Clinical trial NCT01458405
Conditions: Myocardial Infarction
Keywords: Myocardial Infarction Heart Attack Stem cell Left ventricular dysfunction Congestive heart failure
Sponsor: Capricor Inc.
Start date: 2012-11-13; Completion date: 2019-02-28
Enrollment: 135 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to determine whether Allogeneic Cardiosphere-Derived Cells (CAP-1002) is safe and effective in decreasing infarct size in patients with a myocardial infarction.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: CAP-1002 Allogeneic Cardiosphere-Derived Cells intervention 2: Placebo
Intervention descriptions: intervention 1: Single dose, blinded, intracoronary infusion of 25 Million cardiosphere-derived cells intervention 2: Single, blinded, intracoronary infusion of a placebo solution

Protocol documents:
Prot_000.pdf: 
 
 
 
Clinical Trial Protocol: 1002-01 
 
Study Title: 
Randomized, Double-Blind, Placebo-Controlled Phase I/II Study of the 
Safety and Efficacy of Intracoronary Delivery of Allogeneic 
Cardiosphere-Derived Cells in Patients with a Myocardial Infarction and 
Ischemic Left Ventricular Dysfunction (ALLogeneic Heart STem Cells to 
Achieve Myocardial Regeneration, ALLSTAR) 
Study Number: 
1002-01 
Study Phase: 
Phase I/II 
Product Name: 
CAP-1002 Allogeneic Cardiosphere-Derived Cells 
IND Number: 
15118 
Indication: 
Treatment and/or prevention of left ventricular dysfunction following 
myocardial infarction 
Lead 
 
Investigators: 
 
 
Sponsor: 
Capricor, Inc. 
Medical Monitor: 
 
 
 
 
Original Protocol: 
15 May 2012 
Amendment 1: 
14 June 2012 
Amendment 2: 
26 June 2012 
Amendment 3: 
30 January 2013 
Amendment 4: 
13 June 2013 
Amendment 5: 
25 October 2013 
Amendment 6: 
01 December 2014 
Amendment 7: 
15 May 2015 
Amendment 7.1: 
05 June 2015 
Amendment 8: 
15 January 2016 
Amendment 8.1:        22 February 2017 
 
Confidentiality Statement 
This document is confidential and proprietary to Capricor, Inc. and its 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of this document constitutes agreement by the recipient that no unpublished information 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 or 
used without the prior written approval of Capricor, Inc. and its 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. 


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Table of Contents 
 
LIST OF IN-TEXT TABLES ....................................................................................................................... 5 
LIST OF IN-TEXT FIGURES ...................................................................................................................... 5 
SYNOPSIS .................................................................................................................................................... 6 
List of Abbreviations and Definitions of Terms ......................................................................................... 16 
1 
INTRODUCTION .............................................................................................................................. 20 
1.1 
Summary of Preclinical Data ...................................................................................................... 20 
1.2 
Summary of Clinical Data ........................................................................................................... 21 
1.2.1 
Other Cell Therapies ........................................................................................................... 21 
1.2.2 
CADUCEUS ....................................................................................................................... 22 
1.3 
ALLSTAR................................................................................................................................... 23 
1.3.1 
Information on CAP -1002 ................................................................................................. 23 
1.3.2 
Justification for Dose .......................................................................................................... 24 
1.3.3 
Risks to Human Subjects .................................................................................................... 24 
1.4 
DYNAMIC ................................................................................................................................. 25 
2 
STUDY OBJECTIVES ....................................................................................................................... 26 
2.1 
Primary Safety Objective ............................................................................................................ 26 
2.2 
Primary Efficacy Objective ......................................................................................................... 26 
2.3 
Secondary Objectives .................................................................................................................. 26 
2.4 
Safety Assessments ..................................................................................................................... 26 
2.4.1 
Efficacy Assessments .......................................................................................................... 28 
2.5 
Exploratory Assessments ............................................................................................................ 29 
2.5.1 
Presence of DSAs (mismatched) against all donors............................................................ 29 
3 
INVESTIGATIONAL PLAN ............................................................................................................. 29 
3.1 
Overall Study Design and Plan ................................................................................................... 29 
3.2 
Rationale for Study Design and Control Group .......................................................................... 31 
3.3 
Study Duration and Dates ........................................................................................................... 31 
4 
STUDY POPULATION SELECTION .............................................................................................. 32 
4.1 
Study Population ......................................................................................................................... 32 
4.2 
Inclusion Criteria ........................................................................................................................ 32 
4.3 
Exclusion Criteria ....................................................................................................................... 33 
5 
STUDY TREATMENT(S) ................................................................................................................. 35 
5.1 
Description of Treatment(s) ........................................................................................................ 35 
5.1.1 
Study Drug .......................................................................................................................... 35 


