Regress-HFpEF: Regression of Fibrosis & Reversal of Diastolic Dysfunction in HFpEF Patients Treated With Allogeneic CDCs
Phase: PHASE2
Conditions: Congestive Heart Failure, Heart Failure, Diastolic
Sponsor: Cedars-Sinai Medical Center

Regression of Fibrosis & Reversal of Diastolic 
Dysfunction 
in HFpEF Patients 
Treated 
With 
Allogeneic CDCs (RegressHFpEF) 
NCT02941705
Rev. October 12, 2020 

IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
Confidential 
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October 12, 2020 
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Item 6: 
Clinical Protocol: Revision #3   October 12, 2020 
 
Study Title: 
Regress-HFpEF:  Regression of fibrosis & reversal of 
diastolic dysfunction in HFpEF patients treated with 
allogeneic CDCs 
A Phase 2 Study of the safety and feasibility of 
intracoronary delivery of allogeneic human cardiosphere- 
derived stem cells (CDCs) in patients with heart failure and 
a preserved ejection fraction (HFpEF). 
 
Study Phase: 
Phase 2 
 
Product Name: 
CAP-1002, with allogeneic human cardiosphere-derived 
cells as the active ingredient 
 
Indication: 
Heart failure with a preserved ejection fraction 
 
Investigators: 
Michael R. Zile, MD, Sheldon Litwin, MD, Valerian 
Fernandes, MD, Eduardo Marbán, MD, PhD 
 
Sponsor: 
Eduardo Marbán, MD, PhD - Cedars-Sinai Heart Institute 
 
Sponsor Contact: 
Cedars-Sinai Heart Institute 
1090 Davis Building 
8700 Beverly Blvd. 
Los Angeles, CA 90048 
 
 
Date Original Protocol:  January 15, 2016 
Amendment #1:  September 6, 2017 
Amendment #2: August 3, 2020 
Amendment #3: October 12, 2020 
 
 
Confidentiality Statement 
This document is confidential and proprietary to Cedars-Sinai Medical Center and their affiliates. Acceptance of this 
document constitutes agreement by the recipient that no unpublished information contained herein will be reproduced, 
published, or otherwise disseminated or disclosed without prior written approval of Cedars-Sinai Medical Center and all of 
their affiliates, except that this document may be disclosed in any medium to appropriate clinical investigators, Institutional 
Review Boards, and others directly involved in the clinical investigation that is the subject of this information under the 
condition that they keep the information strictly confidential. 
 

IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
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TABLE OF CONTENTS 
 
Study Synopsis 
 
 
 
 
 
 
 
 
 
     6-11 
Abbreviations 
 
 
 
 
 
 
 
 
 
   12-14 
1.1 Rationale for Study and Patient Population: ............................................................ 15 
1.2. Prior Human Experience with Cardiosphere-Derived Cells: ................................... 16 
2. STUDY OBJECTIVES ............................................................................................... 17 
2.1. Primary Objective ................................................................................................... 17 
2.2. Secondary Objective .............................................................................................. 17 
3. STUDY ENDPOINTS ................................................................................................ 17 
3.1 Primary Endpoints ............................................................................................. 17 
3.1.1 Primary Safety Endpoints .......................................................................... 17 
3.1.2 Secondary Safety endpoints (Short and Long Term): ................................ 18 
3.2 Secondary Endpoints ........................................................................................ 18 
3.2.1. Efficacy Endpoints (Exploratory): 6- and 12-month follow-up periods*: .... 18 
4. INVESTIGATIONAL PLAN ........................................................................................ 19 
4.1 Overall Study Design and Plan ......................................................................... 19 
4.2 Study Duration and Dates ................................................................................. 25 
5. STUDY POPULATION SELECTION ......................................................................... 25 
5.1 Study Population ............................................................................................... 25 
5.2 Inclusion Criteria ............................................................................................... 26 
5.3 Exclusion Criteria .............................................................................................. 26 
6. STUDY TREATMENT(S) .......................................................................................... 28 
6.1 Description of Treatment(s) .............................................................................. 28 
6.1.1 Study Drug ................................................................................................. 28 
6.2 Treatment Administered .................................................................................... 28 
6.3 Selection and Timing of Dose ........................................................................... 29 
6.4 Method of Assigning Patients to Treatment Groups .......................................... 29 
6.5 Concomitant Therapy ........................................................................................ 29 
6.6 Restrictions ....................................................................................................... 30 
6.6.1 Prior Therapy ............................................................................................. 30 
6.6.2 Fluid and Food Intake ................................................................................ 30 
6.6.3 Patient Activity Restriction ......................................................................... 30 

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6.7 Treatment Compliance ...................................................................................... 30 
6.8 Packaging and Labeling .................................................................................... 30 
6.9 Storage and Accountability ............................................................................... 30 
6.10 Investigational Product Retention at Study Site .............................................. 31 
7. STUDY PROCEDURES ............................................................................................ 31 
7.1. Informed Consent ............................................................................................ 31 
7.2. Medical History ................................................................................................ 31 
7.3. Physical Examination ....................................................................................... 32 
7.4. Vital Signs ........................................................................................................ 32 
7.4.1. Laboratory Parameters ............................................................................. 32 
7.5 12-Lead ECG .................................................................................................... 33 
7.6 Echocardiography ............................................................................................. 33 
7.7 Holter Monitor ................................................................................................... 33 
7.8 Six Minute Walk Test ........................................................................................ 33 
7.9 Magnetic Resonance Imaging Protocol ............................................................ 33 
7.10 Image Analysis ............................................................................................... 33 
7.11 Cardiac CT ...................................................................................................... 33 
7.12 Clinical Functional Capacity and Quality of Life Measures ............................. 34 
7.13 Adverse Events ............................................................................................... 34 
7.13.1 Timing ...................................................................................................... 35 
7.13.2 Severity .................................................................................................... 35 
7.13.3 Relationship ............................................................................................. 35 
7.13.4 Expectedness .......................................................................................... 36 
7.13.5 Clinical Significance ................................................................................. 37 
7.13.6 Clinical Laboratory Adverse Events ......................................................... 37 
7.13.7 Serious Adverse Events .......................................................................... 38 
7.13.7.1 Definition ........................................................................................... 38 
7.13.7.2 Reporting Serious Adverse Events.................................................... 38 
7.13.7.3 Sponsor Monitoring of Adverse Events .............................................41 
7.13.7.4 DSMB Monitoring of Adverse Events ................................................ 42 
7.13.7.5 Data Safety Monitoring Board: Further Specifics ................................ 43 
7.13.8 Post-Study Adverse Events and Serious Adverse Events ....................... 43 

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Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
7.13.9 Treatment-Emergent Adverse Events ...................................................... 44 
7.14 Concomitant Medication Assessments ........................................................... 44 
7.15 Removal of Patients from the Trial or Study Drug ........................................... 44 
7.16 Other Study Procedures .................................................................................. 44 
7.17 Appropriateness of Measurements ................................................................. 44 
8. STUDY ACTIVITIES .................................................................................................. 45 
8.1 Pre-Treatment Screening Phase (Days -28 to -1) ............................................. 45 
8.2 Hemodynamic Screening ................................................................................. 46 
8.2.1 Intracoronary Infusion Procedure (Day 0) .................................................. 46 
8.2.2 
2 Week Visit (Day 14 +/- 4 days) Procedures ......................................... 47 
8.2.3 
3 Month Visit (Day 90 +/- 14 days) Procedures ...................................... 48 
8.2.4 
6 Month Visit (Day 180 +/- 14 days) Procedures..................................... 48 
8.2.5 
12 Month Visit (Day 360 +/- 30 days) Procedures .................................. 48 
8.3 Payments to Patients ........................................................................................ 49 
8.4 Early Termination Procedures ........................................................................... 49 
9. QUALITY CONTROL AND ASSURANCE ................................................................. 50 
10. PLANNED STATISTICAL METHODS ..................................................................... 51 
10.1 General Considerations .................................................................................. 51 
10.2 Analysis Populations ....................................................................................... 51 
10.3 Demographics and Baseline Characteristics ................................................... 52 
10.4 Interim Analysis. .............................................................................................. 52 
11. ADMINISTRATIVE CONSIDERATIONS ................................................................. 50 
11.1 Investigators and Study Administrative Structure ............................................ 52 
11.2 Institutional Review Board (IRB) Approval ...................................................... 52 
11.3 Ethical Conduct of the Study ........................................................................... 53 
11.4 Patient Information and Consent ..................................................................... 53 
11.5 Patient Confidentiality ..................................................................................... 54 
11.6 Study Monitoring ............................................................................................. 54 
11.7 CRFs and Study Records ............................................................................... 55 
11.8 Protocol Violations/Deviations ......................................................................... 55 
11.9 Access to Source Documentation ................................................................... 55 
11.10 Data Generation and Analysis ...................................................................... 55 

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11.11 Retention of Data .......................................................................................... 56 
11.12 Financial Disclosure ...................................................................................... 56 
LIST OF APPENDICES ................................................................................................ 57 
Appendix 1: SCHEDULE OF STUDY ACTIVITIES/ASSESSMENTS ............................ 58 
Appendix 2: STUDY RECRUITMENT TIMELINE .......................................................... 59 
Appendix 3: PROHIBITED CONCOMITANT MEDICATIONS ....................................... 60 
Appendix 4: INFORMED CONSENT TEMPLATE ......................................................... 64 
REFERENCES .............................................................................................................. 65 

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STUDY SYNOPSIS 
Sponsor: Eduardo Marbán, MD, PhD - Cedars-Sinai Heart Institute Investigators: 
Michael R Zile, MD, Sheldon Litwin, MD, Valerian 
Fernandes, MD, Eduardo Marbán, MD, PhD 
 
 
Name of Study Therapy: 
Allogeneic Cardiosphere-Derived Cells - CAP-1002 
 
Title of Study: 
 
Regress-HFpEF:  Regression of fibrosis & reversal of diastolic dysfunction  in 
HFpEF patients treated with allogeneic CDCs 
 
Study Phase: 2 Objectives: 
Primary: To determine the safety profile of CAP-1002 administered by 
intracoronary infusion in patients with Heart Failure and a Preserved Ejection 
Fraction (HFpEF). 
 
Secondary: To assess exploratory efficacy endpoints to determine whether 
treatment of HFpEF patients with intracoronary allogeneic CDCs affects clinical 
functional status (QOL scores), exercise tolerance (6 Minute Walk Test - 6MWT), 
exercise hemodynamics (supine exercise ergometry during right heart 
catheterization), myocardial interstitial fibrosis (MRI with native T1 mapping and 
calculation of extracellular volume [ECV] after gadolinium administration), 
macroscopic fibrosis by delayed gadolinium enhancement (DGE), and diastolic 
function (catheterization, echocardiography, BNP). 
 
Study Rationale: 
HFpEF is a distinct clinical heart failure syndrome and represents a critical unmet 
need in cardiovascular medicine. 1-4 HFpEF patients have a marked increase in 
morbidity and mortality and a profound clinical disability. 5, 6-13 However, to date, no 
management strategies have been definitively demonstrated to decrease morbidity 
and mortality or decrease the clinical disability suffered by HFpEF patients. 14-20 We 
postulated that one pivotal reason that previous randomized clinical studies have 
failed to show efficacy in HFpEF trials centers around the incomplete understanding 
of the pathophysiologic mechanisms underlying the development of HFpEF. 
Studies in patients with HFpEF and in relevant animal models of HFpEF have 
demonstrated that one critical mechanism contributing to HFpEF involves changes 
in the cardiac interstitium and extracellular matrix (ECM) fibrillar collagen 
homeostasis. 21,22 

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Our pre-clinical studies demonstrated that a highly novel application of cell therapy 
(Allogeneic Cardiosphere-Derived Cells - CAP-1002) to a rodent model of HFpEF 
results in regression of ECM fibrosis and reversal of LV diastolic dysfunction 57. 
Thus, use of CDCs in patients with HFpEF has the potential to significantly reduce 
fibrosis and improve diastolic function. 
 
Study Design: 
 
Patients with HFpEF meeting all inclusion and no exclusion criteria will be enrolled. 
A randomized, double blind, placebo-controlled (RCT) Phase 2 feasibility study will 
be conducted. This Phase 2 RCT will study a reasonably homogeneous HFpEF 
patient population. The goal is to recruit an enriched sample of patients with 
structural/functional abnormalities like those in the pre- clinical rat model, with a 
limited number/extent of co-morbid conditions. A randomized, double blind, 
placebo-controlled design in 40 patients with 1:1 randomization (20 placebo, 20 
CDC treated) will be performed. Patients will be assessed at screening, post-
infusion, 2 weeks, 3, 6, and 12 months after treatment. The effects of one-time 
administration of CDCs in patients with HFpEF will be examined. 
 
Patient Population: 
Three (Zile, Litwin, Fernandes) of the 4 study investigators have dual appointments 
at the RHJ Department of Veterans Administration Medical Center (VAMC) and 
Medical University of South Carolina Hospital Authority (MUSC). These individuals 
will be the ones responsible for clinical trial execution, including patient enrollment. 
Patients referred from either center are screened at MUSC, where all tests, 
procedures and study visits are performed and which will have sole responsibility 
for the conduct of the trial. Screening for enrollment is from three primary sources: 
patients hospitalized for HF, patients in primary and specialty care clinics with HF 
as a listed problem, and patients undergoing echocardiography with a request 
listing HF as a problem or a result identifying evidence of increased LV filling 
pressures. Over the last 6 months, these screening methods have yielded a list of 
337 patients that would fulfill the inclusion and exclusion criteria for Regress-HFpEF 
listed below. Our previous studies indicate that we have been successful in 
recruiting 54–69 % of eligible subjects into RCTs and investigator initiated studies. 
Therefore, recruitment expectations are justifiable. 
 
Recruitment time-line: 2.0 patients / month, 40 patients by month 20 
(approximately 20 males and 20 females from VAMC or MUSC), 6 month endpoints 
at month 26, 12 month endpoints at month 32, complete analysis finished by month 
36. (See Appendix 2). 
 
Main Criteria for Inclusion/Enrollment: 
 

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Inclusion Criteria: 
• ≥ 18 years old, male or female 
• LVEF ≥ 50% 
• Symptoms and physical findings of chronic heart failure (NYHA class II- ambulatory 
IV) 
• Treatment with a stable, maximally tolerated dose of diuretic(s) for a minimum of 30 
days prior to randomization. 
• Left atrial (LA) enlargement [defined by at least one of the following: LA width 
(diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm or LA area ≥ 20 cm2 or LA volume ≥ 55 
mL or LA volume index ≥ 29 mL/m2] or LV concentric remodeling (LV posterior or 
septal wall thickness ≥ 1.2 cm) using echo or MRI  
• BNP > 125 pg/ml for patients in NSR or > 150 pg/ml for patients in AF or resting 
PCWP > 15 mmHg, or exercise PCWP > 18 mmHg 
• Ability to provide informed consent and follow-up with protocol procedures. 
 
