NIH-funded clinical trials have 
completed Human Subjects Protection and ICH GCP Training. 
OR 
2. The trial will be conducted in accordance with International Council on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and 
the [specify NIH Institute or Center (IC) [ Terms and Conditions of Award. The Principal 
Investigator will assure that no deviation from, or changes to the protocol will take place 
without prior agreement from the funding agency and documented approval from the 
Institutional Review Board (IRB), and the Investigational New Drug (IND) or Investigational 
Device Exemption (IDE) sponsor, if applicable, except where necessary to eliminate an 
immediate hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed Human Subjects Protection and ICH GCP Training. 
For either option above, the following paragraph would be included: 
The protocol, informed consent form(s), recruitment materials, and all participant materials will 
be submitted to the IRB for review and approval. Approval of both the protocol and the consent 
form(s) must be obtained before any participant is consented. Any amendment to the protocol 
will require review and approval by the IRB before the changes are implemented to the study. 
All changes to the consent form(s) will be IRB approved; a determination will be made regarding 
whether a new consent needs to be obtained from participants who provided consent, using a 
previously approved consent form. 

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1 PROTOCOL SUMMARY 
1.1 SYNOPSIS 
Title: 
HCMR Re-Imaging Study  
Study Description: 
  
Objectives: 
Primary Objective: 
To assess the change in biomarkers and CMR 
parameters including LV mass, maximal wall 
thickness, and LGE extent from baseline over a 
minimum of 7 years of follow-up extent in HCM 
patients who would have been candidates for 
clinical trials of aficamten. 
Secondary Objectives:   
Endpoints: 
Primary Endpoint: 
% LGE mass 
Secondary Endpoints: LV mass, end-diastolic volume (EDV), end-systolic 
volume (ESV), stroke volume (SV), ejection fraction 
(EF), and LV mass index (I), EDVI, ESVI, SVI 
RV EDV, ESV, SV, EF, EDVI, ESVI, SV, EF 
Maximal wall thickness 
LV and RV longitudinal, circumferential, and radial 
strain 
LGE – presence, mass 
T1 – regional and global 
Extracellular volume – regional and global 
LA volume, LAVI, and LA strain 

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Study Population: 
Within the HCMR original cohort who have 
1. Obstructive HCM and  
  
• 
BMI < 35 kg/m2  
• 
LVOT-G at entry as follows:  
Resting gradient ≥50 mmHg OR  
Resting gradient ≥30 mmHg and <50 mmHg with post-Valsalva LVOT-G ≥50 
mmHg  
NYHA Class II or III  
or 
  
2. Nonobstructive HCM 
  
Same criteria as above except resting LVOT-G is <30mmHg and post-
Valsalva gradient <50mm Hg 
  
• 
BMI <40kg/m2 
• 
Elevated NT-proBNP > 300 pg/mL at the time of enrollment  
• 
LVEF ≥55%  
Phase: 
Observational 
Description of 
Sites/Facilities Enrolling 
Participants: 
Selected from original HCMR sites in the U.S. and U.K. 
Description of Study 
Intervention: 
Observational only. No intervention 
Study Duration: 
1 year 
Participant Duration: 
One visit 
  
 
 
1.2 SCHEMA 
 
 

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1.3 SCHEDULE OF ACTIVITIES (SOA) 
Study visit Day  
Informed consent 
 
Medical history and medication review 
 
Vital signs 
 
Brief physical exam 
  
Cardiac MRI with and without gadolinium contrast 
  
Blood draw for biomarkers 
 
 

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2 INTRODUCTION 
2.1 STUDY RATIONALE 
A meta-analysis of 5 pooled studies and 2993 patients followed for a median of 3 years has 
demonstrated that after adjusting for baseline characteristics, the extent of late gadolinium 
enhancement (LGE) was associated with SCD (1.36 for every 10% increase in LGE as % of LV mass). 
HCMR data already show a primary event rate of 4% in patients with >10% LGE, 1.3% in patients with 1-
10% LGE, and 0.4% in those without LGE. It is this type of observation that underscores the power of this 
cohort. Two small studies have shown progression of LGE in patients with HCM, primarily in patients 
with greater hypertrophy and LGE at baseline and progression is associated with a decline in ejection 
fraction, heart failure hospitalizations, and arrhythmias.7,8 
 