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5.1.2 
Placebo ................................................................................................................................ 35 
5.1.3 
Wash Solution ..................................................................................................................... 35 
5.2 
Method of Assigning Subjects to Treatment Groups .................................................................. 35 
5.3 
Blinding ....................................................................................................................................... 36 
5.4 
Concomitant Therapy .................................................................................................................. 37 
5.5 
Restrictions ................................................................................................................................. 37 
5.5.1 
Prior Therapy ...................................................................................................................... 37 
5.5.2 
Fluid and Food Intake ......................................................................................................... 38 
5.5.3 
Subject Activity Restrictions .............................................................................................. 38 
5.6 
Treatment Compliance ................................................................................................................ 38 
5.7 
Packaging and Labeling .............................................................................................................. 38 
5.8 
Storage and Accountability ......................................................................................................... 38 
5.9 
Investigational Product Retention at Study Site .......................................................................... 39 
5.10 
Investigational Product Accountability and Reconciliation ........................................................ 39 
6 
STUDY PROCEDURES .................................................................................................................... 39 
6.1 
Informed Consent ........................................................................................................................ 39 
6.2 
Medical History........................................................................................................................... 40 
6.3 
Physical Examinations ................................................................................................................ 40 
6.4 
Vital Signs ................................................................................................................................... 40 
6.5 
Clinical Laboratory Tests ............................................................................................................ 40 
6.5.1 
Laboratory Parameters ........................................................................................................ 40 
6.5.2 
Sample Collection, Storage, and Shipping .......................................................................... 42 
6.6 
12-Lead ECG .............................................................................................................................. 42 
6.7 
Echocardiography ....................................................................................................................... 42 
6.8 
24 Hour Ambulatory ECG Monitor ............................................................................................ 43 
6.9 
Magnetic Resonance Imaging Protocol ....................................................................................... 43 
6.9.1 
Cine Imaging Protocol ........................................................................................................ 43 
6.9.2 
Delayed Contrast-Enhancement Protocol ........................................................................... 43 
6.9.3 
Image Analysis .................................................................................................................... 43 
6.10 
Chest, Abdomen and Pelvis CT .................................................................................................. 43 
6.11 
Clinical Function and Quality of Life Measures ......................................................................... 44 
7 
STUDY ACTIVITIES ........................................................................................................................ 44 
7.1 
Screening Period ......................................................................................................................... 45 
7.2 
Treatment Period ......................................................................................................................... 46 
7.2.1 
Intracoronary Infusion Visit (Day 0)................................................................................... 46 
7.2.2 
Intracoronary Infusion Procedure ....................................................................................... 48 
7.3 
Follow-Up Period ........................................................................................................................ 51 


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7.3.1 
Week 2 Visit (Day 14 ± 3 days) Procedures ....................................................................... 51 
7.3.2 
Month 1 Visit (Day 30 ± 3 days) Procedures ...................................................................... 51 
7.3.3 
Month 2 Visit (Day 60 ± 6 days) Procedures (Phase I Safety Cohort Only) ...................... 52 
7.3.4 
Month 3 Visit (Day 90 ± 6 days) Procedures ...................................................................... 52 
7.3.5 
Month 6 Visit (Day 180 ± 6 days) Procedures .................................................................... 52 
7.3.6 
Month 12 Visit (Day 360 ± 6 days) Procedures .................................................................. 53 
7.3.7 
Annual Follow-up Phone Call ............................................................................................. 54 
7.4 
Performing Adverse Events Assessments ................................................................................... 54 
7.4.1 
Timing ................................................................................................................................. 55 
7.4.2 
Severity ............................................................................................................................... 55 
7.4.3 
Relationship ........................................................................................................................ 55 
7.4.4 
Expectedness ....................................................................................................................... 56 
7.4.5 
Clinical Significance ........................................................................................................... 57 
7.4.6 
Clinical Laboratory Adverse Events ................................................................................... 57 
7.4.7 
Serious Adverse Events ...................................................................................................... 58 
7.4.8 
Post-Study Adverse Events and Serious Adverse Events ................................................... 61 
7.5 
Removal of Subjects from the Trial or Study Drug .................................................................... 61 
7.6 
Other Study Procedures............................................................................................................... 62 
7.7 
Appropriateness of Measurements .............................................................................................. 62 
7.8 
Payment to Subjects .................................................................................................................... 62 
7.9 
Early Termination Procedures ..................................................................................................... 63 
8 
QUALITY CONTROL AND ASSURANCE ..................................................................................... 63 
9 
PLANNED STATISTICAL METHODS ............................................................................................ 64 
9.1 
General Considerations ............................................................................................................... 64 
9.2 
Determination of Sample Size .................................................................................................... 64 
Table 4. Sample Size Assumptions ............................................................................................................. 65 
9.3 
Analysis Populations ................................................................................................................... 65 
9.4 
Demographics and Baseline Characteristics ............................................................................... 66 
9.5 
Primary Endpoint(s) .................................................................................................................... 66 
9.5.1 
Primary Safety Endpoint(s) ................................................................................................. 66 
9.5.2 
Primary Efficacy ................................................................................................................. 67 
9.6 
Secondary Endpoint(s) .................................................................................................................... 68 
9.6.1 
Secondary Safety Endpoint(s) ............................................................................................. 68 
9.6.2 
Secondary Efficacy ............................................................................................................. 69 
9.7 
Administrative Interim Analysis ................................................................................................. 70 
9.8 
Study Stopping Guidelines .......................................................................................................... 71 
9.8.1 
Safety Cohort (Phase I) ....................................................................................................... 71 