Exclusion Criteria: 
• Any confirmed prior echocardiographic measurement of LVEF < 40 % 
• Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery, 
or percutaneous coronary intervention (PCI) within the 3 months prior to 
randomization or previous CABG or Non-revascularized, hemodynamically 
significant CAD (FFR < 0.75) 
• Current acute decompensated HF 
• Alternative diagnoses that in the opinion of the investigator could account for the 
patient’s HF symptoms such as severe pulmonary disease (i.e., requiring home 
oxygen, chronic nebulizer therapy, chronic oral steroid therapy); hemoglobin (Hgb) 
< 10 g/dl; body mass index (BMI) > 45 kg/m2 
• Use of investigational drugs or treatments at the time of enrollment 
• Systolic blood pressure > 150 mmHg unless receiving ≥ 3 antihypertensive drugs 
• History of any dilated cardiomyopathy; right sided HF in the absence of left-sided 
structural 
heart 
disease; 
pericardial 
constriction, 
genetic 
hypertrophic 
cardiomyopathy, or infiltrative cardiomyopathy; clinically significant congenital heart 
disease; hemodynamically significant valvular heart disease 
• Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within 3 
months 
• Uncontrolled dysrhythmia; symptomatic or sustained ventricular tachycardia or atrial 
fibrillation or flutter with a resting ventricular rate > 110 beats per minute  
• Prior major organ transplant or intent to transplant (i.e., on transplant list) 
• Hepatic disease as determined by any one of the following: SGOT (AST) or SGPT 
(ALT) values exceeding 3x the upper limit of normal (ULN), bilirubin > 1.5 mg/dl; 
history of chronic viral hepatitis 
• Chronic Kidney Disease with eGFR < 30 mL/min/1.73 m2; serum potassium > 5.5 
mmol/L (mEq/L) 
• History or presence of any other disease with a life expectancy of < 3 years 
• Non-compliance to medical regimens 
• Drug or alcohol abuse within the last 12 months 
• Devices that are MRI incompatible 

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• History of malignancy within the past 5 years 
• Pregnant or nursing (lactating) women confirmed by a positive human chorionic 
gonadotropin (hCG); women of child-bearing potential (physiologically capable 
of becoming pregnant), unless using highly effective contraception methods 
during study 
• Diagnosis of active myocarditis 
• Known hypersensitivity to contrast agents 
• Known hypersensitivity to dimethyl sulfoxide (DMSO) 
• Known hypersensitivity to bovine products 
• History of heparin induced thrombocytopenia (HIT) 
• Active infection not responsive to treatment 
• Active allergic reactions or connective tissue diseases. 
• History of cardiac tumor or cardiac tumor demonstrated on screening 
• History of previous stem cell therapy 
• Human Immunodeficiency Virus (HIV) infection 
OUTCOME MEASURES 
 
Primary Safety endpoints: 
The primary endpoint is the proportion of subjects experiencing any of the 
following safety-related events during or post intracoronary delivery during the 
six and twelve month follow-up period: 
• TIMI myocardial perfusion grade: New TIMI flow 0–2 or TIMI myocardial 
perfusion grade (TMPG) 0–2, noted immediately following intracoronary infusion 
of CAP-1002 and persisting > 3 min after cell infusion, despite intracoronary 
vasodilator administration. 
• Acute myocarditis within one month of intracoronary infusion, possibly 
attributable to CAP-1002, diagnosed with consideration of clinical context, with 
or without a clinically indicated endomyocardial biopsy. In order to be considered 
related to CAP-1002, humoral or cellular immune reaction specific to CAP-1002 
must also be documented. 
• Ventricular tachycardia or ventricular fibrillation (defined as occurring with ECG 
documentation of these arrhythmias during ambulatory ECG monitoring in an 
outpatient setting, or during routine ECG monitoring while hospitalized) resulting 
in death, or requiring medical intervention, within 72 hours of intracoronary 
infusion. 
• Sudden unexpected death within 72 hours of intracoronary infusion defined as 
occurring within 1 hour of symptom onset, or unwitnessed death in a person 
previously observed to be well within the preceding 24 hours without an identified 
cause. 
• Major adverse cardiac events (MACE) within 72 hours of intracoronary infusion, 
including death, non-fatal myocardial infarction and re-hospitalization for 

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cardiovascular event (including heart failure hospitalizations). Evidence of 
myocardial injury will be assessed by a rule out MI cardiac enzyme protocol 
performed following administration of CAP-1002 or placebo. Troponin I and CK- MB 
will be obtained in a serial fashion over 24 hours after CAP-1002 infusion. 
 
Secondary Safety endpoints (Short and Long Term): 
• Major adverse cardiac events (MACE), including death, non-fatal myocardial 
infarction, hospitalization for cardiovascular event (including heart failure 
hospitalizations), emergency room treatment for heart failure (including outpatient 
infusion). 
• Any hospitalization due to a cardiovascular cause or related to CAP-1002. 
• Any inter-current cardiovascular illness or one related to CAP-1002. Evidence of 
myocardial injury will be assessed by a rule out MI cardiac enzyme protocol, 
troponin I and CKMB levels. 
• Development of increased DSA levels specific to the CAP-1002 CDC donor at 
immunologically significant titers. 
 
 
Efficacy Endpoints (Exploratory): 6- and 12-month follow-up periods*: 
• Absolute and relative change in myocardial structure and function: measured by 
echocardiogram, MRI: 
• LV volume, mass, EF, regional wall motion. Based on rodent data, none of these 
parameters are expected to change either as a function of time or treatment. 
• Regression of myocardial fibrosis ECV by MRI T1 mapping. 
• Improvement of diastolic dysfunction by echo parameters and reduction in LV 
filling pressures by catheterization and exercise hemodynamics. 
• Absolute and relative reduction in BNP. 
• Absolute and relative increase of 6MWT Distance 
• Absolute and relative improvement in Quality of Life (QOL) questionnaire 
MLWHF. 
• Absolute and relative reduction in pro-inflammatory and pro-fibrotic signaling 
measured by plasma biomarkers and plasma proteomics. 
* Cath and MRI will only be done at the 6-month time point. 
 
• Transthoracic Echocardiogram: 
 
 Rationale: evaluate indices of LV systolic and diastolic function and LV and left 
atrial structure estimates to characterize any improvement or stability over time with 
the use of CDCs 
 Indices for safety: 
EF, LVEDV, regional wall motion 
 Indices for efficacy: 
E/E’, LA Volume, RV systolic pressure estimates, LV mass 
 
 
• Cardiac MR (with and without contrast):  Unless known contra-indications 

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 Rationale: evaluate myocardial interstitial fibrosis 
 Indices: 
MRI with native T1 mapping and calculation of extracellular volume [ECV] 
Macroscopic fibrosis by delayed gadolinium enhancement (DGE) 
 
• Right Heart Catheterization: 
 
 Rationale: assess LV diastolic function at rest and during supine bicycle 
ergometry. 
 
 Indices: PCWP, PA systolic and diastolic pressure, cardiac output 
 
• BNP: 
 
 Rationale: Reflects changes in LV filling pressure using non-invasive method 
 
• 6MWT: 
 
 Rationale: Assess exercise capacity using noninvasive method 
 
• Quality of Life Questionnaire (QOL): 
 
 Rationale: to obtain baseline and follow-up evaluation of QOL spanning key 
domains pertinent to HFpEF 
 
 Tool: Minnesota Living with Heart Failure (MLWHF) 
 
Test Product, Dose, and Mode of Administration: 
Non-occlusive, sequential, three-vessel intracoronary delivery of 25 million CDCs 
(or placebo) in each of the three coronary arteries, as used safely to date in 14 
subjects in the DYNAMIC trial. This method achieves broad myocardial coverage 
and is atraumatic to vessel walls, as a flexible guiding catheter is used to deliver the 
cells. Capricor has extensive experience with manufacturing of CAP-1002 and 
identical-appearing 
placebo 
(both 
provided 
in 
amber-colored 
syringes). 
Transplant-quality donor hearts that could not be used clinically are used as the 
starting material for CAP-1002, in a manufacturing process described previously. 
Using SAS or comparable software, the company will provide the master 
randomization list of a 1:1 (CAP-1002 to placebo) randomization using permuted 
blocks with random block sizes of 2 or 4 without stratification. In addition, the 
company, through its third-party drug depot, will ship investigational product to the 
MUSC research pharmacy on a just in time, per patient basis before each 
scheduled infusion. 
 
Duration of Treatment: 
All patients will be followed until they have reached 12 months follow-up. 
 
 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
 
 
μl 
Microliter 
AE 
Adverse Event 
ALB 
Albumin 
ALK-P 
Alkaline phosphatase 
ALT 
 Alanine aminotransferase (same as SGPT) 
AST 
Aspartate aminotransferase (same as SGOT) 
ATM 
Atmospheres 
β-HCG 
 Beta Human Chorionic Gonadotropin 
BP 
Blood Pressure 
BNP 
Brain natriuretic peptide 
BUN 
Blood urea nitrogen 
C 
Celsius 
CCU 
Critical (or Coronary) Care Unit 
CDC 
Cardiosphere Derived Cell 
ceMRI 
Contrast-Enhanced Magnetic Resonance Imaging 
CFR 
Code of Federal Regulations 
CHF 
Congestive Heart Failure 
CI 
Cardiac Index 
CK-MB 
 Creatine phosphokinase MB isoenzyme 
CMV 
Cytomegalovirus 
CO 
Cardiac output 
CRF 
Case Report Form 
CRP 
C-reactive protein 
CS 
Clinically Significant 
CT 
Computerized Tomography 
DLCO 
Diffusing Capacity for Carbon Monoxide 
DMSO 
Dimethyl Sulfoxide 
DSMB 
Data Safety Monitoring Board 
DCE-CMR 
Dynamic Contrast Enhanced Cardiac Magnetic Resonance 
ECG 
 Electrocardiogram 
EDV 
End-Diastolic Volume 
ESR 
Erythrocyte Sedimentation Rate 
ESRP 
Expedited Safety Report 
ESV 
End-Systolic Volume 
F 
Fahrenheit 
FDA 
Food and Drug Administration 
FFR 
Fractional Flow Reserve 
GCP 
Good Clinical Practice 

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GFR 
Glomerular Filtration Rate 
HR 
Heart Rate 
HBsAg 
Hepatitis B Surface Antigen 
Hct 
Hematocrit 
HCV 
Hepatitis C Virus 
HF 
Heart Failure 
Hb 
Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
HLA 
Human Leukocyte Antigen 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IgG 
Immunoglobulin G 
IgM 
Immunoglobulin M 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
K 
Potassium 
kg 
Kilogram 
LDH 
Lactate dehydrogenase 
LV 
Left Ventricle 
LVEF 
Left Ventricular Ejection Fraction 
M 
Million 
MACE 
Major Adverse Cardiac Event 
mcg 
Microgram 
MCHC 
Mean corpuscular hemoglobin concentration 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MI 
Myocardial Infarction 
min 
Minute 
mL 
Milliliter 
mm 
Millimeters 
mmol 
Millimole 
Na 
Sodium 
NCS 
 Not clinically significant 
NYHA 
New York Heart Association 
p 
Probability 
PA 
Pulmonary Artery 
PBS 
Phosphate buffered saline 
PCWP 
Pulmonary capillary wedge pressure 
mPAP 
Mean pulmonary artery pressure 
PRA 
 Panel Reactive Antibodies 
PSP 
Patient Specific Probability 
PT 
Prothrombin time 
PTT 
 Activated partial thromboplastin time 
r 
Correlation coefficient 
RBC 
Red blood cell 

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SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SE 
Standard Error 
SVT 
Supraventricular Tachycardia 
6MWT 
Six Minute Walk Test 
SGOT 
Serum Glutamic Oxaloacetic Transaminase 
SGPT 
Serum Glutamic Pyruvic Transaminase 
SPRO 
Serious Procedure Related Outcome 
TTE 
Transthoracic Echocardiography 
UA 
Urinalysis 
VGEF 
Vascular Endothelial Growth Factor 
VT 
Ventricular Tachycardia 
WBC 
White Blood Cell 

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1.1 Rationale for Study and Patient Population: 
HFpEF is a distinct clinical heart failure syndrome and represents a critical unmet need 
in cardiovascular medicine. 1-4 HFpEF patients have a marked increase in morbidity and 
mortality and a profound clinical disability. 5, 6-13 However, to date, no management 
strategies have been definitively demonstrated to decrease morbidity and mortality or 
decrease the clinical disability suffered by HFpEF patients. 14-20 We have postulated that 
one pivotal reason that previous randomized clinical studies have failed to show efficacy 
in HFpEF trials centers around the incomplete understanding of the pathophysiologic 
mechanisms underlying the development of HFpEF. Studies in patients with HFpEF and 
in relevant animal models of HFpEF have demonstrated that one critical mechanism 
contributing to HFpEF are changes in the cardiac interstitium and extracellular matrix 
(ECM) fibrillar collagen homeostasis. 21, 22 Preliminary studies presented demonstrate that 
a highly novel application of stem cell therapy to a rodent model of HFpEF results in 
regression of ECM fibrosis and reversal of LV diastolic dysfunction57. These preliminary 
studies form the foundation for this proposed application in HFpEF. 
Health care utilization and costs in HFpEF: HFpEF patients consume an enormous 
percentage of all health care utilization costs. Previous studies and preliminary data 
demonstrate that HFpEF health care utilization costs are driven in part by very high 
hospitalization and repeat hospitalization rates. 1,11,12 Hospitalization for HFpEF exceeds 
15%/year in selected patients in RCTs, 25 %/year in unselected epidemiologic studies, 
and 25% / year in our preliminary VA data. We reviewed 800 consecutive HF 
hospitalizations at the Charleston VA site in patients with an echocardiogram at the time 
of hospitalization to determine presence of HFpEF, frequency and costs. There were 412 
HFpEF admissions, mean age 72 ± 10 (SD) years, length of stay 5 ± 2 (SD) days, total 
inpatient cost $13,322 ± 5,5051 (SD) including bed day, laboratory, radiology, pharmacy 
and other costs and a frequency of 1.5 ± 0.5 (SD) HF hospitalizations/patient/2 years 
observation. Once hospitalized for HFpEF, the incidence of re-hospitalization is ~50% in 
6 months and patients require frequent outpatient visits by primary and specialty care, 
frequent tele-health care visits, diagnostic testing and medications. In addition, there is a 
high risk of death with a 5-year mortality rate ~50%. The annual VA cost / HFpEF patient 
is ~$15,000; based on one five-day hospitalization ($12,500), four outpatient visits ($500), 
four medications ($100/month), annual echo, blood tests, X-rays ($1,500). Thus, HFpEF 
represents an important target for cost and health care utilization reduction. 
Quality of life (QOL) in HFpEF: HFpEF patients have a low QOL with debilitating 
symptoms. This cardiac disability has been objectively assessed by a 6-minute hall walk 
(6-MHW), standard exercise treadmill, and cardiopulmonary exercise testing. 1,11,12 Our 
studies have demonstrated that serial 6-MHW performed successfully in > 92% of our 
HFpEF patients has very high reproducibility and is significantly reduced (220 m vs 550 
m in age- and sex-matched controls). 24 Cardiac symptom status can be assessed by 
QOL tools validated in HFpEF, including New York Heart Association Class (NYHC), 
Quality of Life in Severe Heart Failure Questionnaire (QLSHFQ), the Chronic Heart 
Failure Questionnaire (CHQ), the Left Ventricular Dysfunction Questionnaire (LVD), and 
the Minnesota Living with Heart Failure Questionnaire (MLHFQ). MLHFQ has been 
successfully applied in HFpEF RCTs and correlates well with our preliminary studies. 8 In 
addition, preliminary studies indicate that overall VA-specific QOL tool (VA SF-12) is 
abnormal in HFpEF. 

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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
October 12, 2020 
 
 
 
 
 
 
1.2. Prior Human Experience with Cardiosphere-Derived Cells: 
CDCs, CAP-1002 safe in patients with HF: CDCs, the active ingredient in CAP-1002, are 
known to secrete numerous bioactive elements after myocardial delivery, which act to 
attenuate fibrosis and reduce inflammation. 28-33 One completed and three ongoing clinical 
trials indicate that intracoronary delivery of CDCs appears to be safe: 
1) CADUCEUS (CArdiosphere-Derived aUtologous Stem CElls to reverse ventricUlar 
dySfunction), IND #13930, NCT00893360; first-in-human trial demonstrated preliminary 
safety and efficacy of autologous CDCs in reducing fibrosis post-myocardial infarction 
(MI) in patients with pre-symptomatic HFREF. Once the indirect mechanism of CDC 
action became evident, 34,32 emphasis shifted to the allogeneic product (CAP-1002). 
2) ALLSTAR (ALLogeneic heart STem cells to Achieve myocardial Regeneration), IND 
#15118, NCT01458405; a randomized, double-blind, placebo-controlled Phase 1/2 study 
of the safety and efficacy of intracoronary delivery of CAP-1002 in subjects with an MI 
and pre-symptomatic ischemic HFREF. ALLSTAR did not reveal an increase in adverse 
events. In the completed 14-patient Phase 1 portion, a relatively small, non-clinically 
significant increase in cardiac enzymes of the scale common with any intracoronary 
intervention, the lack of high level immune response to donor cells, and the absence of 
any immune-related clinical sequelae support the safety of CAP-1002. 35 The randomized, 
double-blind multicenter Phase 2 portion of ALLSTAR is currently undergoing final 
analysis. A prespecified 6-month administrative interim analysis demonstrated a low 
probability (futility) of achieving a statistically-significant difference in the 12-month 
primary efficacy endpoint of percent change from baseline in infarct size as a percent of 
left ventricular mass as measured by cardiac magnetic resonance imaging (MRI). At 6 
months, a near-statistically significant (p=0.05) reduction of mean end-diastolic volume 
as well as a trend of reduction of mean end-systolic volume, were seen in the CAP-1002 
treatment group. There was no notable difference between treatment groups with respect 
to the change in ejection fraction. There were no safety signals in the CAP-1002 treatment 
cohort. 
3) DYNAMIC (Dilated cardiomYopathy iNtervention with Allogeneic MyocardIally- 
regenerative Cells), IND #15418, NCT02293603; Phase 1 study of the safety of CAP- 
1002 in HFREF patients. Phase 1a portion of DYNAMIC has completed enrollment, with 
14 open-label subjects that received CAP-1002. There have been no serious adverse 
events through completed 6-month follow-up.58 This study is particularly relevant as it 
used identical doses of CAP-1002 and follows the same nonocclusive sequential 
multivessel delivery strategy as this protocol. The randomized, double blind, placebo- 
controlled Phase 1b portion of DYNAMIC has not been initiated. 
4) HOPE-Duchenne (Halt cardiOmyopathy ProgrEssion in Duchenne), IND 16479, 
NCT02485938. Phase 2a study of CAP-1002 delivered as in the DYNAMIC trial (#3 
above) in boys and young men with Duchenne muscular dystrophy and associated 
cardiomyopathy. This multicenter randomized study is presently enrolling. All participants 
will be completing their final follow-up visit in September 2017 with final analysis planned 
in the fourth quarter of 2017. In a prespecified 6-month interim analysis, there was no 
significant difference in the incidence of treatment-emergent adverse events between the 

Confidential 
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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
October 12, 2020 
 
 
 
CAP-1002 treatment group and usual care control group. MRI revealed greater scar size 
reduction (-5.02% vs -0.23%, p=0.09) and increased inferior wall systolic thickening 
(p=0.02) in CAP-1002 subjects vs. controls. A post hoc responder analysis of mid-distal 
performance of the upper limb (PUL) score improved at week six by ≥ 10% in 42% of 
CAP-1002 patients compared to none of the usual-care participants (p=0.045). 
 