 
2.2 BACKGROUND 
Hypertrophic cardiomyopathy (HCM) has a prevalence of between 1 in 200 and 1 in 500 in the general 
population and is the most common monogenic heart disease. It is characterized by unexplained left 
ventricular hypertrophy (LVH), diffuse and patchy fibrosis, and myofibrillar disarray1, 2. It is an important 
cause of sudden cardiac death (SCD) in young individuals3. While many patients experience a mild 
clinical course, cumulative disease burden is considerable and most will experience complications, 
particularly heart failure (HF) or atrial fibrillation (AF)4. Accurately predicting prognosis and stratifying 
risk are important unmet clinical needs5. Risk scores to predict SCD using demographic, clinical, and 
echocardiographic markers have been developed9 and tested10. However, existing risk scores fail to 
precisely predict risk. Furthermore, based on current guideline-based risk assessment, most patients will 
be deemed to be at low or intermediate risk, and yet most events occur in these patients10, 11. 
Identifying novel risk markers is required to improve upon present models. In addition, updated 
predictive models that focus on other clinically relevant endpoints that can be intervened upon, e.g. HF 
and AF, will advance the field and improve patient care. Previously available medical therapy for HCM 
focuses on symptom palliation and does not alter the natural history, protect against SCD, or prevent 
the development of AF or HF. However, novel disease-modifying therapies are now available12. 
Therefore, creating a new prognostic model will identify patients at increased risk for SCD, AF or HF, and 
will foster the evaluation of novel therapeutic strategies aimed at altering phenotypic expression and 
natural history. In turn, this would lead to improved survival and quality of life and reduced healthcare 
costs in HCM. 
Our group has set out to redefine risk markers for critical cardiovascular outcomes in HCM through 
HCMR, Novel Markers of Prognosis in Hypertrophic Cardiomyopathy, U01HL117006-01A1.6 In this unique 
and carefully designed study, we have recruited 2750 patients from 44 sites in 6 countries and collected 
comprehensive demographic, clinical, imaging, biomarker, and genetic data from each. This is the 
largest systematic prospective study of this disease performed to date. Recruitment was completed in 

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April 2017. To date, mean follow-up is at 6.3 years. Baseline data analysis was completed and 
published.13 The principal findings are summarized in the Figure below. 
 
 Figure Legend: 2755 patients from 44 sites in 6 countries were recruited. Two relatively distinct 
populations were identified as depicted. Left – 4 chamber inversion recovery gradient echo LGE image in 
a patient with reverse curvature asymmetric septal hypertrophy. Patchy LGE is noted in mid-septum. 
Right – similar orientation and image type in a patient with reverse curvature asymmetric septal 
hypertrophy. No LGE is noted. One group was sarcomere mutation positive, and more likely had reverse 
septal curvature morphology, more fibrosis, and less obstruction whereas the other was sarcomere 
mutation negative, and more likely had isolated basal septal hypertrophy with obstruction and less 
fibrosis. 
  
 
2.3 RISK/BENEFIT ASSESSMENT 
2.3.1 KNOWN POTENTIAL RISKS 
Blood Draw and IV placement 
The risk of IV line placement and blood draw are of bruising, bleeding, and local infection. A vagal 
reaction and fainting due to either procedure is quite rare (<1%). 
  
CMR 
CMR uses strong magnetic fields to obtain images. During the switching (slewing) of the magnetic fields, 
the MR scanner makes loud banging sounds that may cause discomfort to patients being scanned. 
Earplugs will be provided to minimize this discomfort. In addition, the switching of the magnetic field 
gradients can, under some circumstances, cause peripheral nerve stimulation, which may be 

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experienced as a mild twitching reaction in certain muscles. Such effects are rare and the switching rates 
are kept well below the levels where such effects are known to occur frequently. All magnetic field 
gradient slewing will be within FDA-approved parameters and have not been reported to have adverse 
health effects. To generate MR images, radio waves are used that can cause a mild warming sensation 
similar to exposure to hot weather or tanning on the beach. Body temperature may increase slightly 
(less than 1°C). The total CMR scanning protocol will be accomplished within 60 minutes. ECG leads or 
fiber-optic detectors will be placed on the subject’s body to obtain a triggering signal for the purpose of 
cardiac gating. ECG leads under very rare circumstances have caused local skin irritation during MR 
scans. The technical staff has been trained as per standard-of-care to place leads in such a manner as to 
avoid such burns. There are risks of IV catheter placement that include tenderness, swelling, warmth at 
the injection site, extravasation of the contrast agent and, rarely, infection. Should the patient 
experience any of the above discomfort to an intolerable degree, the CMR examination can and will be 
stopped at any time upon the request of the subject. 
  