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9.8.2 
Randomized Cohort (Phase II) ............................................................................................ 71 
9.8.3 
Exploratory Randomized Cohort (Phase II) ........................................................................ 71 
10  ADMINISTRATIVE CONSIDERATIONS ......................................................................................... 72 
10.1 
Investigators and Study Administrative Structure....................................................................... 72 
10.2 
Institutional Review Board (IRB) or Independent Ethics Committee (IEC) Approval .............. 73 
10.3 
Ethical Conduct of the Study ...................................................................................................... 73 
10.4 
Subject Information and Consent ................................................................................................ 73 
10.5 
Subject Confidentiality ............................................................................................................... 74 
10.6 
Study Monitoring ........................................................................................................................ 74 
10.7 
Case Report Forms and Study Records ....................................................................................... 75 
10.8 
Data Monitoring Committee ....................................................................................................... 75 
10.9 
Protocol Violations/Deviations ................................................................................................... 76 
10.10 Access to Source Documentation.................................................................................................. 76 
10.11 Data Generation and Analysis ....................................................................................................... 76 
10.12 Retention of Data .......................................................................................................................... 77 
10.13 Financial Disclosure ...................................................................................................................... 77 
10.14 Publication, Use and Disclosure Policy ........................................................................................ 77 
11  REFERENCE LIST .............................................................................................................................. 78 
Appendix 1 
 Schedule of Events8 ............................................................................................................ 82 
Appendix 2 
 Prohibited Concomitant Medications ................................................................................. 84 
Appendix 3 
 CDC Futility Boundaries .................................................................................................... 89 
Appendix 4 
 Sponsor Signature ............................................................................................................. 92 
Appendix 5 
 Investigator’s Signature ..................................................................................................... 93 
 
 
LIST OF IN-TEXT TABLES 
 
Table 1. List of Laboratory Tests ................................................................................................................ 41 
Table 2. Infusion Scenarios for Nitroglycerin and Heparin Doses .............................................................. 51 
Table 3. Serious Adverse Event Reporting Requirements .......................................................................... 61 
Table 4. Sample Size Assumptions ............................................................................................................. 65 
 
LIST OF IN-TEXT FIGURES 
 
Figure 1. Schematic of Infusion Protocol .................................................................................................... 50 
 
 
 


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Amendment 8.1 
SYNOPSIS 
 
Sponsor: Capricor, Inc.  
Name of Finished Product:  
CAP-1002 Allogeneic Cardiosphere-Derived Cells 
Name of Active Ingredient:  
Allogeneic Cardiosphere-derived stem cells 
Study Title:  
Randomized, Double-Blind, Placebo-Controlled Phase I/II Study of the Safety and Efficacy of 
Intracoronary Delivery of Allogeneic Cardiosphere-Derived Cells in Patients with a Myocardial 
Infarction and Ischemic Left Ventricular Dysfunction (ALLogeneic Heart STem Cells to 
Achieve Myocardial Regeneration, ALLSTAR)  
Study Number: 1002-01 
Study Phase: Phase I/II 
Primary Safety Objective:  
The primary safety objective is to determine the safety profile of CAP-1002 administered by 
intracoronary infusion in subjects with ischemic left ventricular dysfunction and a previous 
myocardial infarction (MI); specifically, to test the null hypothesis that the incidence rate of the 
primary safety endpoint (composite of peri-procedural clinical events) differs by no more than 
0.20 between treatment groups.  
Primary Efficacy Objective:  
The primary efficacy objective is to evaluate whether administration of CAP-1002 by 
intracoronary infusion may result in structural cardiac benefits for subjects with ischemic left 
ventricular dysfunction and a previous MI as measured by infarct size expressed as a percent of 
left ventricular mass 12 months after infusion; specifically, to test the hypothesis that CAP-1002 
is superior to placebo in reducing infarct size, expressed as a percent of left ventricular mass, 12 
months after infusion, either in all subjects combined or in subjects with recent MI (≤ 90 days 
before infusion).  
Secondary Objectives:  
The secondary safety objective is to compare the safety profiles of CAP-1002 and placebo over 
12 months based on pre-specified clinical events and development of increased HLA antibody 
levels.  
 