2. STUDY OBJECTIVES 
 
2.1. Primary Objective 
 
To determine the safety profile of CAP-1002 administered by intracoronary infusion 
in patients with Heart Failure and a Preserved Ejection Fraction (HFpEF). 
 
2.2. Secondary Objective 
 
To assess exploratory efficacy endpoints to determine whether treatment of HFpEF 
patients with intracoronary allogeneic CDCs affects clinical functional status (QOL 
scores), exercise tolerance (6MWT), exercise hemodynamics (supine exercise 
ergometry during right heart catheterization), myocardial interstitial fibrosis (MRI with 
native T1 mapping and calculation of extracellular volume [ECV] after gadolinium 
administration), macroscopic fibrosis by delayed gadolinium enhancement (DGE), 
and diastolic function (catheterization, echocardiography, BNP). 
 
3. STUDY ENDPOINTS 
 
3.1 Primary Endpoints: 
 
3.1.1 Primary Safety Endpoints 
The primary endpoint is the proportion of subjects experiencing any of the following 
safety-related events during or post intracoronary delivery during the six and twelve 
month follow-up period: 
• TIMI myocardial perfusion grade: New TIMI flow 0–2 or TIMI myocardial perfusion 
grade (TMPG) 0–2, noted immediately following intracoronary infusion of CAP- 
1002 and persisting > 3 min after cell infusion, despite intracoronary vasodilator 
administration. 
• Acute myocarditis within one month of intracoronary infusion, possibly attributable 
to CAP-1002, diagnosed with consideration of clinical context, with or without a 
clinically indicated endomyocardial biopsy. In order to be considered related to 
CAP-1002, humoral or cellular immune reaction specific to CAP-1002 must also 
be documented. 

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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
October 12, 2020 
 
 
 
• Ventricular tachycardia or ventricular fibrillation (defined as occurring with ECG 
documentation of these arrhythmias during ambulatory ECG monitoring in an 
outpatient setting, or during routine ECG monitoring while hospitalized) resulting 
in death, or requiring medical intervention, within 72 hours of intracoronary 
infusion. 
• Sudden unexpected death within 72 hours of intracoronary infusion defined as 
occurring within 1 hour of symptom onset, or unwitnessed death in a person 
previously observed to be well within the preceding 24 hours without an identified 
cause. 
• Major adverse cardiac events (MACE) within 72 hours of intracoronary infusion, 
including death, non-fatal myocardial infarction and re-hospitalization for 
cardiovascular event (including heart failure hospitalizations). Evidence of 
myocardial injury will be assessed by a rule out MI cardiac enzyme protocol 
performed following administration of CAP-1002 or placebo. Troponin I and CK- 
MB will be obtained after CAP-1002 infusion. 
 
 
3.1.2 Secondary Safety endpoints (Short and Long Term): 
• Major adverse cardiac events (MACE), including death, non-fatal myocardial 
infarction, hospitalization for cardiovascular event (including heart failure 
hospitalizations or emergency room treatment for heart failure). 
• Any hospitalization due to a cardiovascular cause or related to CAP-1002. 
• Any inter-current cardiovascular illness or one related to CAP-1002. Evidence of 
myocardial injury will be assessed by a rule out MI cardiac enzyme protocol, 
troponin I and CKMB levels. 
• Development of increased DSA levels specific to the CAP-1002 CDC donor at 
immunologically significant titers. 
 
 
3.2 Secondary Endpoints 
 
3.2.1. Efficacy Endpoints (Exploratory): 6- and 12-month follow-up periods*: 
• Absolute and relative change in myocardial structure and function: measured by 
echo, MRI: 
• LV volume, mass, EF, regional wall motion. Based on rodent data, none of 
these parameters are expected to change either as a function of time or 
treatment. 
• Regression of myocardial fibrosis ECV by MRI T1 mapping. 
• Improvement of diastolic dysfunction by echo parameters and reduction in LV filling 
pressures by catheterization and exercise hemodynamics. 
• Absolute and relative reduction in BNP. 
• Absolute and relative increase of 6MWT Distance. 
• Absolute and relative improvement in Quality of Life (QOL) questionnaire, MLWHF. 

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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
October 12, 2020 
 
 
 
• Absolute and relative reduction in pro-inflammatory and pro-fibrotic signaling 
measured by plasma biomarkers and plasma proteomics. 
* Cath and MRI will only be done at the 6-month time point. 
 
4. INVESTIGATIONAL PLAN 
4.1 Overall Study Design and Plan 
 
Hypothesis: Treatment of patients with symptomatic hypertensive heart disease-induced 
HFpEF with allogeneic CDCs will be safe and will improve clinical functional status, 
exercise tolerance/hemodynamics, myocardial interstitial structure, and diastolic function; 
the mechanisms underlying these improvements will be reflected in changes in plasma 
biomarkers that indicate a reduction in pro-inflammatory and pro-fibrotic signaling. 
Specific Aims: 
Perform a randomized, double blind, placebo-controlled Phase 2a feasibility study to 
determine whether treatment of HFpEF patients with intracoronary allogeneic CDCs 
affects clinical functional status (QOL scores), exercise tolerance (6MWT), exercise 
hemodynamics (supine exercise ergometry during right heart catheterization), myocardial 
interstitial fibrosis (MRI with native T1 mapping and calculation of extracellular volume 
[ECV] after gadolinium administration), macroscopic fibrosis by delayed gadolinium 
enhancement (DGE), and diastolic function (catheterization, echocardiography, BNP). 
Determine whether treatment with CDCs affects plasma biomarkers that indicate 
alterations in proinflammatory and profibrotic mechanisms and whether these biomarker 
changes correlate with alterations in clinical symptom status, myocardial structure and/or 
diastolic function. 
Use these feasibility and exploratory efficacy data study data to 1) confirm that the 
application of CDCs is safe in HFpEF patients and 2) optimize the design of a Phase 2b 
trial including determination of sample size power estimates and appropriate primary and 
secondary endpoints. 
Research Strategy / Clinical Trial Design: This Phase 2a RCT will study a reasonably 
homogeneous HFpEF patient population. The goal is to recruit an enriched sample of 
patients with structural/functional abnormalities like those in the DS rat model 57, with a 
limited number/extent of co-morbid conditions. A randomized, double blind, placebo- 
controlled design in 40 patients with 1:1 randomization (20 placebo, 20 CDC treated) will 
be performed. Patients will be assessed at baseline, post-infusion, pre-discharge, 24-48 
hours post discharge, 0.5, 3, 6, and 12 months after treatment. 
Here we are studying the effects of one-time administration of CDCs in patients with 
HFpEF. While CDCs benefits persist for at least several weeks in the DS rat model, it is 
possible that benefits in humans may wear off over time. Thus, one of the objectives here 
is obtain preliminary indications of the duration of therapeutic benefits over the year of 
follow-up. If benefits are evident initially but wane over time, future clinical studies may 
be designed to include multiple repeated doses. 

IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
Confidential 
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October 12, 2020 
 
 
 
Team: The clinical study will be conducted by Dr. Zile and colleagues in Charleston, SC. 
Dr Eduardo Marbán will collaborate on study design and analysis. Capricor Inc., a 
NASDAQ-traded biotechnology company (ticker symbol CAPR), has licensed all relevant 
intellectual property and is conducting the ongoing ALLSTAR, DYNAMIC, and HOPE- 
Duchenne trials. Capricor will collaborate by providing at-cost investigational product 
(CAP-1002 or placebo) produced under Good Manufacturing Practices (GMP) standards 
approved for Phase 2 clinical testing, as well as randomization services, and 
immunological assays performed through its contracted central immunology laboratory. 
Pre-Screen: Patients will be referred from either the RHJ Department of Veterans 
Administration Medical Center (VAMC) or the Medical University of South Carolina 
Hospital Authority (MUSC) and identified from three primary sources: patients 
hospitalized for HF, patients in primary and specialty care clinics with HF as a listed 
problem, and patients undergoing echocardiography with a request listing HF as a 
problem or a result identifying evidence of increased LV filling pressures. Over the last 6 
months, these screening methods have yielded a list of 337 patients that would fulfill the 
inclusion and exclusion criteria for Regress-HFpEF listed below. The referred Veterans, 
will be predominantly male, and MUSC will provide the necessary additional female 
patients to reflect the real-world demographic sex distribution of HFpEF. Our previous 
studies indicate that we have been successful in recruiting 54–69 % of eligible subjects 
into RCTs and investigator initiated studies. Therefore, recruitment expectations are 
justifiable. 
Consent and Screen: If a patient fulfills the inclusion criteria of clinical HF, preserved EF, 
increased BNP or increased PCWP, and increased LA size or concentric LVH and has 
none of the exclusion criteria (see details below), they will be consented and undergo CT 
coronary angiography (to define the coronary anatomy; CT scan will not be needed if 
patient has had a recent coronary arteriogram or previous CT scan within 1 year showing 
no significant CAD). If significant CAD is identified by CT and confirmed by subsequent 
coronary arteriography and FFR, subjects will be referred to their physician for 
consideration of a revascularization procedure. If such subjects undergo a 
revascularization procedure, they may be reconsidered and rescreened for the study, 
minus a repeat CT, after a minimum of 3 months post- revascularization. 
The originally approved protocol called for HLA typing and testing for donor-specific 
antibodies (DSAs), and using this information to choose a CAP-1002 master cell bank 
that lacks expression of the relevant antigen(s), if applicable. We now have clinical 
information from the randomized placebo-controlled ALLSTAR trial of 134 subjects 
treated with CAP-1002, some of whom were cross-matched and others (n=13) of whom 
had no possible cross-match and so were treated with cells from randomly selected CAP- 
1002 master cell banks. There was no difference in efficacy or safety between the cross- 
matched and non-cross-matched groups, with a tendency to larger therapeutic responses 
(i.e., greater attenuation of adverse remodeling after myocardial infarction) in the non- 
cross-matched subjects. Accordingly, we made a protocol modification to eliminate the 
cross-matching requirement for investigational product CAP-1002. We will still perform 
HLA typing and measure DSAs pre and post-treatment (for documenting de novo immune 
responses if any) but not cross-match cells. We will also eliminate ELISpot testing, as its 
value is theoretical and there has been no evidence of a clinically significant cell-mediated 
immune response in any of the N=95 subjects tested to date. 

IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
Confidential 
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October 12, 2020 
 
 
 
 
Endpoint measurement: Prior to randomization, the patient will undergo measurement of 
all exploratory efficacy endpoints as listed below: 
Echocardiography and MRI: Assess myocardial structure, function, fibrosis using 
previously published methods; 36, 37-41 interpretation in our imaging core lab by Dr. Litwin. 
Catheterization and bicycle ergometry: Assess hemodynamics at rest and during exercise 
using previously published methods; 10,42-46 interpretation in our hemodynamics core lab 
by Dr. Fernandes. If PCWP ≥ 20 mmHg at rest, bicycle ergometry will not be performed. 
Biomarkers: Blood will be drawn for the assessment of various candidate biomarkers 
indicative of inflammation (IL1, 6), fibrosis (Gal-3, sST-2, collagen pro- and telo-peptides), 
ECM homeostasis (MMPs, TIMPs, SPARC, other matricellular proteins/peptides, TGF- 
b), and t-tubule remodeling (BIN-1) from a peripheral vein. 47-50 
Quality of life: Six-minute hall walk, NYHA class, MLWHF questionnaire. 
Randomization: Non-occlusive, sequential, three-vessel intracoronary delivery of 25 
million CDCs (or placebo) in each of the three coronary arteries, as used safely to date in 
the DYNAMIC trial. This method achieves broad myocardial coverage and is atraumatic 
to vessel walls, as a flexible guiding catheter is used to deliver the cells. Capricor has 
extensive experience with manufacturing of CAP-1002 and identical-appearing placebo 
(both provided in syringes masked with amber film-covered barrels). Transplant-quality 
donor hearts that could not be used clinically are used as the starting material for CAP- 
1002, in a manufacturing process described previously.23 Using SAS or comparable 
software, the company will provide the master randomization list of a 1:1 (CAP-1002 to 
placebo) randomization using permuted blocks with random block sizes of 2 or 4 without 
stratification. In addition, the company, through its third-party drug depot, will ship 
investigational product to the MUSC research pharmacy on a just in time, per patient 
basis before each scheduled infusion. 
Follow-up: Safety measurements will be made immediately post infusion, pre-discharge, 
24-48 hours post-discharge at 2 weeks and at 3, 6, and 12 months after treatment 
(described below). Efficacy measurements and safety measurements will be made at 6 
and 12 months. 
Inclusion criteria: 
1. ≥ 18 years old, male or female 
2. LVEF ≥ 50% 
3. Symptoms and physical findings of chronic heart failure (NYHA class II- ambulatory 
IV) 
4. Treatment with a stable, maximally tolerated dose of diuretic(s) for a minimum of 30 
days prior to randomization. 
5. Left atrial (LA) enlargement defined by at least one of the following: LA width 
(diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm or LA area ≥ 20 cm2 or LA volume ≥ 55 mL 
or LA volume index ≥ 29 mL/m2 or LV concentric remodeling (LV posterior or septal 
wall thickness ≥ 1.2 cm) using echo or MRI. 
6. BNP > 125 pg/ml for patients in NSR or > 150 pg/ml for patients in AF or resting 
PCWP > 15 mmHg, or exercise PCWP > 18 mmHg 
7. Ability to provide informed consent and follow-up with protocol procedures. 

IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
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October 12, 2020 
 
 
 
Exclusion criteria-Specific to HFpEF 
1. Any confirmed prior echocardiographic measurement of LVEF < 40 % 
2. Acute coronary syndrome (including MI), cardiac surgery, other major CV surgery, or 
percutaneous coronary intervention (PCI) within the 3 months prior to randomization 
or previous CABG or Unrevascularized, hemodynamically significant CAD (FFR < 
0.75) 
3. Current acute decompensated HF 
4. Alternative diagnoses that in the opinion of the investigator could account for the 
patient’s HF symptoms (i.e., dyspnea, fatigue) such as severe pulmonary disease (i.e., 
requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy); 
hemoglobin (Hgb) < 10 g/dl; body mass index (BMI) > 45 kg/m2 
5. Use of investigational drugs or treatments at the time of enrollment 
6. Systolic blood pressure > 150 mmHg but < 180 mmHg unless receiving 3 or more 
antihypertensive drugs 
7. History of any dilated cardiomyopathy; right sided HF in the absence of left-sided 
structural 
heart 
disease; 
Pericardial 
constriction, 
genetic 
hypertrophic 
cardiomyopathy, or infiltrative cardiomyopathy; clinically significant congenital heart 
disease; hemodynamically significant valvular heart disease 
8. Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within the 3 
months 
9. Uncontrolled dysrhythmia; symptomatic or sustained ventricular tachycardia or atrial 
fibrillation or flutter with a resting ventricular rate > 110 beats per minute (bpm) 
10. Prior major organ transplant or intent to transplant (i.e., on transplant list) 
11. Hepatic disease as determined by any one of the following: SGOT (AST) or SGPT 
(ALT) values exceeding 3x the upper limit of normal (ULN), bilirubin > 1.5 mg/dl; 
history of chronic viral hepatitis 
12. Chronic Kidney Disease with eGFR < 30 mL/min/1.73 m2; serum potassium > 5.5 
mmol/L (mEq/L) 
13. History or presence of any other disease with a life expectancy of < 3 years 
14. Non-compliance to medical regimens 
15. Drug or alcohol abuse within the last 12 months 
16. History of malignancy within the past 5 years 
17. Pregnant or nursing (lactating) women confirmed by a positive human chorionic 
gonadotropin (hCG); women of child-bearing potential (physiologically capable of 
becoming pregnant), unless using highly effective contraception methods during study 
18. Devices that are MRI incompatible 
 
Exclusion criteria-Specific to CAP-1002 (not listed above) 
1. Diagnosis of active myocarditis 
2. Known hypersensitivity to contrast agents 
3. Known hypersensitivity to dimethyl sulfoxide (DMSO) 
4. Known hypersensitivity to bovine products 
5. History of heparin induced thrombocytopenia (HIT) 
6. Active infection not responsive to treatment 
7. Active allergic reactions or connective tissue diseases 
8. History of cardiac tumor or cardiac tumor demonstrated on screening 
9. History of previous stem cell therapy 

IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
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October 12, 2020 
 
 
 
10. Human Immunodeficiency Virus (HIV) infection 
 
Endpoints: The primary objective is to determine the safety of CAP-1002 administered by 
multi-vessel, non-occlusive intracoronary infusion in subjects with HFpEF. A secondary 
objective is to explore, in a non-hierarchical manner, efficacy end-points that will be of 
value intrinsically as indicators of bioactivity as well as in guiding future trials with CAP- 
1002. 
Safety endpoints: The primary endpoint is the proportion of subjects experiencing any of 
the following safety-related events during or post intracoronary delivery during the six and 
twelve month follow-up period: 
1. New TIMI flow 0–2 or TIMI myocardial perfusion grade (TMPG) 0–2, noted 
immediately following intracoronary infusion of CAP-1002 and persisting > 3 min after 
cell infusion, despite intracoronary vasodilator administration. 
2. Acute myocarditis within one month of intracoronary infusion, possibly attributable to 
CAP-1002, diagnosed with consideration of clinical context, with or without a clinically 
indicated endomyocardial biopsy. In order to be considered related to CAP-1002, 
humoral or cellular immune reaction specific to CAP-1002 must also be documented. 
3. Ventricular tachycardia or ventricular fibrillation (defined as occurring with ECG 
documentation of these arrhythmias during ambulatory ECG monitoring in an 
outpatient setting, or during routine ECG monitoring while hospitalized) resulting in 
death, or requiring medical intervention, within 72 hours of intracoronary infusion. 
4. Sudden unexpected death within 72 hours of intracoronary infusion defined as 
occurring within 1 hour of symptom onset, or unwitnessed death in a person previously 
observed to be well within the preceding 24 hours without an identified cause. 
5. Major adverse cardiac events (MACE) within 72 hours of intracoronary infusion, 
including 
death, 
non-fatal 
myocardial 
infarction 
and 
re-hospitalization 
for 
cardiovascular event (including heart failure hospitalizations). Evidence of myocardial 
injury will be assessed by a rule out MI cardiac enzyme protocol performed following 
administration of CAP-1002 or placebo. Troponin I and CK-MB will be obtained after 
CAP-1002 infusion. 
 
Secondary safety endpoints: 
1. Major adverse cardiac events (MACE), including death, non-fatal myocardial 
infarction, hospitalization for cardiovascular event (including heart failure 
hospitalizations and emergency room treatment for heart failure). 
2. Any hospitalization due to a cardiovascular cause or related to CAP-1002. 
3. Any inter-current cardiovascular illness or one related to CAP-1002. Evidence of 
myocardial injury will be assessed by a rule out MI cardiac enzyme protocol, troponin 
I and CKMB levels. 
4. Development of increased DSA levels specific to the CAP-1002 CDC donor at 
immunologically significant titers. 

Confidential 
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 October 12, 2020 
 
 
IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
Efficacy endpoints (exploratory): 6- and 12-month follow-up periods*: 
1. Absolute & relative change in myocardial structure & function: measured by echo, MRI: 
a) LV volume, mass, EF, regional wall motion. Based on rodent data, none of these 
parameters are expected to change either as a function of time or treatment. 
b) Regression of myocardial fibrosis ECV by MRI T1 mapping. 
c) Improvement of diastolic dysfunction by echo parameters and reduction in LV filling 
pressures by cath and exercise hemodynamics. 
2. Absolute and relative reduction in BNP. 
3. Absolute and relative increase of 6MWT distance. 
4. Absolute and relative improvement in Quality of Life (QOL) questionnaires VA SF-12, 
MLWHF. 
5. Reduction in pro-inflammatory and pro-fibrotic signaling. 
* Cath and MRI will only be done at the 6-month time point. 
Statistical analysis: An independent DSMB, with roles and responsibilities defined in a 
written charter, was appointed to oversee safety of the study. The DSMB will consist of 
three heart failure cardiologists, one with additional expertise in interventional cardiology, 
one with additional expertise in imaging, one with additional expertise in 
transplant/immunology, and a statistician. The DSMB may request additional interim 
analyses and develop other criteria for determining when to intervene in the enrollment 
or treatment of subjects in the study. Monitoring of all safety endpoints will be conducted. 
Individual cases reported to regulatory bodies will be reported to the DSMB Chair and will 
be reviewed by the DSMB. The DSMB will have access to reports evaluating group trends 
for CAP-1002 vs. Control as well as data from the literature for CAP-1002-treated 
subjects. In addition, any external concerns regarding CDC safety will be brought to the 
attention of the DSMB. 
The proportion of subjects experiencing an adverse event or a protocol-specific safety 
event (PSE) will be monitored at pre-planned intervals set by the DSMB. A futility chart 
will be created to allow for DSMB safety monitoring. The excess for CAP-treated subjects 
is of primary concern as Phase 2a data accrue. The boundaries are computed using 
StatXact v7 (CyTel, Cambridge MA); a one-sided 95% exact test is performed assuming 
binomially distributed outcomes. The chart will be applied to any binary outcome 
pertaining to safety. The chart will be computed over a broad range of possible PSE 
outcomes. No adjustment for Type I error will be made for repeated looks since the 
ultimate decision regarding safety represents a clinical decision involving all safety 
endpoints in the context of efficacy. Descriptive summaries will be provided for all primary 
and secondary endpoints for both safety and efficacy. A prospective statistical analysis 
plan (SAP) will be generated for DSMB review with their input. All analyses and reports 
will be developed per Good Clinical Practices. All analyses will be performed using SAS 
Version 9.2 or greater. 
Efficacy data will be presented as mean changes from screening at designated visits. 
These Phase 2a data will be used to calculate effect sizes for planning subsequent Phase 
2b studies. If there are sufficient follow-up data, longitudinal models (SAS PROC MIXED 
for continuous endpoints and SAS PROC GENMOD for binary endpoints) will be 
explored. A formal SAP will be developed in a collaboration between Dr. Zile, MUSC 
statistician Dulaney Wilson (in the Department of Public Health Sciences), CSMC and 
Capricor. Dr. Wilson, Professor, MUSC Department of 

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October 12, 2020 
 
 
IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
Public Health Sciences, and the PI/PD Dr. Zile have collaborated on development of 
SAPs for a number of published studies. 
 
4.2 Study Duration and Dates 
Recruitment time line: 2.0 patients / month, 40 patients by month 20 (approximately 20 
males and 20 females from the VAMC and MUSC), 6 month endpoints at month 26, 12 
month endpoints at month 32, complete analysis finished by month 36. (See Appendix 2) 
Covid-19 pandemic and FDA review postponed completion of recruitment and 
established new time line. 
 
5. STUDY POPULATION SELECTION 
5.1 Study Population 
Research Strategy / Clinical Trial Design: This Phase 2a RCT will study a 
reasonably homogeneous HFpEF patient population. The goal is to recruit an 
enriched sample of patients with structural/functional abnormalities like those in 
the DS rat model57, with a limited number/extent of co-morbid conditions. A 
randomized, double blind, placebo-controlled design in 40 patients with 1:1 
randomization (20 placebo, 20 CDC treated) will be performed. Patients will be 
assessed at screening, post infusion, pre-discharge, 24-48 hrs post-discharge, 0.5, 
3, 6, and 12 months after treatment. 
 
Here we are studying the effects of one-time administration of CDCs in patients 
with HFpEF. It is possible that benefits in humans may wear off over time. Thus, 
one of the objectives here is obtain preliminary indications of the duration of 
therapeutic benefits over the year of follow-up. If benefits are evident initially but 
wane over time, future clinical studies may be designed to include multiple 
repeated doses. 
 
Team: The clinical study will be conducted by Dr. Zile and colleagues in 
Charleston, SC. Dr. Eduardo Marbán will collaborate on study design and analysis. 
Capricor Inc., a NASDAQ-traded biotechnology company (ticker symbol CAPR), is 
conducting the ongoing ALLSTAR, DYNAMIC, and HOPE-Duchenne trials. 
Capricor will collaborate by providing at-cost investigational product (CAP-1002 or 
placebo) produced under Good Manufacturing Practices (GMP) standards 
approved for Phase 2 clinical testing, as well as randomization schedule, and 
immunological assays through a third-party vendor. 
 
Consent and Screen: If a patient fulfills the inclusion criteria and has none of the 
exclusion criteria (see details below), they will be consented and undergo CT 
coronary angiography (to define the coronary anatomy; CT scan will not be needed 
if patient has had a recent coronary arteriogram within 3 months showing no 
significant CAD) and donor-specific antibodies (DSA). If significant CAD is 
identified by CT and confirmed by subsequent coronary arteriography and FFR, the 
patient will be referred to their physician for consideration of a 

Confidential 
26 
October 12, 2020 
IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
revascularization procedure. After a minimum of 3 months following such a 
revascularization procedure, the patient can be reconsidered and rescreened for the 
study, minus a repeat CT. 
The originally approved protocol called for HLA typing and measurement of donor- 
specific antibodies (DSAs), and using this information to choose a CAP-1002 master 
cell bank that lacks expression of the relevant antigen(s), if applicable. We now have 
clinical information from the randomized placebo-controlled ALLSTAR trial of 134 
subjects treated with CAP-1002, some of whom were cross-matched and others 
(n=13) of whom had no possible cross-match so were treated with cells from randomly 
selected CAP-1002 master cell banks. There was no difference in efficacy or safety 
between the cross-matched and non-cross-matched groups, with a tendency to larger 
therapeutic responses (i.e., greater attenuation of adverse remodeling after 
myocardial infarction) in the non-cross-matched subjects. Accordingly, we made a 
protocol modification to eliminate the cross-matching requirement for investigational 
product CAP-1002. We will still perform HLA typing and measure DSAs pre and post-
treatment (for documenting de novo immune responses if any) but not cross-match 
cells. We will also eliminate ELISpot testing, as its value is theoretical and there has 
been no evidence of a clinically significant cell-mediated immune response in any of 
the N=95 subjects tested to date. 
 
5.2 Inclusion Criteria 
Inclusion criteria: 
Inclusion criteria: 
1. ≥ 18 years old, male or female 
2. LVEF ≥ 50% 
3. Symptoms and physical findings of chronic heart failure (NYHA class II- ambulatory 
IV) 
4. Treatment with a stable, maximally tolerated dose of diuretic(s) for a minimum of 30 
days prior to randomization. 
5. Left atrial (LA) enlargement defined by at least one of the following: LA width 
(diameter) ≥ 3.8 cm or LA length ≥ 5.0 cm or LA area ≥ 20 cm2 or LA volume ≥ 55 
mL or LA volume index ≥ 29 mL/m2 or LV concentric remodeling (LV posterior or 
septal wall thickness ≥ 1.2 cm) using echo or MRI. 
6. BNP > 125 pg/ml for patients in NSR or > 150 pg/ml for patients in AF or resting 
PCWP > 15 mmHg, or exercise PCWP > 18 mmHg. 
7. Ability to provide informed consent and follow-up with protocol procedures. 
5.3 Exclusion Criteria 
Exclusion criteria-Specific to HFpEF 
1. 
Any prior echocardiographic measurement of LVEF < 40 % 
2. 
Acute coronary syndrome (including MI), cardiac surgery, other major CV 
surgery, or percutaneous coronary intervention (PCI) within the 3 months prior to 
randomization or previous CABG or Unrevascularized, hemodynamically significant 
CAD (FFR < 0.75) 
3. 
Current acute decompensated HF 
4. 
Alternative diagnoses that in the opinion of the investigator could account for 
the patient’s HF symptoms (i.e., dyspnea, fatigue) such as severe pulmonary disease 
(i.e., requiring home oxygen, chronic nebulizer therapy, chronic oral steroid therapy); 

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hemoglobin (Hgb) < 10 g/dl; body mass index (BMI) > 45 kg/m2 
5. 
Use of investigational drugs or treatments at the time of enrollment 
6. 
Systolic blood pressure > 150 mmHg but < 180 mmHg unless receiving 3 or 
more antihypertensive drugs 
7. 
History of any dilated cardiomyopathy; right sided HF in the absence of left- 
sided structural heart disease; Pericardial constriction, genetic hypertrophic 
cardiomyopathy, or infiltrative cardiomyopathy; clinically significant congenital heart 
disease; hemodynamically significant valvular heart disease 
8. 
Stroke, transient ischemic attack, carotid surgery or carotid angioplasty within 
the 3 months 
9. 
Uncontrolled dysrhythmia; symptomatic or sustained ventricular tachycardia or 
atrial fibrillation or flutter with a resting ventricular rate > 110 beats per minute (bpm) 
10. 
Prior major organ transplant or intent to transplant (i.e., on transplant list) 
11. 
Hepatic disease as determined by any one of the following: SGOT (AST) or 
SGPT (ALT) values exceeding 3x the upper limit of normal (ULN), bilirubin > 1.5 mg/dl; 
history of chronic viral hepatitis 
12. 
Chronic Kidney Disease with eGFR < 30 mL/min/1.73 m2; serum potassium 
> 5.5 mmol/L (mEq/L) 
13. 
History or presence of any other disease with a life expectancy of < 3 years 
14. 
Non-compliance to medical regimens 
15. 
Drug or alcohol abuse within the last 12 months 
16. 
History of malignancy within the past 5 years 
17. 
Pregnant or nursing (lactating) women confirmed by a positive human chorionic 
gonadotropin (hCG); women of child-bearing potential (physiologically capable of 
becoming pregnant), unless using highly effective contraception methods during study 
18. 
Devices that are MRI incompatible 
 
Exclusion criteria-Specific to CAP-1002 (not listed above) 
1. 
Diagnosis of active myocarditis 
2. 
Known hypersensitivity to contrast agents or previous H/O HIT 
3. 
Known hypersensitivity to dimethyl sulfoxide (DMSO) 
4. 
Known hypersensitivity to bovine products  
5. 
History of heparin induced thrombocytopenia (HIT) 
6. 
Active infection not responsive to treatment 
7.  
Active allergic reactions or connective tissue diseases  
8.  
History of cardiac tumor or cardiac tumor demonstrated on screening 
9.  
History of previous stem cell therapy 
10.  
Human Immunodeficiency Virus (HIV) infection 
 
Endpoints: The primary objective is to determine the safety of CAP-1002 administered 
by multi-vessel, non-occlusive intracoronary infusion in subjects with HFpEF. A 
secondary objective is to explore, in a non-hierarchical manner, efficacy end-points that 
will be of value intrinsically as indicators of bioactivity as well as in guiding future trials 
with CAP-1002.  
 