Gadolinium 
 
There are rare reports of allergies to gadolinium. With the use of cyclic gadolinium chelates, 
nephrogenic systemic fibrosis, which was reported with linear chelates before 2010, is no longer an 
issue. All of the patients recruited will have received gadolinium with their intake CMR in HCMR and 
have not had a problem with it. Gadolinium is xx in pregnancy 
2.3.2 KNOWN POTENTIAL BENEFITS 
There are no definite benefits of participating in this study. However, the patient's physician may receive 
information from the CMR that may be of benefit in the patient's care. 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS 
The risks of this study are extremely low as are the potential benefits. 
 
 

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3 OBJECTIVES AND ENDPOINTS 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
To assess the change in LGE extent 
from baseline over a minimum of 7 
years of follow-up extent in HCM 
patients who would have been 
candidates for clinical trials of 
aficamten. 
Change in % LGE mass 
LGE extent is a risk factor for 
SCD. The progression of LGE 
over time is incompletely 
understood. 
Secondary 
To assess the change in CMR 
parameters including LV mass, 
volumes, and maximal wall 
thickness, from baseline over a 
minimum of 7 years of follow-up 
extent in HCM patients who would 
have been candidates for clinical 
trials of aficamten. 
LV mass, end-diastolic volume (EDV), 
end-systolic volume (ESV), stroke 
volume (SV), ejection fraction (EF), and 
LV mass index (I), EDVI, ESVI, SVI 
RV EDV, ESV, SV, EF, EDVI, ESVI, SV, EF 
Maximal wall thickness 
LV and RV longitudinal, 
circumferential, and radial strain 
LGE – presence, mass 
T1 – regional and global 
Extracellular volume – regional and 
global 
LA volume, LAVI, and LA strain 
Prior f/u CMR studies in 
HCM are short-term and 
with a small n. This would be 
the largest f/u study to date 
with the largest n. 
Tertiary/Exploratory 
To assess the change in biomarkers 
from baseline over a minimum of 7 
years of follow-up extent in HCM 
patients who would have been 
candidates for clinical trials of 
aficamten. 
NTproBNP and hsTNT and change in 
these measures from baseline 
Changes in biomarkers over 
time are also important to 
understand in HCM 

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4 STUDY DESIGN 
4.1 OVERALL DESIGN 
A total of 314 patients from 9 sites (187 with oHCM, 127 with nHCM) will be approached to consent for 
re-imaging and repeat blood draw. Patients will be approached by the individual site PI and/or CRC and 
all studies will be performed at that site. Patients who consent will undergo a repeat CMR with  similar a 
protocol to that performed as per the initial study in 2014-17. The only substitution would be a 
wideband sequence for LGE imaging in patients with devices, as available. 
 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
This would represent the largest f/u CMR study to date in HCM and the largest n. 
 
 
4.3 JUSTIFICATION FOR DOSE 
n/a 
 
 
4.4 END OF STUDY DEFINITION 
When the last patient has had a study visit for CMR and blood draw 
 
 

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5 STUDY POPULATION 
5.1 INCLUSION CRITERIA 
Patients in the original HCMR cohort with: 
  
1) Obstructive HCM  
• 
Males and females between 18 and 65 years of age  
• 
BMI < 35 kg/m2  
• 
LVOT-G at entry as follows:  
Resting gradient ≥50 mmHg OR  
Resting gradient ≥30 mmHg and <50 mmHg with post-Valsalva LVOT-G ≥50 mmHg  
• 
NYHA Class II or III  
or 
  
2) Non-obstructive HCM  
• 
Same criteria as above except resting LVOT-G is <30mmHg and post-Valsalva gradient <50mm 
Hg 
  
• 
BMI <40kg/m2 
• 
Elevated NT-proBNP > 300 pg/mL at the time of enrollment  
• 
LVEF ≥55%  
 
 
5.2 EXCLUSION CRITERIA 
• 
Paroxysmal atrial fibrillation or flutter documented prior to entry.  
• 
Paroxysmal or permanent atrial fibrillation requiring rhythm restoring treatment (eg, direct-
current cardioversion, ablation procedure, or antiarrhythmic therapy) ≤6 months prior to entry. 
(This exclusion does not apply if atrial fibrillation has been treated with anticoagulation and 
adequately rate-controlled for >6 months.)  