The secondary efficacy objective is to evaluate whether administration of CAP-1002 by 
intracoronary infusion may result in other left ventricular structural or functional cardiac benefits 
for subjects with ischemic left ventricular dysfunction and a previous MI.  Also evaluations will 
investigate whether administration of CAP-1002 may result in clinical or biomarker benefits for 
subjects with ischemic left ventricular dysfunction and a previous MI.  
Study Design:  


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Amendment 8.1 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
In Phase 2, the Primary Randomized Cohort will enroll up to approximately 103 subjects with a 
previous myocardial infarction (MI) and resultant ischemic left ventricular dysfunction meeting 
all inclusion and no exclusion criteria. The Primary Randomized Cohort will include the Recent 
and Chronic MI strata (n= approximately 51-52 per stratum). These 103 subjects will be 
randomized in a double-blind fashion to receive either CAP-1002 or placebo (collectively 
referred to as Investigational Product [IP]) in a 2:1 ratio favoring CAP-1002 to achieve up to 93 
subjects with complete 12 month data (assumes 10% non-completion rate and 103 subjects 
randomized).  After completion of the screening procedures and meeting all inclusion and 
exclusion criteria, study subjects will be randomized to receive CAP-1002 or placebo 
administered via intracoronary infusion.  All  subjects  in the Primary Randomized Cohort will 
be followed at week 2 and at months 1, 3, 6 and 12 after planned CAP-1002 or placebo infusion. 
Efficacy will be assessed at all specified post-infusion visits, with the 12 month visit being the 
primary efficacy endpoint. An administrative interim analysis of the final 6 month data will be 
performed when all subjects in the Primary Randomized Cohort have completed the 6 month 
visit to assist in planning Phase III studies. 
 
The double-blind, placebo-controlled design of the Primary Randomized Cohort will maximize 


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Amendment 8.1 
the study’s ability to assess both safety and efficacy, as both may be subject to bias from the 
perspective of Investigators and subjects. 
 
The Exploratory Randomized Cohort will enroll up to 17 subjects in addition to the Primary 
Randomization Cohort.  Exploratory Randomized Cohort subjects are those subjects who are 
mismatched against all available donors. The Exploratory Randomized Cohort will also include 
Recent and Chronic subjects (up to n=8-9 per stratum). The Exploratory Randomized Cohort will 
be randomized in a double-blind fashion as described in the Primary Randomized Cohort.  The 
Exploratory Randomized Cohort will undergo the same tests as all other subjects based on the 
schedule of events. This group will be analyzed separately from the Primary Randomized Cohort 
using descriptive analyses to assess the prevalence and impact on safety and efficacy, if any.  
 
The Primary Randomized Cohort will consist of up to approximately 103 subjects who can be 
matched to receive IP from one or more donor.  A match is achieved when a subject is found at 
screening to have no antibodies against a donor’s HLA antigens (i.e. no donor specific antibodies 
[DSAs]). Subjects that are mismatched to all available donors will be enrolled into a Phase II 
Exploratory Randomized Cohort to gather information on potential differences in safety/efficacy. 
A mismatch situation occurs when a subject is found at screening to have DSAs against all 
available donors. Up to 17 subjects will be enrolled into the Phase II Exploratory Randomized 
Cohort.  
 
These Exploratory Randomized Cohort subjects will be randomized independently from the 
Primary Randomized Cohort.  The Exploratory Randomized Cohort is designed to assess the 
potential effect of donor mismatching, if any, on the primary safety and efficacy endpoints. 
Using a distinct arm in the study design allows for the inclusion of all subjects meeting eligibility 
criteria, but preserves the design integrity of the Phase II Randomized Cohort. 
Study Population:  
When fully enrolled, the ALLSTAR study will include a total of up to approximately 134 
subjects with ischemic left ventricular dysfunction and a previous MI. Of these, up to 
approximately 83 will be treated (infused) with CAP-1002 (n=14 Safety Cohort, n=69 Primary 
Randomized Cohort) and up to approximately 34 will receive placebo (Primary Randomized 
Cohort only).  Up to 17 subjects may be enrolled into the Phase II Exploratory Randomized 
Cohort. However, since this group is exploratory in nature, enrollment of the Primary 
Randomized Cohort will define the end of the study; that is, once the Primary Randomized 
Cohort is fully enrolled, the study will be considered closed for further subject enrollment.  
Test Product, Dose, and Mode of Administration:  
 
 
 
 
 
 
 
 


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Amendment 8.1 
 
 
  