 
 
 
 
 

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6. STUDY TREATMENT(S) 
 
6.1 Description of Treatment(s) 
 
6.1.1 Study Drug 
 
CAP-1002 CDCs will be grown from an unrelated donor and manufactured by 
Capricor Inc. CAP-1002 is delivered in a ready-to-use format. CDCs are grown in 
media that contains bovine products, are washed prior to formulation such that 
only trace amounts remain (<0.001%), but patients with known hypersensitivity are 
excluded. Each dose of 25 million cells (CAP-1002) or placebo for delivery to the 
patient will be in a final volume of 11.1 mL of cryogenic cell preservation solution 
(CryoStor® CS10, BioLife Solutions, Inc.) with 10% dimethyl sulfoxide (DMSO), 
heparin (1800 U) and nitroglycerin (450 mcg). A 12-mL normal saline and heparin 
(1200 U) wash solution, with or without nitroglycerin (800 mcg), is used to wash 
the lumen of the catheter before and after infusion of CAP-1002 or placebo. The 
wash solution with nitroglycerin is the preferred wash solution; however, a wash 
solution without nitroglycerin is also prepared for patients who may be intolerant to 
nitroglycerin during the infusion procedure. Capricor, the manufacturer of CAP- 
1002 and placebo, will provide detailed instructions for the preparation of the saline 
wash solutions and investigational product (CAP-1002 or placebo). The 
investigational pharmacy will prepare the wash solutions in 20 mL barrel syringes 
and each of the three doses of investigational product in 12 mL barrel coronary 
control syringes with amber masking tape around the barrel. The investigational 
pharmacist should maintain sterility of the outside of the syringes so they can be 
dropped onto the sterile field in the cardiac catheterization laboratory. 
 
6.2 Treatment Administered 
 
All patients will have CAP-1002 or placebo delivered through a coronary catheter 
inserted in the right and left coronary arteries using standard techniques in the cardiac 
catheterization laboratory. A right heart catheter will be used to obtain baseline (pre- 
infusion) hemodynamics. Standard diagnostic angiography will be performed prior to 
infusion of the investigational product to confirm patency of the coronary arteries and 
final determination of whether the patient is suitability to undergo the investigational 
procedure. All patients will receive 25 million cells (CAP-1002) or placebo in each of 
the 3 coronary arteries. Prior to infusion of the investigational product, the lumen of 
the catheter is flushed with saline-heparin wash solution (with or without nitroglycerin 
depending on individual patient tolerance) for approximately 30 seconds (±5 
seconds). Sequential dose administration of 25 million cells or placebo, as described 
above, will be infused over 10 minutes (±30 seconds) via a TERUMO FinecrossTM 
MG guiding catheter, the only catheter that has undergone biocompatibility testing 
with CAP-1002. Following the infusion of the investigational product, any residual 
investigational product within the lumen is flushed with saline-heparin wash solution 
(with or without nitroglycerin) for approximately 30 seconds (±5 seconds). Patency of 
the vessel and TIMI grade 3 flow should be confirmed before moving to the next 

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vessel; allow at least a five-minute interval between each infusion of investigational 
product while remaining mindful of the labeled expiry time of the investigational 
product. All procedures will be performed by the cardiac interventionist (Dr 
Fernandes). The patient will receive local anesthesia +/- gentle conscious sedation if 
undue anxiety. During and in between infusions, multiple measures of O2 sat, 
hemodynamics, including blood pressure and heart rate and monitoring for any 
arrhythmias (ventricular and supra-ventricular). Fluids are permitted for hypotension 
during the procedure, as are low dose inotropes such as dobutamine and use of 
inhaled nitric oxide. VPCs or NSVT can be seen with insertion of the PA catheter as 
it traverses the RV and is easily remedied by catheter withdrawal. Oxygen will be 
used if needed to treat temporary hypoxia should this occur. If significant adverse 
events occur, the infusion will be terminated (see details below). 
 
6.3 Selection and Timing of Dose 
 
This Phase 2 cohort will include 40 patients randomized in a double-blind fashion to 
receive either CAP-1002 or placebo in a 1:1 ratio. CAP-1002 will be grown from 
unrelated donors. After completion of the screening and baseline procedures, 
patients will receive either CAP-1002 or placebo Infusions within 3 weeks of 
screening and completion of any outstanding baseline studies required to confirm a 
diagnosis of HFpEF. All patients (those who have undergone CAP-1002 or placebo 
infusion) will be followed until the last enrolled patient has reached 12-month follow- 
up. Patients will be followed post infusion, pre-discharge, 24-48 hrs post-discharge, at 
week 2 and at months 3, 6, and 12 after CAP-1002 or placebo infusion. 
 
6.4 Method of Assigning Patients to Treatment Groups 
 
Randomization: Non-occlusive, sequential, three-vessel intracoronary delivery of 25 
million CDCs (or placebo) in each of the three coronary arteries, as used safely to 
date in the DYNAMIC trial. This method achieves broad myocardial coverage and is 
atraumatic to vessel walls, as a flexible guiding catheter is used to deliver the cells. 
Capricor has extensive experience with manufacturing of CAP-1002 and identical- 
appearing placebo (both provided in amber-colored syringes). Transplant-quality 
donor hearts that could not be used clinically are used as the starting material for 
CAP-1002, in a manufacturing process described previously.23 Using SAS or 
comparable software, Capricor will prepare the master randomization list of a 1:1 
(CAP-1002 to placebo) randomization using permuted blocks with random block 
sizes of 2 or 4 without stratification. Following randomization, Capricor, through its 
third-party drug depot vendor, will ship out investigational product (CAP-1002 or 
placebo) on a just in time, per patient basis to the MUSC Center for Cellular Therapy. 
 
6.5 Concomitant Therapy 
Concomitant therapies are defined as all therapies received on or after the day of 
infusion. Those received before the day of infusion are considered prior therapies. 
Prior therapies will be recorded during initial screening. Concomitant therapies with 
HFpEF –specific agents will be recorded at each study visit, beginning with the day 

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of infusion, as well as all other medications. All patients with HFpEF will be on stable 
background diuretic therapy prior to enrollment as well as any adjunctive therapies 
for HFpEF deemed to be necessary in that particular patient. 
 
6.6 Restrictions 
 
6.6.1 Prior Therapy 
Patients who have had previous stem cell therapy or any organ transplant may not 
participate in this study. There are no medication restrictions except those listed in 
Appendix 3. Individual patient medication will be advised by the patient’s physician 
according to the usual practice of the study site. Coumadin / other anticoagulant 
discontinuation prior to catheterization will be managed according to standard of 
care practices. 
 
6.6.2 Fluid and Food Intake 
There are no fluid or food intake restrictions. Patients should follow the diet and 
fluid intake prescribed by their physician. 
 
6.6.3 Patient Activity Restriction 
Patients should follow the activity recommendations prescribed by their physician. 
 
 
6.7 Treatment Compliance 
 
Since the treatment is a one-time procedure, dosing compliance is not a concern. 
Study site personnel will document compliance with medications and study follow-up 
procedures at each study visit. 
 
 
6.8 Packaging and Labeling 
 
CAP-1002 will be formulated and frozen in labeled cryogenic bags with 510K 
approval for the use in protecting, storing and freezing cells and tissues. A cryogenic 
overwrap bag will be used to protect the cell storage bag and label during freezing. A 
secondary label will be attached to the cryogenic overwrap bag for quick 
identification. The frozen product will be delivered overnight from Capricor’s third- 
party drug depot vendor to the clinical trial site via a liquid nitrogen dry vapor shipper 
(dewar). The frozen product will remain in the shipper (dewar) until ready for use. 
 
6.9 Storage and Accountability 
 
The frozen product will only be dispensed once a patient has (1) provided written 
informed consent, (2) met all eligibility criteria for entry into the study, and (3) 
completed all baseline evaluations. Detailed instructions for storage and handling will 
be provided by Capricor. Once removed from shipper (dewar), Investigators are 
instructed to store the study agent at room temperature (~25oC), and to   administer 

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the study agent within 2 hours of removal from storage. The study site is responsible 
for study agent accountability, reconciliation, and record maintenance. In accordance 
with all applicable regulatory requirements, designated study center personnel must 
maintain accountability records throughout the study. 
 
6.10 Investigational Product Retention at Study Site 
 
Since product will be delivered as needed on a per patient basis, there will be no 
product to retain at the site. The site will be instructed to retain labels and packaging 
materials - as part of the patient records. Should a patient be found unsuitable or 
ineligible for infusion after a product has been delivered to the CVIC, a Quality 
representative at Capricor will provide direction on how to return the investigational 
product. 
 
7. STUDY PROCEDURES 
 
7.1. Informed Consent 
 
Before being admitted to the clinical study, all patients must consent in writing to 
participate. An Informed Consent Form (ICF) will be given to each patient, which will 
contain all United States federally required elements, all ICH-required elements, and 
Health Insurance Portability and Accountability Act (HIPAA) authorization information 
in language that is understandable to the patient. The process of obtaining the 
informed consent will be in compliance with all federal regulations, International 
Conference on Harmonization (ICH) requirements, and local laws. The Investigator 
will review the study with each patient. The review will include the nature, scope, 
procedures, and possible consequences of the patient's participation in the study. 
The ICF and review will be in a form understandable to the patient. The Investigator 
or designee and the patient must both sign and date the ICF after review and before 
the patient can participate in the study. The patient will receive a copy of the signed 
and dated form, and the original will be retained in the site study files. The Investigator 
or his/her designee will emphasize to the patient that study participation is entirely 
voluntary and that consent regarding study participation may be withdrawn at any 
time without penalty or loss of benefits to which the patient is otherwise entitled. If the 
ICF is amended during the study, the Investigator must follow all applicable regulatory 
requirements pertaining to approval of the amended ICF by the IRB/IEC. The site 
must use the amended consent form for all new patients and repeat the consent 
process with the amended ICF for any ongoing patients. 
 
7.2. Medical History 
 
A complete medical history, including all elements pertinent to HFpEF (e.g., effort 
intolerance, NYHA FC, exercise–induced chest pain or dizziness/syncope, edema, 
etc., medications, etc.) of patients enrolled in the study will be documented as part of 
the screening process and reviewed prior to enrollment into the study. At subsequent 
visits (day of infusion forward), medications, general health and cardiopulmonary 

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health will be reviewed including all elements pertinent to HFpEF at each patient visit 
and new information will be updated in the patient’s study documentation. 
 
7.3. Physical Examination 
 
A qualified physician, either the Principal Investigator or Sub-Investigators will 
perform a comprehensive physical examination aimed at examining all signs 
pertinent to HFpEF at each study visit. 
 
7.4. Vital Signs 
 
Temperature, heart rate, blood pressure, respiration rate, and body weight will be 
recorded at each visit on the case report form (CRF). 
 
7.4.1. Laboratory Parameters 
Subjects will be in a seated or supine position during blood collection. Clinical 
laboratory tests will include the following: 
 
List of laboratory tests 
 
Hematology: 
CBC with differential 
 
Immunology: 
HLA/DSA 
 
Urine Pregnancy Test (for women of 
childbearing potential 
 
Biomarkers 
HIV 
Hepatitis panel 
Serum Chemistry: 
Albumin (ALB) 
Alkaline phosphatase (ALK-P) 
Alanine aminotransferase (ALT; 
SGPT) 
Aspartate aminotransferase (AST; 
SGOT) 
Blood urea nitrogen (BUN) 
Brain natriuretic peptide (BNP) 
Creatinine 
Creatine kinase and subtypes 
Glucose 
Lactate dehydrogenase (LDH) 
Potassium (K) 
Sodium (Na) 
Total bilirubin 
Direct bilirubin 
Total protein 
Troponin I (baseline and as needed) 
 
Coagulation: 
 
Prothrombin time (PT) 
Activated partial thromboplastin time 
(PTT) 
International Normalized Ratio (INR) 

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7.5 12-Lead ECG 
 
Beginning at the screening period, a 12 lead ECG will be performed and then post 
infusion, day of discharge from the hospital, day14, and months 3, 6 and 12. The 
purpose will be to assess any change in axis, look for new features of LVH, MI, and 
assess rhythm. 
 
7.6 Echocardiography 
 
An echocardiogram will be performed during the screening period as well as at months 
6 and 12 visits. Echocardiography will be performed to measure LV structure, systolic 
and diastolic function. 
 
7.7 Holter Monitor (24 Hour ECG) 
 
The 24-hour ECG (Holter) will be performed during the screening phase, 0.5, and 6 
months after Cap-1002 to rule out the presence of significant arrhythmias or 
conduction defects. 
 
7.8 Six Minute Walk Test 
 
The 6MWT will be performed at screening and at 6 and 12-month follow-up visit. While 
we will be looking for an improvement in 6MWT distance, a ≥ 15% reduction in 6MWT 
distance from baseline will be consider a significant decline. 
 
7.9 Magnetic Resonance Imaging Protocol 
 
With the exception of those patients with a known contra-indication for MRI, all 
patients will undergo contrast-enhanced magnetic resonance imaging (ceMRI) at 
screening and at month 6. The imaging protocol will first include sagittal, axial and 
oblique scout images to localize the heart. It is anticipated that the duration of each 
MRI session will be 45-60 minutes. Acquisition parameters and techniques will be 
protocoled such that there is standardization regarding acquisition of the studies. 
Specific measures of note will include LV structure and function. Delayed contrast 
enhancement can also reflect the presence of myocardial fibrosis. This will not be 
required in patients in whom there are contraindicated to undergo an MRI. 
 
7.10 Image Analysis 
 
The imaging data will be read by cardiovascular imaging expert: Sheldon Litwin, MD. 
 
7.11 Cardiac CT 
 
A computerized tomography (CT) of the chest and heart will be performed at the 
screening visit to ensure that there are no clinically significant pre-existing 
abnormalities particularly calcification, atherosclerosis in the coronary arteries. The 
CT will be performed with (provided no renal dysfunction) and without contrast. If any 

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abnormalities are found that affect the patient’s participation in the study, the patient 
will be withdrawn from the study as a screen failure and not followed further. The 
patient must continue to meet all inclusion and no exclusion criteria in order to 
continue in the study 
 
7.12 Clinical Functional Capacity and Quality of Life Measures 
 
New York Heart Association (NYHA) functional status will be evaluated at screening, 
0.5, 3, 6 months, 12 months. A MLWHF QOL questionnaire will be completed at 
baseline, 6 months and 12 months. 
 
7.13 Adverse Events 
 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical 
investigation subject associated with the use of a medicinal product, whether or not 
considered related to the medicinal product. The occurrence does not necessarily 
have to have a causal relationship with the medicinal product. An AE can therefore 
be any unfavorable and unintended sign (including an abnormal laboratory finding, 
for example), symptom, or disease (new or exacerbated) temporally associated with 
the use of a medicinal product, whether or not considered related to the medicinal 
product. 
 
 
Examples of an AE include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency or intensity of the condition. 
• Significant or unexpected worsening or exacerbation of the condition/indication 
under study. 
• A new condition detected or diagnosed after study therapy administration even 
though it may have been present prior to the start of the study. 
• Pre- or post-treatment events that occur as a result of protocol-mandated 
procedures (e.g., invasive protocol-defined procedures, modification of a patient’s 
previous treatment regimen). 
 
 
An AE does not include: 
• Medical or surgical procedures (e.g., colonoscopy, biopsy). The medical condition 
that leads to the procedure is an AE. 
• Social or convenience hospital admissions where an untoward medical occurrence 
did not occur. 
• Day to day fluctuations of pre-existing disease or conditions present or detected at 
the start of the study that do not worsen. 
• The disease/disorder being studied or expected progression, signs, or symptoms 
of the disease/disorder being studied unless more severe than expected for the 
patient’s condition. 

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The Investigator will review all documentation (e.g., hospital progress notes, 
laboratory, or diagnostic reports) relative to the event being reported. The Investigator 
or his/her designee will then record all relevant information regarding an AE/SAE into 
the CRF. It is not acceptable for the Investigator to send photocopies of the patients’ 
medical records in lieu of completion of the appropriate AE/SAE pages. However, 
there may be instances when the DSMB Chair requests copies of medical records 
for certain cases. In this instance, all patient identifiers will be blinded on the copies 
of the medical records prior to submission to the DSMB Chair. 
 
The Investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. In such cases, the diagnosis should be 
documented as the AE/SAE and not the individual signs and symptoms. 
 
7.13.1 Timing 
 
Adverse event assessment and documentation will occur at each study visit from 
during and immediately after infusion and then throughout the study. On the day 
of treatment administration, a patient’s medical complaint will be considered to be 
a treatment-emergent adverse event if the event occurs any time after the infusion 
of CAP-1002 or placebo. 
 