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• 
History of syncope or sustained ventricular tachyarrhythmia with exercise within 6 months prior 
to entry.  
• 
Pregnancy due to potential risk of gadolinium to the fetus 
• 
Patients with a pacemaker that are pacer-dependent as they cannot undergo MRI 
  
 
 
5.3 LIFESTYLE CONSIDERATIONS 
n/a 
 
 
5.4 SCREEN FAILURES 
Patients who have died or been lost to follow-up since entry into the original study 
 
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
Phone calls to prospective patients will be made by site study coordinators who have been in touch with 
these same patients through the original HCMR study. All studies will be performed at the site that the 
patient was enrolled at in the original HCMR study. 
 
 

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6 STUDY INTERVENTION 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
  
6.1.1 STUDY INTERVENTION DESCRIPTION 
A limited physical examination will be performed including heart rate and blood pressure 
Results of recent testing will be recorded including ECG, exercise testing, Holter monitoring, and 
echocardiography. 
• 
Intravenous access will be obtained 
• 
Blood draw (80 cc or approximately 5 tbsp.) for biomarkers, specimen banking and 
Hematocrit. No genetic testing will be performed. 
Blood (80 cc or approximately 5 tablespoons) will be collected by peripheral venipuncture at enrollment 
as a source of serum and plasma for biomarker analysis. Fasting samples are requested but if this is not 
possible logistically, non-fasting samples can be acquired and noted as such.  
A urine sample will be collected, as applicable, to determine pregnancy status.  
Full details of the protocol will be in the Blood Draw Manual 
• 
CMR 
A CMR will be performed and will take approximately one hour. 0.15mM of gadolinium contrast will be 
infused through an intravenous line during the MRI. 
Full details of the protocol will be in the Imaging Manual. 
6.1.2 DOSING AND ADMINISTRATION 
n/a 
 
 
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
n/a 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
n/a 

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6.2.3 PRODUCT STORAGE AND STABILITY 
n/a 
6.2.4 PREPARATION 
n/a 
 
 
6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
n/a 
 
 
6.4 STUDY INTERVENTION COMPLIANCE 
n/a 
 
 
6.5 CONCOMITANT THERAPY 
  
6.5.1 RESCUE MEDICINE 
n/a 
 
 

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7 STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
n/a 
 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
The patients are able to withdraw from the study at any point in time. 
 
 
7.3 LOST TO FOLLOW-UP 
Patients lost to f/u will be accounted for. They will be considered lost to follow-up if they do not respond 
to 3 phone calls and a certified letter. Should there be substantial losses additional sites can be added, 
as only a fixed number of patients per site can be recruited based on the strict entry criteria. 
 

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8 STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS 
n/a. No therapy is being studied and thus efficacy is not addressed. 
 
 
8.2 SAFETY AND OTHER ASSESSMENTS 
The patient will be monitored by MRI staff and the CRC during the CMR from the control room. Blood 
pressure and heart rate will be monitored during the MRI. A few patients will have devices (pacer or 
implantable cardioverter-defibrillator) and this will increase the needed ECG monitoring by device nurse 
or MRI staff. These devices will need to be interrogated by a device nurse prior to the MRI scan, 
adjusted to the proper setting for MRI, and then reset after the scan. 
 