Inclusion Criteria: 
1. History of MI (STEMI or NSTEMI) within the prior 12 months due to a coronary artery 
event and evidenced by at least two of the following: typical ischemic symptoms, serial ST-T 
changes (new ST elevation or new left bundle block) and/or elevated troponin or CK-MB >5 
times the upper limit of normal. Also at least one of the following: development of 
pathological Q wave ECG changes, imaging evidence of new loss of viable myocardium, or 
new regional wall motion abnormalities. 
 The following assessments will be permitted within 28 days immediately 
following the subject’s MI: signing ICF, review of medical history, review of 
concomitant medications, and collection of laboratory samples required for 
assessment of study eligibility criteria (e.g., eGFR, HbA1c, hepatitis serology, 
HIV serology, LFTs, hematocrit, WBC, and platelet count). All other screening 
tests, including the subject’s cardiac MRI and CT (chest, abdomen, pelvis), 
must be conducted greater than 28 days post-MI. Infusion must occur within 28 
days of the first screening procedure that is performed greater than 28 days 
post-MI. Relevant safety laboratory sample collections (e.g., chemistry, 
hematology, urinalysis) may need to be repeated as they must be obtained 
within 28 days of the subject’s infusion. 
2. History of percutaneous coronary intervention (PCI), with stent placement resulting in TIMI 
flow = 3, in the coronary artery supplying the infarcted, dysfunctional territory and through 
which the treatment will be infused. 
3. At least one assessment of left ventricular ejection function (LVEF) ≤0.45 as determined by 
any one of the standard modalities (echocardiography, ventriculogram, nuclear imaging, CT 
and/or MRI) prior to or during the screening period.   
 For subjects that fulfill the criteria of Recent MI (i.e., within 90 days of MI) at 
time of screening visit:  assessment must be post-reperfusion after index MI and 
be the most recent test prior to or during the screening period.   
 For subjects that fulfill the criteria of Chronic MI (i.e., greater than 90 days 
from MI) at time of screening visit:  assessment must be at least 21 days post-
reperfusion after index MI and the most recent test prior to or during the 
screening period.  
Note: subjects may screen as a Recent MI but be randomized into the Chronic 
MI strata if the infusion date is > 90 days post-MI. 
4. Left ventricular infarct size of ≥ 15% of left ventricular mass in the qualifying infarct-related 
region to be infused as determined by centrally read screening MRI, with associated thinning 
and/or hypokinesis, akinesis, or dyskinesis, with no large aneurysmal area in the infarcted 
regions.  
5. No further revascularization clinically indicated at the time the subject is assessed for 
participation in the clinical trial. 
6. Ability to provide informed consent and follow-up with protocol procedures. 
7. Age ≥18 years. 


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Exclusion Criteria: 
1. Subjects with a history of coronary artery bypass surgery, and a patent graft (arterial or 
saphenous vein graft) attached to the coronary artery to be infused. 
2. Diagnosed or suspected myocarditis. 
3. History of cardiac tumor, or cardiac tumor demonstrated on screening MRI. 
4. History of acute coronary syndrome in the 4 weeks prior to study infusion. 
5. History of previous stem cell therapy. 
6. History of radiation treatment to the central or left side of thorax. 
7. Current or history (within the previous 5 years) of systematic auto-immune or connective 
tissue disease including, but not limited to, giant cell myocarditis, cardiac or systemic 
sarcoidosis, Dressler’s syndrome, chronic, recurrent or persistent pericarditis. 
8. History of or current treatment with immunosuppressive, anti-inflammatory, or other agents 
to treat manifestations of systemic immunologic reactions, including chronic systemic 
corticosteroids, biologic agents targeting the immune system, anti-tumor and anti-neoplastic 
drugs, anti-VEGF, or chemotherapeutic agents within 3 months prior to enrollment. 
9. Prior ICD and/or pacemaker placement where study imaging site has not been trained and 
certified specifically for this protocol to conduct cardiac MRI in subjects with ICD and/or 
pacemaker placement. 
a. Presence of a pacemaker and/or ICD generator with any of the following 
limitations/conditions are excluded: 
i. Manufactured before the year 2000, 
ii. Leads implanted < 6 weeks prior to signing informed consent, 
iii. Non-transvenous epicardial, abandoned, or no-fixation leads, 
iv. Subcutaneous ICDs, 
v. Leadless pacemakers, 
vi. Any other condition that, in the judgement of device-trained staff, would 
deem an MRI contraindicated. 
b. Pacemaker dependence with an ICD (Note: pacemaker-dependent candidates 
without an ICD are not excluded). 
c. A cardiac resynchronization therapy (CRT) device implanted < 3 months prior to 
signing informed consent. 
10. Estimated glomerular filtration rate < 30 mL/min. 
11. Participation in an ongoing protocol studying an experimental drug or device, or participation 
in an interventional clinical trial within the last 30 days. 
12. Diagnosis of arrhythmogenic right ventricular cardiomyopathy. 
13. Current alcohol or drug abuse. 
14. Pregnant/nursing women and women of child-bearing potential that do not agree to use at 
least two forms of active and highly reliable method(s) of contraception. Acceptable methods 
of contraception include contraceptive pills, depo-progesterone injections, a barrier 
contraceptive such as a condom with or without spermicide cream or gel, diaphragms or 
cervical cap with or without spermicide or gel, or an intrauterine device (IUD).   
15. Human Immunodeficiency Virus (HIV) infection. 
16. Viral hepatitis. 
17. Uncontrolled diabetes (HbA1c >9%). 
18. Abnormal liver function (SGPT/ALT > 3 times the upper reference range) and/or abnormal 
hematology (hematocrit < 25%, WBC < 3000 µl, platelets < 100,000 µl) studies without a 
reversible, identifiable cause. 