7.13.2 Severity 
 
The Investigator will make an assessment of intensity for each AE and SAE 
reported during the study. The assessment will be based on the Investigator’s 
clinical judgment. The intensity of each AE and SAE will be assigned to one of 
the following categories: 
 
Mild: 
An event that is easily tolerated by the patient, causing minimal 
discomfort and not interfering with everyday activities. 
Moderate: An event that is sufficiently discomforting to interfere with normal 
everyday activities. 
Severe: 
An event that prevents normal everyday activities. 
 
An AE that is assessed as severe will not be confused with an SAE. Severity is a 
category utilized for rating the intensity of an event; and both AEs and SAEs can 
be assessed as severe. An event is described as ‘serious’ when it meets one of 
the pre-defined outcomes as described in the Section 7.13.7.1, Serious Adverse 
Events. 
 
7.13.3 Relationship 
 
The Investigator is obligated to assess the relationship between study therapy and 
the occurrence of each AE/SAE. The Investigator will use clinical judgment to 
determine if there is a reasonable possibility that the pharmacological action of the 
study agent was responsible for the AE/SAE being reported. Alternative causes 
such as natural history of the underlying diseases, concomitant therapy, other risk 

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factors, and the temporal relationship of the event to the study agent will be 
considered and investigated. The Investigator will also consult the Investigator’s 
Brochure and/or Product Information, for marketed products, in the determination 
of his/her assessment. 
 
All AE/SAE that occur during the course of the clinical study will be evaluated and 
a determination of relatedness to the investigational product (CAP-1002 or 
placebo) will be defined according to one of the following categories: 
 
Related: The AE/SAE is clearly related to the investigational product. 
Not related: The AE/SAE is clearly NOT related to the investigational product. 
Unable to Determine: The investigator should make every attempt to assign 
causality based on his best clinical judgment, all available information about the 
investigational product, and consultation with the Capricor chief medical officer. In 
the rare case causality cannot be determined, “unable to determine” may be used; 
however, for determining whether an event meets expedited reporting 
requirements, “unable to determine” shall be treated the same as a “related” event. 
 
There may be situations when an SAE has occurred and the Investigator has 
minimal information to include in the initial report. However, it is very important that 
the Investigator make an assessment of causality. 
 
7.13.4 Expectedness 
 
The following events are those that could be expected to occur as a result of the 
catheterization and infusion procedure: 
• 
Premature ventricular contractions, non-sustained ventricular tachycardia 
• 
Possible atrial tachyarrhythmias (e.g. atrial fibrillation). 
• 
Possible bradycardias and conduction block 
• 
Hypotension (Systolic Blood Pressure <80mmHg) with symptoms, requiring 
intravenous fluid administration, during the cell infusion procedure 
• 
Desaturation below 90% requiring O2 administration or up titration of O2 
• 
Bleeding and /or hematoma formation at the site of vascular access for the 
cell infusion procedure. Complications such as pneumothorax or pulmonary 
artery rupture are extremely rare SAE of any cath procedure and are not 
anticipated. ( Access using ultrasound guidance and safe process for balloon 
inflation to determine PCWP) 
 
Note: For this study, the standard definitions of non-sustained and 
sustained ventricular tachycardia will be employed: 
- 
non-sustained VT: “ventricular tachycardia with a heart rate 
of at least 120 beats per minute, lasting for at least three beats and 
persisting less than 30 second” 
- 
sustained VT: “ ventricular tachycardia that lasts more than 
30 seconds and leads to hemodynamic collapse 

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All adverse events expected or otherwise, should be reported in the patient data. 
Serious adverse events should be reported to the Sponsor within 24 hours of the 
site learning of the event. 
 
 
7.13.5 Clinical Significance 
 
An abnormal lab value or test result should be deemed clinically significant if either 
of the following conditions is met: 
 
The abnormality suggests a disease and/or organ toxicity that is new or has 
worsened from baseline. The abnormality is of a degree that requires additional 
active management, e.g., change of dose, discontinuation of a drug, close 
observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
 
A qualified physician at the investigative site, either the Investigator or a Sub- 
Investigator, will review all study-related laboratory and other test results. The 
reviewing Investigator will use his/her medical judgment to classify and document 
any results that are outside of the normal results range. The Investigator indicate 
whether the abnormal result is clinically significant (CS) or not clinically significant 
(NCS) on the source document and CRF. The Investigator will also date and sign 
the source document next to the circled abnormal result. 
 
Once the Investigator deems an abnormal value to be clinically significant (CS), 
he or she will determine whether there is a clinical exam finding or symptom (new 
or pre-existing) that explains the abnormal value. A progress note summarizing the 
findings, including the reason(s) why the results are deemed CS will be written to 
provide documentation for an adverse event report. If the Investigator is able to 
provide a differential diagnosis for the CS result, he or she should describe the AE 
accordingly, e.g., urinary tract infection or suspected anemia. In the absence of an 
associated clinical sign or symptom, and if only a single value is deemed CS, list 
the abnormal value itself as the AE, e.g., elevated potassium or decreased 
calcium. As more information about the abnormal value is known that provides a 
diagnosis, the AE should be updated in the electronic data system to reflect the 
diagnosis. 
 
 
7.13.6 Clinical Laboratory Adverse Events 
 
Abnormal laboratory findings (e.g. clinical chemistry, hematology, and urinalysis) 
that are judged by the Investigator as clinically significant (CS) will be documented 
as described in Section 7.13.5 and will be recorded as AEs or SAEs if they meet 
the definition of an AE as defined in Section 7.13 or SAE, as defined in Section 
7.13.7.1. 

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Clinically significant abnormal laboratory findings that are detected during the 
study or are present at baseline and significantly worsen following the start of the 
study will be reported as AEs or SAEs. However, clinically significant abnormal 
laboratory findings that are associated with the disease being studied, unless 
judged by the Investigator as more severe than expected for the patient’s 
condition, or that are present or detected at the start of the study but do not worsen, 
will not be reported as AEs or SAEs. 
 
The Investigator will exercise medical judgment in deciding whether abnormal 
laboratory values are clinically significant. 
 
 
7.13.7 Serious Adverse Events 
 
7.13.7.1 Definition 
 
A serious adverse event (SAE) is defined by federal regulation as any AE 
occurring at any dose that results in any of the following outcomes: death, 
life-threatening AE, in-patient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, a congenital 
anomaly/birth defect or important medical event. 
 
Important medical events that may not result in death, be life threatening, 
or require hospitalization may be considered an SAE when, based upon 
appropriate medical judgment, they may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse. 
 
Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. Hospitalization for elective treatment of a pre-existing condition that 
did not worsen from baseline is not considered to be an AE. 
 
The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include 
experiences of relatively minor medical significance such as uncomplicated 
headache, nausea, vomiting, diarrhea, influenza, accidental trauma (i.e., 
sprained ankle) that may interfere or prevent everyday life functions but do 
not constitute a substantial disruption. 
 
7.13.7.2 Reporting Serious Adverse Events 
 
 

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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
Step 1- If an SAE occurs that is possibly related to protocol, procedure or product, the 
study site will notify the following within 24 hours: 
1- Sponsor (Cedars-Sinai Heart Institute) 
2- Regress-HFpEF DSMB 
3- MUSC IRB 
4- Capricor 
 
Step 2- Send most current, updated SAE CRF and other available documentation to 
DSMB within 72 hours (3 days). Every attempt will be made to obtain all necessary 
documentation from all involved health care providers and facilities both MUSC and any 
other location. However, even if documents and information are “pending”, the DSMB will 
be sent all currently available information in this timely fashion. 
 
Step 3- DSMB will complete adjudication using the adjudication SAE form within 5 days. 
However, if the DSMB requests additional information, documentation or primary 
documents or if the study site receives additional information, revised adjudication by the 
DSMB may occur. The DSMB will send the results of the adjudication to the study site 
who will in turn send the adjudication result to the Sponsor. 
 
Step 4- FDA will be informed by the Sponsor of the DSMB adjudication within 5 days after 
the adjudication is completed by the DSMB. 
 
Step 5- If, based on the DSMB adjudication, and, at the request of the DSMB, a change in 
the Clinical Protocol needs to be made, the following sequential steps will be taken and 
completed within 30 business days after the adjudication is completed: 
1- The study site will revise the Clinical Protocol. 
2- The study site will submit these changes to the MUSC IRB for review and approval. 
3- The study site will send the revised clinical protocol to the Sponsor for review and 
approval. 
4- The Sponsor will send the revised clinical protocol to the FDA for review and approval. 
 
After DSMB review of an SAE is completed, a clear record will be established of the 
adjudication, recommendations, and sponsor follow-up. 
Site notification of SAE and all other communications regarding the SAE will be sent to 
sponsor, DSMB, IRB as appropriate by email together with all appropriate SAE CRFs and 
a paper copy of this email and any email response will be kept in the individual patient 
binder. The DSMB completed SAE adjudication form will be sent to sponsor by email and 
a paper copy of this email and any email response will be kept in the individual patient 
binder. All communications regarding SAE will be sent to FDA by the sponsor. 
 
Specific SAEs to our patient population are those included in the 
definition of clinical worsening as defined above. For example: 
 
 
Death (all-cause mortality) 
 
Hospitalization for worsening HFpEF: 
- 
Non-elective hospitalization for ≥ 24 hours 

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October 12, 2020 
 
 
 
 
IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
- 
Signs and symptoms of LV failure to include one or more of: 
increased dyspnea, clinically significant deterioration in exercise 
capacity, 
syncope 
or 
pre-syncope, 
hypoxemia, 
edema, 
hepatomegaly, ascites 
 
 

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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
Per ICH E2A and 21 CFR 312, regulatory agencies will be notified by the 
Sponsor by telephone or fax of any unexpected, serious adverse event 
potentially associated with treatment as soon as possible, but in no event 
later than 14 business days after the Sponsor’s initial receipt of the 
information; fatal or life-threatening unexpected SAEs associated with 
treatment will be reported to regulators within 14 business days. Follow-up 
information will be provided as required. 
After the initial AE/SAE report, the Investigator is required to proactively 
follow each patient and provide further information to the medical monitor 
on the patient’s condition. All AEs and SAEs documented at a previous 
visit/contact that are designated as ongoing will be reviewed at subsequent 
visits/contacts. 
 
Adverse events and SAEs will be followed until resolution, until no further 
changes in the event are expected (i.e. the point at which a patient 
experiencing a critical adverse event is treated successfully and stabilized 
even though they may continue to experience lingering sequelae that may 
never resolve), until the patient is lost to follow-up, or until it is agreed that 
further follow-up of the event is not warranted (e.g. non-serious, study 
therapy unrelated, mild or moderate adverse events ongoing at a patient’s 
final study visit). If a patient dies during participation in the study or during 
a recognized follow-up period, the DSMB will be provided with a copy of any 
post-mortem findings, including histopathology. New or updated information 
will be recorded by modifying the AE forms in the paper CRFs. 
 
The Investigator will promptly report all SAEs within the timeframes 
specified above. The Investigator will comply with the applicable local 
regulatory requirements related to reporting of SAEs to his or her 
Institutional Review Board (IRB). 
This protocol is being filed under an Investigational New Drug (IND) 
application with the FDA in the US. A given SAE may qualify for an 
Expedited Safety Report (ESRP) if the SAE is both attributable to study 
therapy and unexpected. In this case, all Investigators participating in the 
study will receive the ESR. The purpose of the ESR is to fulfill specific 
regulatory and Good Clinical Practice (GCP) requirements regarding the 
product under investigation. 
 
7.13.7.3 Sponsor Monitoring of Adverse Events 
 
This study will be overseen by an independent data safety monitoring board 
(DSMB) appointed by the Sponsor, which will have access to all the reports 
of patients receiving CAP-1002 infusion. 

IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
 
• The following list summarizes the Sponsor’s role in monitoring AE/SAEs: 
• All AEs will be reviewed on a monthly basis by the study site. 
• All SAEs will be reviewed by the DSMB within 5 days of receiving the 
adverse event form from the clinical center. 
• If the DSMB requires additional information to make an assessment, the 
clinical centers will respond to the request for additional information as 
soon as the requested information is made available. 
• The Sponsor is responsible for notifying the DSMBs of all SAEs, and of 
any concerns regarding the frequency or type of SAE(s) on a study or 
treatment cohort. 
• The attribution, and expected/unexpected nature of event as assessed 
by the clinical center, will be provided to the DSMBs within 5 days of 
receiving the report. 
• All SAEs deemed at least possibly related to study treatment will also be 
sent to the DSMB within 72 hours of the Sponsor becoming aware of the 
event. 
 
The Sponsor will prepare summary reports every annually of all 
AEs/SAEs occurring in all enrolled patients for the DSMB. 
 
7.13.7.4 DSMB Monitoring of Adverse Events 
 
The following list summarizes roles of the DSMBs in monitoring AE/SAEs: 
• 
The DSMB will review SAEs with at least a possible relationship to 
study treatment within 5 days and all other SAEs in advance of every 
DSMB meeting. The Sponsor anticipates (1) phone conversation with 
DSMB chair within 5 days of every death or life-threatening event, and 
(2) communications within 5 days for all other SAEs with at least a 
possible relationship to the study therapy. The DSMB chair (or 
designee) will be requested to acknowledge receipt of SAEs within 5 
days of notification. 
• 
On an annual basis the DSMB will be provided with a summary of all 
AEs and SAEs, regardless of attribution, and additional safety and 
outcomes data as part of their scheduled interim reviews. In addition to 
AE and SAE review, specific safety and outcomes data will be identified 
for review by the DSMB. 
• 
The DSMB Chair (or designee) is responsible for reviewing the SAE 
materials to determine if the documents are complete. If there are any 
concerns regarding the type or frequency of the event, the DSMB Chair 
may request additional information from the Sponsor. The DSMB Chair 
will determine whether additional DSMB review is required and make 
recommendations to the Sponsor and study site regarding continuation 
of the study. 
 
 
 
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7.13.7.5 Data Safety Monitoring Board: Further Specifics 
 
An independent Data Safety and Monitoring Board (DSMB) will oversee 
the safety of all subjects. Interim data reviews will be conducted at times 
coincident with regularly scheduled meetings of the DSMB in accordance 
with reaching accrual and follow up milestones. The DSMB Chair will be 
notified each time that an SAE occurs. The DSMB will evaluate blinded AE 
data (including SAEs) as group A vs B without identification as CDC vs 
Control unless there is a safety signal present in one of the 2 groups, then 
the data will be reviewed in an unblinded manner. The DSMB will review 
data after all 10 subjects have completed their three-month study visit. The 
DSMB will then review the data after 20 subjects have completed their 
month 3 follow up visits. The DSMB will then review the data after 40 
subjects have completed their month 3 follow up visits. All patients will 
continue to undergo protocol assessments through 12 months of follow-up, 
including DSMB reviews. 
 
The DSMB will review all safety parameters. Monitoring of key safety 
endpoints will be conducted as described above. Policies of the DSMB are 
described in the DSMB Charter. The stopping guidelines serve as a trigger 
for consultation with the DSMB for additional review, and do not mandate 
automatic closure of study enrollment. Stopping will be at the discretion of 
the Sponsor, after consideration of DSMB recommendation. The Sponsor 
always retains the final responsibility to stop a study. Given the 
complexities of the disease and treatment there cannot be more specific 
stopping rules. 
 
After DSMB review of an SAE is completed, a clear record will be 
established of the adjudication, recommendations, and sponsor follow-up. 
Site notification of SAE and all other communications regarding the SAE 
will be sent to sponsor, DSMB, IRB as appropriate by email together with 
all appropriate SAE CRFs and a paper copy of this email and any email 
response will be kept in the individual patient binder. The DSMB completed 
SAE adjudication form will be sent to sponsor by email and a paper copy 
of this email and any email response will be kept in the individual patient 
binder. All communications regarding SAE will be sent to FDA by the 
sponsor. 
 
 
7.13.8 Post-Study Adverse Events and Serious Adverse Events 
 
The Sponsor will notify the DSMB of any death or SAE occurring at any time after a 
patient has completed or terminated a clinical trial, when such death or SAE may 
reasonably be related to the study therapy used in this investigational trial. 
Investigators are not obligated to actively seek AEs from former study participants. 
 
 
43 
 

IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
7.13.9 Treatment-Emergent Adverse Events 
 
Adverse event assessment and documentation will occur at every study visit from 
screening throughout the study. On the day of treatment administration, a patient’s 
medical complaint will be considered to be a treatment-emergent adverse event if 
the event occurs any time after the infusion of CAP-1002 or placebo. 
 