 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
  
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
AN AE IS ANY UNTOWARD MEDICAL OCCURRENCE IN A SUBJECT UNDERGOING THE INITIAL 
STUDY PROCEDURES.8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
An SAE is any untoward medical occurrence that: 
• 
Results in death. 
• 
Is life-threatening.  Any 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 it occurred in a more serious form, might have caused death). 
• 
Requires in-patient hospitalization or prolongation of existing hospitalization. 
• 
Results in persistent or significant disability or incapacity. 
• 
Is a congenital anomaly/birth defect. 
• 
An event that required intervention to prevent permanent impairment or damage.. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
 Mild, moderate, severe 
 

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8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 Related or unrelated to the study 
 
8.3.3.3 EXPECTEDNESS 
Expected or unexpected 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
During and immediately after the CMR and blood draw 
8.3.5 ADVERSE EVENT REPORTING 
Adverse events that are not serious will not be reported in this study.  
8.3.6 SERIOUS ADVERSE EVENT REPORTING 
Adverse events that are deemed to be serious, related and unexpected will be reported to each site’s 
local IRB.  
8.3.7 REPORTING EVENTS TO PARTICIPANTS 
Reporting events to participants will occur on necessary basis. 
8.3.8 EVENTS OF SPECIAL INTEREST 
n/a 
8.3.9 REPORTING OF PREGNANCY 
pregnancy testing will be required for women of childbearing potential as pregnant patients will be 
excluded. 
 
8.4 UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
Any other adverse event that is not expected 
8.4.2 UNANTICIPATED PROBLEM REPORTING 
To the IRB 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS 
As necessary 
 
 

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9 STATISTICAL CONSIDERATIONS 
9.1 STATISTICAL HYPOTHESES 
• 
Primary Efficacy Endpoint(s): 
n/a 
• 
Secondary Efficacy Endpoint(s): 
  
 
 
9.2 SAMPLE SIZE DETERMINATION 
n/a 
 
 
9.3 POPULATIONS FOR ANALYSES 
All patient data collected 
 
 
9.4 STATISTICAL ANALYSES 
9.4.1 GENERAL APPROACH 
CMR, echocardiographic parameters and biomarkers will be described by means and standard 
deviations, medians and interquartile ranges for continuous variables, minimum and maximum values 
and counts and percentages for categorical variables. 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Change from baseline to follow-up CMR, echocardiographic and biomarkers will be described by 
absolute difference (follow-up value minus baseline value) and percent change from baseline((follow-up 
value – baseline value)/baseline value x 100). Associations with baseline values will be examined. 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
The association between changes in collected CMR, echocardiography and biomarker measures and 
clinical outcomes (as collected as part of the HCMR study) will be examined. 

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9.4.4 SAFETY ANALYSES 
n/a 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
CMR, echocardiographic parameters and biomarkers will be described by means and standard 
deviations, medians and interquartile ranges for continuous variables, minimum and maximum values 
and counts and percentages for categorical variables. 
9.4.6 PLANNED INTERIM ANALYSES 
n/a 
9.4.7 SUB-GROUP ANALYSES 
n/a 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
n/a 
9.4.9 EXPLORATORY ANALYSES 
n/a 
 
 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
To be performed by PI or research coordinator. All questions will be answered and concerns will be 
addressed. Each subject will receive a copy of the signed consent form. Consent will be documented as 
completed in local EMR system used. 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
By PI or CRC 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Consent will be obtained and signatures documented 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
n/a 
10.1.3 CONFIDENTIALITY AND PRIVACY 
All patient data will be de-identified and their previous site-specific code will be applied to imaging data 
and blood samples. All will be HIPPAA compliant.  
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA 
Biomarker specimens will be stored at the Brigham and Women's Core laboratory for potential future 
biomarker analysis 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Principal Investigator 
Medical Monitor 
Christopher M. Kramer MD (overall PI) 
University of Virginia Health, ckramer@virginia.edu 
  
Stefan Neubauer MD (co-PI) 
University of Oxford, Stefan.Neubauer@cardiov.ox.ac.uk 
  
Carolyn Ho MD (biomarker core lab director) 
Brigham and Women’s Hospital, cho@bwh.harvard.edu 
  
Raymond Kwong MD, (CMR core lab director) 
Brigham and Women’s Hospital, rykwong@partners.org 
  
William Weintraub MD, (data coordinating center) 
MedStar Research Institute, william.s.weintraub@medstar.net 
  
  