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19. Sustained ventricular tachycardia (VT) or non-sustained ventricular tachycardia > 30 beats, 
not associated with the acute phase of a previous MI (> 48 hours after the MI onset) or a new 
acute ischemic episode. 
20. Ventricular fibrillation not associated with a new acute ischemic episode. 
21. New York Heart Association (NYHA) Class IV congestive heart failure. 
22. Evidence of tumor on screening chest/abdominal/pelvic (body) CT scan. 
23. Any prior transplant. 
24. Known hypersensitivity to dimethyl sulfoxide (DMSO). 
25. Known hypersensitivity to bovine products. 
26. Any malignancy within 5 years (except for in-situ non-melanoma skin cancer and in-situ 
cervical cancer) of signing the ICF. 
27. Any condition or other reason that, in the opinion of the Investigator or Medical Monitor, 
would render the subject unsuitable for the study. 
Duration of Treatment:  
Treated subjects (those who have received intracoronary infusion of CAP–1002 or placebo) will 
be followed for a total of 12 months. Subjects who agree to participate in the annual follow-up 
will then be contacted annually through five years post-treatment (post-infusion).  
Safety Assessments:  
The primary safety endpoint is the one-month post intracoronary infusion proportion of subjects 
experiencing any of the following adjudicated events: 
1. Acute myocarditis possibly attributable to CAP-1002 or placebo, diagnosed with 
consideration of clinical context, with or without a clinically indicated endomyocardial 
biopsy. In order to be considered related to CAP-1002 or placebo, humoral or cellular 
immune reaction specific to CAP-1002 must also be documented for subjects treated with 
CAP-1002, or a temporal relationship with IP administration must exist for subjects 
administered with placebo.  
2. Death due to 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. 
3. Sudden unexpected death defined as occurring within one hour of symptom onset, or un- 
witnessed death in a person previously observed to be well within the preceding 24 hours 
without an identified cause. 
4. Major adverse cardiac event (MACE), defined as the composite incidence of death, non- fatal 
recurrent MI, hospitalization for heart failure, emergency room treatment for heart failure 
(NT-proBNP >450 pg/mL or BNP>100 pg/ml, with treatment including intravenous diuretic 
administration), left ventricular assist device (LVAD) placement or heart transplant. Peri-
infusion MI will be defined as presence of troponin or CK-MB levels > 5 times the upper 
reference limit during the 24 hours following infusion. These elevations must be 
accompanied by symptoms of ischemia > 20 minutes in duration and ECG changes indicative 
of new ischemia (new ST-T changes or new left bundle branch block), development of 
pathological Q waves on the ECG, imaging evidence of new loss of viable myocardium, or 
new regional wall motion abnormality. 
 
Separate strata will be evaluated for subjects with a Recent MI and with a Chronic MI. The 


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following adjudicated events will be evaluated as secondary safety endpoints during the twelve-
month follow- up period: 
 
1. Acute myocarditis possibly attributable to CAP-1002 or placebo, diagnosed with 
consideration of clinical context, with or without a clinically indicated endomyocardial 
biopsy. In order to be considered related to CAP-1002 or placebo, humoral or cellular 
immune reaction specific to CAP-1002 must also be documented for subjects treated with 
CAP-1002, or a temporal relationship with IP administration must exist for subjects 
administered placebo. 
2. Death due to ventricular tachycardia or ventricular fibrillation defined as occurring with prior 
ECG documentation of these arrhythmias during ambulatory ECG monitoring in an 
outpatient setting or during routine ECG monitoring while hospitalized. 
3. Sudden unexpected death defined as occurring within one hour of symptom onset, or un-
witnessed death in a person previously observed to be well within the preceding 24 hours 
without an identified cause. 
4. Major adverse cardiac event (MACE), defined as the composite incidence of death, non- fatal 
recurrent MI, hospitalization for heart failure, emergency room treatment for heart failure 
(NT-proBNP >450 pg/mL or BNP>100 pg/ml, with treatment including intravenous diuretic 
administration), left ventricular assist device (LVAD) placement or heart transplant. Peri-
infusion MI will be defined as presence of troponin or CK-MB levels > 5 times the upper 
reference limit during the 24 hours following infusion. These elevations must be 
accompanied by symptoms of ischemia > 20 minutes in duration and ECG changes indicative 
of new ischemia (new ST-T changes or new left bundle branch block), development of 
pathological Q waves on the ECG, imaging evidence of new loss of viable myocardium, or 
new regional wall motion abnormality. 
5. New cardiac tumor formation on MRI imaging. 
6. Any hospitalization due to a cardiovascular cause or related to CAP-1002 or placebo 
infusion. 
7. Any inter-current cardiovascular illness or one related to CAP-1002 or placebo infusion, 
which prolongs hospitalization. Evidence of myocardial injury will be assessed by a rule out 
MI cardiac enzyme protocol performed following administration of CAP-1002 or placebo. 
Troponin and CK-MB will be obtained approximately every 8 hours for the first 24 hours 
after infusion. 
8. New TIMI flow ≤1, following intracoronary infusion of CAP-1002 or placebo. 
9. Development of, or an increase in the frequency of, ventricular tachycardia with a duration of 
30 beats or longer ascertained by periodic, protocol-mandated 24 hour ambulatory ECG 
monitoring. 
10. Development of increased anti-HLA antibody levels with development of sensitization to 
HLA antigens specific to the CAP-1002 CDC donor. 
Efficacy Assessments:  
The primary efficacy endpoint is the percent change from baseline in MRI assessment of infarct 
size as a percent of left ventricular mass 12 months after administration of treatment (either 
CAP-1002 or placebo).  
The following will be evaluated as secondary efficacy endpoints during the six-month and 
twelve-month follow-up periods:  