7.14 Concomitant Medication Assessments 
 
Study personnel will record both general and cardiac medication use at each study 
visit beginning at the time of enrollment. Concomitant medications are defined as 
those received on or after the day of infusion. All medications will be reviewed by the 
Investigator at individual study sites and will then be entered into the CRF for each 
study visit. 
 
 
7.15 Removal of Patients from the Trial or Study Drug 
 
The Investigator may withdraw a patient from participation in the study for 
any of the following reasons: 
• 
A protocol violation occurs 
• 
A serious or intolerable adverse event occurs 
• 
A clinically significant change in a laboratory parameter occurs 
• 
The Sponsor or Investigator terminates the study, or 
• 
The patient requests to be discontinued from the study. 
7.16 Other Study Procedures 
 
For patients who so consent, serum for clinical research into biomarkers will be 
collected at every scheduled visit. 
 
7.17 Appropriateness of Measurements 
 
Usual safety measurements will be obtained and summarized per standard 
reporting. In addition, more in depth evaluation of safety data as it relates to 
cardiac events will more fully elucidate the safety profile for CAP-1002. Events to 
be assessed in greater detail have been mentioned under primary and secondary 
end-points. 
 
This is a phase IIa study with a primary objective to evaluate the safety of the 
coronary artery infusion of CAP-1002 in patients with HFpEF. In addition to the 
safety end-points, information on numerous potential measures of efficacy, as 
mentioned previously, will also be collected, which will be considered only 
exploratory to help guide possible future clinical trials. 
 
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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
 
8. STUDY ACTIVITIES 
Patients qualifying as potential candidates for the study, based on initial preliminary 
screening, will be consented for the procedure. Patients meeting the screening criteria for 
the study will be consented for CAP-1002 infusion. 
 
The final eligibility of the patient for the study will depend on the hemodynamic profile of 
the patient with patient meeting all inclusion and exclusion criteria. Patients who meet all 
of the inclusion criteria and none of the exclusion criteria will receive intracoronary infusion 
of CAP-1002. Study patients will be observed in the hospital with continuous cardiac and 
respiratory monitoring for at least 24 hours afterwards. 
 
8.1 Pre-Treatment Screening Phase (Days -28 to -1) 
No screening exams will take place until the patient is fully informed of the research 
and signs the informed consent. 
 
 
Screening tests and procedures include: 
• 
History and physical examination 
• 
Vital Signs 
• 
Medication review 
• 
NYHA functional class assessment 
• 
12 lead ECG 
• 
Biomarkers 
• 
24-hour ECG 
• 
Echocardiography 
• 
6MWT 
• 
Laboratory tests (hematology, chemistry, BNP, pregnancy test [if applicable] and 
HLA/DSA, troponin-I, CPKMB) 
• 
Chest CT 
• 
Cath and bicycle ergometry 
• 
Baseline contrast enhanced cardiac MRI; (unless contraindicated); 
• 
Baseline Patient Quality of Life Questionnaire (MLWHF) 
Following screening examinations, once a patient has met all of the inclusion criteria 
and none of the exclusion criteria, the patient will undergo further hemodynamic 
screening. For those enrolled in the study, dosing and randomization will be 
coordinated with Capricor and the Research Pharmacy at MUSC. The test agent will 
be prepared according to instructions in the Pharmacy Manual. The test agent will 
then be drawn into the syringes using sterile technique for administration during the 
cath procedure. 
45 

IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
 
 
 
8.2 Hemodynamic Screening 
 
The final eligibility of the patient will be determined based on the presence of hemodynamic 
inclusion criteria and absence of hemodynamic exclusion criteria. Patients who do not 
proceed to infusion due to violation of eligibility criterion at screening will be withdrawn from 
the study as screen failures and will have no further follow up. 
 
8.2.1 Intracoronary Infusion Procedure (Day 0) 
 
During the infusion period, patients will be clinically stable as judged by no evidence of 
infection, and stable blood pressure, pulse and pulse Ox. 
 
A patient is enrolled and randomized in the study once the patient receives any amount of 
test agent. Conversely, a patient who does not receive any test agent is not considered 
enrolled or randomized in the study. If the operator decides not to administer the test agent, 
the patient is not enrolled or randomized, and subsequent treatment will be determined by 
the responsible physician and will not be protocol- driven. In addition, only those subjects 
that are enrolled, randomized, and receive any amount of test agent will be considered in 
the statistical analysis plan. 
 
Prior to cell infusion, all patients will have a pulmonary artery catheter inserted and 
coronary catheters using standard technique in the cardiac catheterization laboratory. 
Baseline (pre-infusion) hemodynamics will be made. Provided no hemodynamic contra-
indications to proceed, cell infusion will be done. During the infusions, vital signs, SPO2 and 
pulmonary artery hemodynamics will be monitored 
 
Stopping criteria that would trigger halting of the CAP-1002 infusion are: 
 
• Hypotension unresponsive to IV fluids that require pharmacologic intervention 
• VT/ventricular fibrillation that require 
cardioversion or administration of an 
antiarrhythmic. 
• Changes in cardiac rhythm or conduction (such as SVT, atrial fibrillation with 
rapid ventricular response or heart block) that requires cardioversion or 
administration of an antiarrhythmic. 
• Significant hypoxemia/desaturation not corrected by supplemental oxygen or IV 
diuretic (if volume overloaded) or reversal of sedation (if over sedated) 
• Suspected or confirmed pulmonary artery rupture. 
• Suspected or confirmed coronary dissection. 
• Acute onset of rigors or elevated temperature above 99.8oF (symptoms indicative 
of acute sensitivity or infection) 
 
 
 
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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
Following infusion, patients will be observed in the hospital for at least 24 hours with 
continuous cardiac and respiratory monitoring. Note, hemodynamic measurements will 
be obtained if clinically indicated (e.g. fall in blood pressure), prior to withdrawal of PA 
catheter in the cardiac catheterization laboratory over the 1-hour time frame post CDC 
infusion, at which time the patient will be assessed as stable to transfer to the hospital. 
Additionally, troponin I and CK-MB will be obtained. 
 
Cardiac Arrhythmia Monitoring: The electrocardiogram will be continuously monitored 
during the intracoronary infusion and while patients are in the hospital after the procedure. 
IND Submission: Revision #1 
 
Prior to discharge from the hospital, a physical assessment will be performed. The latter 
includes evaluation of symptoms of dyspnea, chest pain, and dizziness with effort. The 
following will also be assessed: O2 needs, serial BP and HR, administration of an 
antiarrhythmic or cardioversion, administration of an inotrope, review of laboratory results, 
ECG, and assessment of adverse events. In the absence of serious adverse events, 
patients will be discharged per standard of care practice. 
 
The timing of follow-up visits is based on the date of study therapy administration. 
8.2.1.1 
Post infusion of CAP-1002 
• History and physical examination 
• Medication review 
• Adverse events assessment 
• 12 lead ECG 
• Laboratory examinations (including troponin I and CK-MB) 
• Troponin and CK-MB will be drawn 8, 16 and 24 hours post infusion 
• If Troponin is not down trending at 24 hours post infusion, the patient will remain in 
hospital until they reach down trending pattern. 
 
Pre Discharge an instruction sheet will be given to patient and reviewed with study 
coordinator 
 
24-48 hours after discharge, the patient will be contacted by the study coordinator to check 
on patient condition and r/o AE or SAE occurance. 
8.2.2 
2 Week Visit (Day 14 +/- 4 days) Procedures 
The following will be performed at the 2-week visit: 
• History and physical examination 
• Medication review 
• Adverse events assessment 
• 12 lead ECG 
• Laboratory examinations (hematology, chemistry, DSA, BNP) 
• Biomarkers 
• NYHA functional class assessment 
• 24 hour ECG 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
 
Outpatient visits will be completed as close to the scheduled visit dates as possible. The 
visit window is ± 4 clinic days from the intended date of the visit. 
 
8.2.3 
3 Month Visit (Day 90 +/- 14 days) Procedures 
The following will be performed at the 3-month visit: 
• History and physical examination 
• Medication review 
• Adverse events assessment 
• 12 lead ECG 
• Laboratory examinations (hematology, chemistry, DSA, BNP) 
• Biomarkers 
• NYHA functional class assessment 
 
8.2.4 
6 Month Visit (Day 180 +/- 14 days) Procedures 
The following will be performed at the 6-month visit: 
• History and physical examination 
• Medication review 
• Adverse events assessment 
• 12 lead ECG 
• 24 hour ECG 
• Echo 
• MRI 
• Laboratory examinations (hematology, chemistry, DSA, BNP) 
• Biomarkers 
• NYHA functional class assessment 
• 6MWT 
• Quality of Life assessment 
• Cath / ergometry 
 
8.2.5 
12 Month Visit (Day 360 +/- 30 days) Procedures 
The following will be performed at the 12-month visit: 
• History and physical examination 
• Medication review 
• Adverse events assessment 
• 12 lead ECG 
• Echo 
• Laboratory examinations (hematology, chemistry, DSA, BNP ) 
• Biomarkers 
• NYHA functional class assessment 
• 6MWT 
• Quality of Life assessment 
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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
Note: Outpatient visits will be completed as close to the scheduled visit dates as 
possible. The visit window is ± 30 clinic days from the intended date of the visit. 
 
8.3 Payments to Patients 
Patients will be reimbursed $50 for each of the 2-week, 3-month and 6 and 12-month visits. 
These disbursements are intended to cover the costs required to complete these study 
visits. Necessary travel expenses (reasonable hotel, meals and fuel) and parking 
expenses may be reimbursed. 
8.4 Early Termination Procedures 
Every reasonable effort will be made to retain patients in the study. In the event that a 
patient must be withdrawn from the study early, study personnel should attempt to obtain 
testing and data required for the 1-month primary safety end-point visit (See Section 
8.3.3) as well as the reason for withdrawal, if known. If the patient permits, he or she 
should be contacted by study personnel at the time of their usual study visits to obtain 
adverse event information. 
 
Follow-up of adverse events that result in discontinuing the patient from the study will 
continue until resolution, until the event has stabilized, or until the event has been 
determined to be caused by an agent other than the study drug. 
 
Patients who withdraw from the study due to pregnancy will be followed during the 
pregnancy and through birth of the newborn. 
 
A patient can be considered “lost to follow-up” if he or she misses a visit and study 
personnel are unable to contact him or her in a timely manner with a minimum of 
three documented phone calls. 
 
If contact with the patient is not accomplished, study personnel will follow-up with 
certified mail in the following manner: 
1. Mail a certified letter with return receipt requesting contact and expressing 
concern for the patient’s well-being. 
2. If the patient does not respond within seven days, mail another certified letter with 
return receipt stating that the patient’s participation in the study has been 
terminated. 
3. If a signed mailing receipt for the second letter is returned, record the termination 
date as the date the patient signed it. Otherwise, record the termination date as 
the date the second letter was mailed. 
 
Stopping Rules Statement: 
 
Stopping Rules that will result in temporary suspension of enrollment and dosing until 
the situation can be fully assessed and addressed will be defined by the independent 
DSMB. The DSMB may also request additional interim analyses and develop other 
criteria for determining when to intervene in the enrollment or treatment of patients in 
the study. Monitoring of primary safety endpoints will be conducted. All SAEs will be 
reported to the DSMB for review. 
 
 
 
 
 
 
 
 
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IND Submission: Revision #3 
Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
The DSMB will carefully evaluate the safety of all patients, including the following: 
 
 Death (all-cause mortality) 
 
 Hospitalization for worsening HFpEF: 
 
- 
Non-elective hospitalization for ≥ 24 hours 
 
- 
Signs and symptoms of LV failure to include one or more of: increased 
dyspnea, clinically significant deterioration in exercise capacity, syncope or pre-
syncope, 
 
- 
hypoxemia, edema, hepatomegaly, ascites 
 
9. QUALITY CONTROL AND ASSURANCE 
Data will be entered into the REDCap clinical database. A detailed description of the data 
collection tools and data management process can be found in the CRF completion 
guidelines and other data management materials. The study site must ensure appropriate 
source data documentation. The Investigator or designee must enter all required patient 
data in a timely fashion and an explanation must be documented for any missing data. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
10. 
PLANNED STATISTICAL METHODS 
Statistical analysis: An independent DSMB, with roles and responsibilities defined in a 
written charter, was be appointed to oversee safety of the study. The DSMB will consist 
of a three heart failure cardiologists, one with additional expertise in an interventional 
cardiology, one with additional expertise in imaging, one with additional expertise in 
transplant/immunology, and a statistician. The DSMB may also request additional interim 
analyses and develop other criteria for determining when to intervene in the enrollment 
or treatment of subjects in the study. Monitoring of all safety endpoints will be conducted. 
Individual cases reported to regulatory bodies will also be reported to the DSMB Chair 
and will be reviewed by the DSMB at each meeting. The DSMB will also have access to 
reports evaluating group trends relative to CAP-1002 vs. Control as well as relative to the 
literature for CAP-1002-treated subjects. In addition, any external concerns regarding 
CAP-1002 safety will be brought to the attention of the DSMB. 
The proportion of subjects experiencing an adverse event or a protocol-specific safety 
event (PSE) will be monitored at pre-planned intervals set by the DSMB. A futility chart 
will be created to allow for DSMB safety monitoring. The excess for CAP-treated subjects 
is of primary concern as Phase 2a data accrue. The boundaries will be computed using 
StatXact v7 (CyTel, Cambridge MA); a one-sided 95% exact test was performed 
assuming binomially distributed outcomes. The chart will be applied to any binary 
outcome pertaining to safety. The chart will be computed over a broad range of possible 
PSE outcomes. No adjustment for Type I error will be made for repeated looks since the 
ultimate decision regarding safety represents a clinical decision involving all safety 
endpoints in the context of efficacy. Descriptive summaries will be provided for all primary 
and secondary endpoints for both safety and efficacy. A prospective statistical analysis 
plan (SAP) will be generated with DSMB review and input. . All analyses will be performed 
using SAS Version 9.2 or greater. 
Efficacy data will be presented as mean changes from screening at designated visits. 
This Phase 2a data will be used to calculate effect sizes for planning subsequent Phase 
2b studies. If there are sufficient follow-up data, longitudinal models (SAS PROC MIXED 
for continuous endpoints and SAS PROC GENMOD for binary endpoints) will be 
explored.52-56 A formal SAP will be developed in a collaboration as described earlier. 
 
10.1 General Considerations 
Descriptive summaries will be provided for all primary and secondary end-points. All 
analyses will be performed using SAS Version 9.2 or greater. An independent DSMB 
will monitor the study and make recommendations, if needed, regarding stopping the 
study due to safety concerns. 
10.2 Analysis Populations 
Patients receiving CAP-1002/placebo infusion will be followed for 12 months. 
Patients will have study visits at 24-48 hours post discharge 2 weeks, 3, 6 & 12 
months following infusion. 
The analysis population for assessing safety objectives will consist of all patients who 
received an infusion of CAP-1002. For patients with missing follow-up data points, 
missing data will be imputed using predefined rules detailed in the SAP. 
  
 
 
 
 
 
  
 
 
 
 
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Allogeneic Cardiosphere-Derived Cells (CAP-1002) 
October 12, 2020 
 
 
 
 
 
10.3 Demographics and Baseline Characteristics 
Demographics and baseline characteristics of all accrued patients such as race, 
ethnicity, gender and age will be summarized and reported. The gender and minority 
distributions are expected to reflect the HFpEF population in the United States. There 
are no particular recruitment strategies for gender or minorities. We expect a high 
percentage of women in the HFpEF population. 
10.4 Interim Analysis 
The DSMB will be reviewing the data over the course of the study to assess the safety 
of CAP-1002 infusion.  All interim analysis are described above. 
 
11. ADMINISTRATIVE CONSIDERATIONS 
11.1 Investigators and Study Administrative Structure 
 
Information regarding the study will be posted at http:/www.clinicaltrials.gov in the 
listing for this study. Should a question arise during the study from the Investigator or 
study staff or should a SAE occur, the staff should contact the Regress-HFpEF 
DSMB using the contact information below: 
Theo Meyer 
meyert@ummhc.org 
(508) 856-2224 
 
The lead Principal Investigator is Michael R. Zile, MD, 
MUSC. MUSC will be responsible for enrolling subjects. 
A core imaging group (Dr. Litwin, MUSC) will be used to centrally read all 
echocardiography, CT, MRI studies and a core laboratory (UCLA Immunogenetics 
Center) will be used to analyze samples for HLA/donor specific antigens. A core 
hemodynamics lab (Dr. Fernandes, MUSC) will read all cath data. 
 