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10.1.6 SAFETY OVERSIGHT 
By the overall PI's and site PI's 
10.1.7 CLINICAL MONITORING 
Will be performed by site CRC's during the blood draw and MRI as described above. The CRC will be 
observing the subject during and immediately after the blood draw. The CRC will be present in the MRI 
control room and will monitor the vital signs (BP and HR) at least twice during the scan. 
Medstar will monitor incoming data on a regular basis for queries and clarification of data. Brigham and 
Women’s will be responsible for reviewing image quality 
 
10.1.8 Quality Assurance and Quality Control 
Each site will ensure quality of CMR acquisition. UVA site investigator will review MRI images before the 
patient is taken off the scanner to ensure adequate image quality. After images are sent to the core lab 
at Brigham and Women's Hospital, CMR quality will be assessed by Raymond Kwong MD and core lab 
assistants ). 
 
Data will be evaluated for compliance with protocol and accuracy in relation to source documents.  The 
study will be conducted in accordance with procedures identified in the protocol.   
 
Each site will use their individual SOPs at all clinical and laboratory sites. Regular monitoring and an 
independent audit will be performed according to GCP/ICH (e.g., data monitoring). 
 
Medstar will assure protocol compliance, ethical standards, regulatory compliance, data quality and 
proper storage and handling of samples at each site. 
10.1.9 DATA HANDLING AND RECORD KEEPING 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES 
By site PI and CRC's. CRC’s will be responsible for sending CMR to the Brigham core lab and blood 
specimens to the Brigham core lab. Imaging and biomarker data will be analyzed at the respective core 
labs. They will in turn send data to the Data Coordinating Center at MedStar Research Institute where 
statistical analysis will be performed. All patient data will be collected via source documentation on site 
by the CRC and sent to Medstar in a manner compliant with the current institutional and local 
regulations. 
10.1.9.2 STUDY RECORDS RETENTION 
By site for 5 years 
10.1.10 PROTOCOL DEVIATIONS 
Reported to IRB 

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10.1.11 PUBLICATION AND DATA SHARING POLICY 
Publication will be overseen by the HCMR Executive Committee. Data will be shared as abstracts and 
manuscripts as it becomes available. 
10.1.12 CONFLICT OF INTEREST POLICY 
The Executive Committee will track any COI by its members and site PI's. 
 
 
10.2 ADDITIONAL CONSIDERATIONS 
n/a 
 
 
10.3 ABBREVIATIONS 
AE 
Adverse Event 
ANCOVA Analysis of Covariance 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
DCC 
Data Coordinating Center 
DHHS 
Department of Health and Human Services 
DSMB 
Data Safety Monitoring Board 
DRE 
Disease-Related Event 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
FFR 
Federal Financial Report 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
GWAS 
Genome-Wide Association Studies 
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
Investigator’s Brochure 

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ICH 
International Conference on Harmonisation 
ICMJE 
International Committee of Medical Journal Editors 
IDE 
Investigational Device Exemption 
IND 
Investigational New Drug Application 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
ITT 
Intention-To-Treat 
LSMEANS Least-squares Means 
MedDRA Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MSDS 
Material Safety Data Sheet 
NCT 
National Clinical Trial 
NIH 
National Institutes of Health 
NIH IC 
NIH Institute or Center 
OHRP 
Office for Human Research Protections 
PI 
Principal Investigator 
QA 
Quality Assurance 
QC 
Quality Control 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
UP 
Unanticipated Problem 
US 
United States 
 
 
10.4 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
1/13/25 
 N/A 
  
2.0 
2/6/25 
• 
Added missing physical exam, 
vital signs, medical history and 
medication review to study visit.  
• 
Updated eligibility to exclude 
those that are currently 
pregnant.  
 IRB Compliance Reviewer 
requests 

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• 
Clarified amount of blood drawn 
• 
Clarified that there is no genetic 
testing in this study. 
• 
Clarified when subjects would be 
considered “Lost to Follow Up” 
• 
Added details to adverse events 
and serious adverse events 
section 
• 
Added details to consent 
procedures and documentation.  
• 
Clarified that data is coded and 
de-identified. 
• 
Added personnel and 
information regarding key roles 
and study governance. 
• 
Added additional information 
about clinical monitoring. 
• 
Clarified quality assurance and 
control.  
• 
Updated Data handling and 
record keeping 
• 
Added references 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  

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