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Global LV Function measures 
1. Percent change and change from baseline in MRI assessment of LVEF  
2. Percent change and change from baseline in MRI assessment of left ventricular 
end-diastolic and end-systolic volumes indexed to BSA  
Structural measures 
3. Change from baseline in MRI assessment of infarct size as a percent of left ventricular 
mass 
4. Percent change and change from baseline in MRI assessment of infarct size expressed in 
grams 
5. Percent change and change from baseline in MRI assessment of viable mass expressed 
in grams 
Regional measure 
6. Percent change and change from baseline in MRI assessment of function in the region 
which received CAP-1002 therapy 
Clinical function/status measures 
7. Percent change and change from baseline in distance covered in six minute walk test 
8. Change from baseline in Minnesota Living with Heart Failure Questionnaire (MLHFQ) 
scores (Total score, Physical Dimension score, and Emotional Dimension score) 
9. Change from baseline in Patient Global Assessment (PGA) score 
Biomarker 
10. Percent change and change from baseline in NT-proBNP  
11. Change from baseline in log transformed NT-proBNP 
 
Additional detail regarding secondary endpoint analyses can be found in the Statistical Analysis 
Plan (SAP).  
Statistical Methods: 
The safety analysis population will consist of all subjects who received an infusion of either 
CAP-1002 or placebo. The primary efficacy analysis population in the Randomized Cohort 
(Primary Modified Intent-to-Treat (mITT) Population, Exploratory mITT Population) will 
consist of all subjects in the Safety Population who had a baseline observation and at least one 
post-baseline observation. Demographics and baseline characteristics will be summarized and 
reported. The Safety Cohort subjects will be summarized and analyzed distinctly from the 
Randomized Cohorts due to the unblinded nature of the treatment intervention. Similarly, the 
Exploratory Randomized Cohort of mismatched subjects will also be summarized distinctly from 
the Primary Randomized Cohort. Details on additional analysis populations will be addressed in 
the SAP. 
 
Alpha for the study will be controlled by using a closed testing procedure. The primary efficacy 
analyses will be performed for the analysis population using a modified intent-to-treat population 
with post-baseline outcome data using a longitudinal mixed effects model. The final analysis will 
test the hypothesis after 12 months of treatment.  
 
Primary Safety Endpoint: Point estimates and confidence intervals of the proportion of 
subjects that experience acute myocarditis possibly attributable to CAP-1002 (diagnosed with 
consideration of clinical context and accompanied by humoral or cellular immune reaction 


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specific to CAP-1002), death due to ventricular tachycardia or ventricular fibrillation, sudden 
unexpected death, or a major adverse cardiac event (MACE), defined as the composite incidence 
of death, non-fatal recurrent MI, hospitalization for heart failure, emergency room treatment for 
heart failure (NT-proBNP >450 pg/mL or BNP>100 pg/ml, with treatment including intravenous 
diuretic administration), left ventricular assist device (LVAD) placement or heart transplant 
within the first month post-infusion will be calculated.  
 
Secondary Safety Endpoints: Descriptive analyses of all secondary safety endpoints will be 
performed using percentages, means, and ranges where appropriate. For incidence rates, two-
sided 95% confidence intervals will be constructed for the differences between CAP-1002 and 
placebo and a two-sided Fisher Exact test will be used for between-treatment comparisons; the 
Wilcoxon-Mann-Whitney test will be used to compare distributions and ordinal outcomes 
between randomized treatments.  There will be no adjustments for multiple safety assessments by 
the DSMB and at the interim analyses; a two-sided p=0.05 will be used to establish statistical 
significance. 
 
Primary Efficacy Endpoint:  The primary efficacy endpoint is the percent change from 
baseline in MRI assessment of infarct size as a percent of left ventricular mass 12 months after 
administration of treatment (either CAP-1002 or placebo). The primary efficacy hypothesis is 
that CAP-1002 is superior to placebo in reducing infarct size in either all subjects combined 
(“full group”) or in subjects with recent MI (“subgroup”). A closed testing procedure will be 
used so that strong control of type 1 error is maintained.  
 