In order to ensure quality and continuance of patient care, the PI will inform patients 
primary cardiac care physician of his/her participation in HFpEF Study. 
11.2 Institutional Review Board (IRB) Approval 
 
It is the Investigators’ responsibility to ensure that, prior to initiating this study; this 
protocol is reviewed and approved by the appropriate local Institutional Review Board 
(IRB). The composition and conduct of this committee shall conform to the United 
States CFR and ICH E6. 
 
 
 
 
  
 
 
 
 
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October 12, 2020 
The IRB will also review and approve the site’s informed consent form (ICF), other 
written information provided to the patient and all advertisements that may be used 
for patient recruitment. 
 
If it is necessary to amend the protocol or the ICF during the study, the Investigator 
will be responsible for ensuring that the IRB reviews and approves these amended 
documents. An IRB approval of the amended protocol and/or ICF must be obtained 
in writing before implementation of the amended procedures and before new patients 
are consented to participate in the study using the amended version of the ICF. 
 
11.3 Ethical Conduct of the Study 
 
This study will be conducted in accordance with Good Clinical Practice (GCP) 
requirements described in the current revision of International Conference on 
Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) 
Guidelines and all applicable regulations, including current United States Code of 
Federal Regulations (CFR), Title 21, Parts 11, 50, 54, 56, and 312 and Title 45, Part 
164. Compliance with these regulations and guidelines also constitutes compliance 
with the ethical principles described in the current revision of the Declaration of 
Helsinki. This study will also be carried out in accordance with local legal 
requirements. 
 
11.4 Patient Information and Consent 
 
Before being admitted to the clinical study, all patients must consent in writing to 
participate. An ICF will be given to each patient, which will contain all United States 
federally required elements, all ICH-required elements, and Health Insurance 
Portability and Accountability Act (HIPAA) authorization information in language that 
is understandable to the patient. 
 
The process of obtaining the informed consent will be in compliance with all federal 
regulations, ICH requirements, and local laws. 
 
The Investigator will review the study with each patient. The review will include the 
nature, scope, procedures, and possible consequences of the patient's participation 
in the study. The ICF and review will be in a form understandable to the patient. The 
Investigator or designee and the patient must both sign and date the ICF after review 
and before the patient can participate in the study. The patient will receive a copy of 
the signed and dated form, and the original will be retained in the site study files. The 
 
Investigator or his/her designee will emphasize to the patient that study participation 
is entirely voluntary and that consent regarding study participation may be withdrawn 
at any time without penalty or loss of benefits to which the patient is otherwise 
entitled. 
 
 
 
 
 
 
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If the ICF is amended during the study, the Investigator must follow all applicable 
regulatory requirements pertaining to approval of the amended ICF by the IRB/IEC. 
The site must use the amended consent form for all new patients and repeat the 
consent process with the amended ICF for any ongoing patients. 
 
11.5 Patient Confidentiality 
 
Patients’ names will remain confidential and will not be included in the database. Only 
patient number, patient initials, and birth date will be recorded in the data system. If 
the patient name appears on any other document collected (e.g., hospital discharge 
summary), the name will be obliterated before the document is transmitted. All study 
findings will be stored in paper CRFs. The patients will give explicit permission for 
representatives of the Sponsor, regulatory authorities, and the IRB/IEC to inspect 
their medical records to verify the information collected. 
 
Patients will be informed that all personal information made available for inspection 
will be handled in the strictest confidence and in accordance with all state, local, and 
federal data protection/privacy laws, including, without limitation, the HIPAA. 
 
All participants in the study will provide written authorization to disclose private health 
information either as a part of the written ICF or as a separate authorization form. 
The authorization will contain all required elements specified by 45 CFR 164 and ICH 
E6 as applicable, and will contain a waiver of patient access to study-related private 
health information until the conclusion of the clinical study. The authorization will 
remain valid and in full force and effect until the first to occur of (1) the expiration of 
2 years after the study therapy is approved for the indication being studied, or (2) the 
expiration of 2 years after the research program is discontinued. Individual patient 
medical information obtained during this study is confidential and its disclosure to 
third parties (other than those mentioned in this section) is strictly prohibited. In 
addition, medical information obtained during this study may be provided to the 
patient's personal physician or to other appropriate medical personnel when required 
in connection with the patient's continued health and welfare. 
 
The study site will maintain a personal patient identification list (patient and 
treatment numbers with the corresponding patient names) to enable records to be 
identified. 
 
11.6 Study Monitoring 
The DSMB Chair will also serve as study monitor and will determine the frequency of 
monitoring visits primarily based on enrollment and compliance with protocol-dictated 
procedures, with visits generally occurring once every 12 months. The DSMB Chair 
will have continuous access to the electronic data capture system to review 
completion of study documents, and data and adverse event reporting in a timely 
manner. 
 
 
 
 
 
 
 
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11.7 CRFs and Study Records 
 
All CRFs will be completed in accordance with GCP guidelines and as soon as 
possible after each clinical trial visit. 
 
REDCap will be utilized to record all of the protocol-required information to be 
reported to the Sponsor on each trial subject. Study personnel will be trained in how 
to access and use the REDCap to enter and transmit data for the study. Study 
personnel will be trained regarding proper correction of data entries in the REDCap. 
 
Study personnel are responsible to ensure that all entries are accurate, legible and 
verifiable with the source data in the medical record. A source document is defined 
as the place in the medical record where a given data point first appears. REDCap 
will not serve as source documents. 
 
11.8 Protocol Violations/Deviations 
 
As they occur, deviations and violations will be documented and reported to the 
DSMB, Sponsor and MUSC IRB. Upon detection of a violation, the Sponsor will 
ensure reporting to the proper local and federal regulatory authorities in accordance 
with all applicable federal and local regulations. The Sponsor will determine the 
course of action based on the severity of the deviation or violation. These may include 
but are not limited to, withdrawal of the subject, additional training at the site, 
additional site monitoring, etc. In addition, the Site investigator and the Sponsor and 
statistician will review the circumstances of each violation (in a blinded fashion) to 
determine whether the data can reasonably be included in the patient data in the final 
study analysis. 
 
11.9 Access to Source Documentation 
 
The Investigator, Sponsor and site clinical study personnel will be able to access the 
source documentation. De-identified source documentation may be accessed by the 
Sponsor and the DSMB, e.g., in evaluation of an SAE. In addition, the study site must 
allow trial-related monitoring audits, IRB review, and regulatory inspection(s), with 
direct access to source data and documents. 
 
11.10 Data Generation and Analysis 
 
REDCap will be utilized to collect data and generate a database. Study site will be 
responsible for entering data collected at the site and external data sources (i.e., 
central lab and core imaging center) are expected to provide data sets to be entered 
into the database. 
 
 
 
 
 
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11.11 Retention of Data 
In accordance with 21 CFR 312.62, an Investigator participating in this study shall 
retain records, including the CRFs and supporting data including signed and dated 
consent forms, and medical records, progress notes of the physician, the individual's 
hospital chart(s), and the nurses' notes. Records are required to be maintained for a 
period of 2 years following the date the marketing application is approved or, if no 
application is to be filed or if the application is not approved by the FDA, until 2 years 
after the investigation is discontinued and FDA is notified. In any case, the Sponsor 
should be notified prior to the destruction of any study records. 
 
11.12 Financial Disclosure 
 
In accordance with FDA regulatory requirements, 21 CFR 54.4, study personnel who 
are required to complete a financial disclosure form will do so prior to participation in 
the study. Designated individuals shall provide sufficient and accurate financial 
information to allow the Sponsor to submit complete and accurate certification or 
disclosure statements (Forms 3454 and/or 3455) as required by the FDA regulations. 
Those individuals shall promptly update this information if any relevant changes occur 
in the course of the investigation or for 1 year following completion of the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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LIST OF APPENDICES 
Appendix 1: 
SCHEDULE OF STUDY ACTIVITIES/ASSESSMENTS 
 
 
Appendix 2: 
STUDY RECRUITMENT TIMELINE 
 
 
Appendix 3: 
PROHIBITED CONCOMITANT MEDICATIONS 
 
 
Appendix 4: 
INFORMED CONSENT TEMPLATE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
57 
 

 
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October 12, 2020 
 
 
Appendix 1: SCHEDULE OF STUDY ACTIVITIES/ASSESSMENTS 
 
Post Infusion 
Months 
Study Procedure 
Screening Pre D/C Post D/C 
Phone 
24-48 Hr 
0.5 
3 
6 - Pre 
D/C 
6 - Post 
D/C phone 
24-48 hr 
12 
Informed Consent 
x 
 
 
 
 
Medical History 
x 
x 
X 
x 
x 
X 
X 
x 
Physical Exam 
x 
x 
 
x 
x 
X 
 
x 
Medication Review 
x 
x 
 
x 
x 
X 
 
x 
AE Assessment 
x 
X 
x 
x 
X 
X 
x 
ECG 
x 
x 
 
x 
x 
X 
 
x 
Labs 
x 
x 
 
x 
x 
X 
 
x 
Biomarkers 
x 
x 
x 
X 
 
x 
HLA 
x 
 
 
 
 
DSA 
x 
x 
x 
X 
 
x 
Chest CT 
x 
 
 
 
 
Cath/Ergometry 
x 
 
X 
 
 
Cardiac MRI 
x 
 
X 
 
 
24-hour ECG 
x 
x 
 
X 
 
 
Troponin I & CK-MB 
x 
x* 
See 
8 2 1 1
 
 
 
 
 
Echocardiography 
x 
 
X 
 
x 
Six Minute Walk 
x 
 
X 
 
x 
QOL 
x 
 
X 
 
x 
NYHA Assessment 
x 
x 
x 
X 
 
x 
D/C Instructions 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 2: STUDY RECRUITMENT TIMELINE 
 
 
 
 
 
 
 
 
 
 
 
 
 
59 
 
Patient recruitment 
2 patients/month 
Total 40 patients 
6 months 
Endpoint 
12 months 
Endpoint 
Final 
Report 
20 
26 
32 
0 
12 
24 
36 
Time in Months 

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Appendix 3: PROHIBITED CONCOMITANT MEDICATIONS 
 
The following medications are prohibited for three months prior to enrollment in the 
study: 
 
GENERIC NAME 
TRADE NAME 
 
Abacavir 
Epzicom® 
Abacavir 
Ziagen® 
Abacavir sulfate, Lamivudine, and Zidovudine 
Trizivir® 
Adalimumab 
Humira® 
Aldesleukin 
Proleukin® 
Altretamine 
Hexalen® 
Aminoglutethimide 
Cytadren® 
Anakinra 
Kineret® 
Anastrozole 
Arimidex® 
Asparaginase 
Elspar® 
Atazanavir sulfate 
Reyatax® 
Basiliximab 
Simulect® 
Bleomycin 
Blenoxane® 
Busulfan 
Myleran® 
Capecitabine 
Xeloda® 
Carboplatin 
Paraplatin® 
Carmustine 
BiCNU® (BCNU) 
Certolizumab pegol 
Cimzia® 
Chlorambucil 
Leukeran® 
Cidofovir 
Vistide® 
Cisplatin 
Platinol® 
Cladribine 
Leustatin® 
Cyclosporine 
Gengraf® 
Cyclosporine 
Neoral® 
Cyclosporine 
Sandimmune® 
Cytarabine 
Cytarabine 
DepoCyt® 
Dacarbazine 
DTIC-Dome® 
Daclizumab 
Zenopax® 
Dactinomycin 
Cosmegan® 
Darunavir 
Prezista® 
Dasatinib 
Sprycel® 
Daunorubicin 
Cerubidine® 
Delavirdine 
Rescriptor® 
Denileukin diftitox 
Ontak® 
Didanosine 
Videx® 
Docetaxel 
Taxotere® 
Docetaxel 
Docefrez® 
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Doxorubicin 
Adriamycin® 
Doxorubicin 
Doxil® 
Efavirenz 
Sustiva® 
Efavirenz/emtricitabine/tenofovir disoproxil 
Atripla® 
Emtricitabine 
Emtriva® 
Emtricitabine/tenofovir disoproxil fumarate 
Truvada® 
Enfuvirtide 
Fuzeion® 
Epirubicin 
Ellence® 
Erlotinib 
Tarceva® 
Estramustine 
Emcyt® 
Etanercept 
Enbrel® 
Etoposide 
Etopophos® 
Etoposide 
VePesid® 
Etravirine 
Intelence® 
Everolimus 
Afinitor® 
Everolimus 
Zortress® 
Exemestane 
Aromasin® 
Floxuridine 
Fluorodeoxyuridine® 
Floxuridine 
Ancobon® 
Fludarabine 
Oforta® 
Fludarabine 
Fludara® 
Fosamprenavir calcium 
Lexiva® 
Gemcitabine 
Gemzar 
Golimumab injection 
Simponi 
Hydroxyurea 
Droxia® 
Hydroxyurea 
Hydrea® 
Idarubicin 
Idamycin® 
Ifosphamide 
Ifex® 
Imatinib mesylate 
Gleevac 
Indinavir 
Crixivan® 
Infliximab 
Remicade® 
Interferon alfa-2a 
Roferon-A® 
Interferon alfa-2b 
Intron-A® 
Interferon alfacon-1) 
Inferge ® 
Interferon beta-1a 
Avonex® 
Interferon beta-1b 
Betaseron® 
Interferon beta-1b 
Extavia® 
Interferon beta-lb 
Betaseron® 
Interferon gamma-1b 
Actimmune® 
Interleukin-2 
Proleukin 
Irinotecan 
Camptosar 
Lamivudine 
Epivir® 
Lamivudine & Zidovudine 
Combivir® 
Lanreotide 
Somatuline® Depot 
Lapatinib 
Tykerb® 
 
 
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Leflunomide 
Arava® 
Lenalidomide 
Revlimid 
Letrozole 
Femara® 
Leuprolide 
Lupron® 
Leuprolide 
Eligard® 
Lomustine 
CeeNu® (CCNU) 
Maraviroc 
Selzentry® 
Mechlorethamine HCI 
Mustargen® 
Megestrol 
Megace® 
Melphalan 
Alkeran® 
Mercaptopurine 
Purinethol® 
Methotrexate 
Rheumatrex® 
Methotrexate 
Trexall™ 
Mitomycin 
Mutamycin® 
Mitotane 
Lysodren® 
Mitoxantrone 
Novantrone® 
Muromonab-CD3 
Orthoclone-OKT3 
Nelfinavir 
Viracept® 
Nevirapine 
Viramune® 
Nilotinib 
Tasigna® 
Octreotide acetate 
Sandostatin® 
Paclitaxel 
Taxol® 
Paclitaxel 
Abraxane® 
Pazopanib 
Votrient® 
Pegaspargase 
Oncaspar® 
Peginterferon alfa-2a 
Pegasys® 
Peginterferon alfa-2b 
Peg-Intron® 
Penicillamine 
Cuprimine® 
Procarbazine 
Matulane® 
Raltegravir 
Isentress® 
Ribavirin 
Copegus® 
Rilonacep 
Arcalyst™ 
Ritonavir 
Norvir® 
Ritonavir/Lopinovir 
Kaletra® 
Rituximab 
Rituxan® 
Saquinavir 
Invirase® 
Sargramostim 
Leukine® 
Sirolimus 
Rapamune® 
Sorafenib 
Nexavar® 
Stavudine 
Zerit® 
Streptozocin 
Zanosar® 
Sulfasalazine 
Azulfidine EN-tabs® 
Sunitinib malate 
Sutent® 
Tacrolimus 
Prograf® 
Tamoxifen citrate                              
                                                  62 
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Temozolomide 
Temodar® 
Temsirolimus injection 
Torisel® 
Teniposide 
Vumon® 
Tenofovir disoproxil fumarate 
Viread® 
Thalidomide 
Thalomid® 
Thioguanine 
Tabloid® 
Thiotepa 
Tipranavir 
Aptivus® 
Tocilizumab 
Actemra® 
Topotecan 
Hycamtin® 
Toremifene citrate 
Fareston® 
Trastuzumab 
Herceptin® 
Tretinoin 
Vesanoid® 
Tretinoin 
Vesanoid® 
Triamcinolone 
Kenalog® 
Triamcinolone 
Aristospan® 
Valrubicin 
Valstar® 
Vinblastine 
Vincristine 
Vinorelbine 
Navelbine® 
Vorinostat 
Zolinza® 
Zalcitabine 
Hivid® 
Zidovudine 
Retrovir® 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Appendix 4: Approved INFORMED CONSENT 4-24-17 Version 
Please see attached 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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October 12, 2020 
 
 
 
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