The primary analysis will be a longitudinal mixed effects model. The response variable of 
percent change from baseline in infarct size as a percent of left ventricular mass will be modeled 
with the fixed categorical effects of treatment group and time (6 and 12 months), as well as a 
continuous fixed covariate of baseline infarct size. Intercept and subjects will be treated as 
random in this mixed effects model. The primary hypothesis will be tested using the estimated 
treatment effect compared to placebo at 12 months. An additional test will compare the 
treatments at 6 months and will be considered secondary. Model results will be provided for 
fixed affects and estimates for each level of each affect.  
 
Secondary Efficacy Endpoints:  Data analyses will be performed in a manner consistent with 
the primary efficacy endpoints. Secondary efficacy analyses will employ the same longitudinal 
modeling strategy as for the primary efficacy endpoint but will be based on an alpha of 0.05 
without controlling for multiplicity. All comparisons in the secondary analyses will be based on 
a null hypothesis of no difference in the endpoint between subject administered CAP-1002 as 
compared to placebo.    
 
Exploratory Randomized Cohort Analysis: Presence of DSAs (mismatched) against all 
available donors:  The exploratory analysis is designed to evaluate the prevalence of mismatched 
subjects, as well as the safety and efficacy profiles within the enrolled population.  A review and 
descriptive comparison of safety and efficacy between the Primary Randomized Cohort and the 
Exploratory Randomized Cohort will be performed, which preserves the design integrity of the 
Primary Randomized Cohort. The Exploratory Randomized Cohort sample size was estimated 


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based on DSA results observed in the Safety Cohort, where approximately 14% of the screened 
subjects would have been mismatched to all available donors, i.e., assuming at 14% rate of 
mismatch, approximately 120 subjects would be screened to achieve enrollment of 103 in the 
matched Primary Randomized Cohort, thus yielding up to 17 subjects enrolled in the mismatched 
Exploratory Randomized Cohort. 
 
Date of Original Approved Protocol: 14 Jun 2012 
Date of Most Recent Protocol Amendment (if applicable): 15 Jan2015 
 
 


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List of Abbreviations and Definitions of Terms 
 
µl 
Microliter 
 
ADC 
Adipose-Derived Cell 
 
AE 
Adverse Event 
 
ALB 
Albumin 
 
ALK-P 
Alkaline phosphatase 
 
ALT 
Alanine aminotransferase (same as SGPT)  
AMI 
Acute Myocardial Infarction 
AST 
Aspartate aminotransferase (same as SGOT)  
Atm 
Atmospheres 
β-HCG 
Beta Human Chorionic Gonadotropin 
 
BMMNC 
Bone Marrow Mononuclear Cell 
 
BUN 
Blood urea nitrogen 
 
C 
Celsius 
 
CCU 
Critical (or Coronary) Care Unit 
 
CDC 
Cardiosphere Derived Cell  
CFR 
Code of Federal Regulations  
CHF 
Congestive Heart Failure 
CK-MB 
Creatine phosphokinase MB isoenzyme 
 
CMV 
Cytomegalovirus 
 
CRF 
Case Report Form 
 
CRO 
Contract Research Organization 
 
CRT 
Cardiac Resynchronization Therapy 
 
CS 
Clinically Significant 
 
CSC 
Cardiac Stem Cell 
 
CT 
Computerized Tomography 
 
DMSO 
Dimethyl Sulfoxide 
 
DSA 
Donor-Specific Antibody  
DSMB 
Data Safety Monitoring Board  


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EBV 
Epstein-Barr Virus 
ECG 
Electrocardiogram 
 
EDC 
Electronic Data Capture 
 
ELISpot 
Enzyme-Linked Immunosorbent Spot 
 
ESR 
Expedited Safety Report 
 
F 
Fahrenheit 
 
FDA 
Food and Drug Administration 
 
GCP 
Good Clinical Practice  
GFR 
Glomerular Filtration Rate  
HBsAg 
Hepatitis B Surface Antigen  
Hct 
Hematocrit 
HCV 
Hepatitis C Virus 
 
HF 
Heart Failure 
 
Hgb 
Hemoglobin 
 
HbA1c 
Glycosylated Hemoglobin 
 
HIPAA 
Health Insurance Portability and Accountability Act 
 
HIV 
Human Immunodeficiency Virus 
 
HLA 
Human Leukocyte Antigen 
 
IAP 
Interim Analysis Plan 
 
ICD 
Implantable Cardioverter Defibrillator 
 
ICF 
Informed Consent Form 
 
ICH 
International Conference on Harmonisation 
 
IEC 
Independent Ethics Committee 
 
IgG 
Immunoglobulin G  
IgM 
Immunoglobulin M 
IND 
Investigational New Drug 
 
INR 
International Normalized Ratio 
 
IP 
Investigational Product 
 
IRB 
Institutional Review Board 
 
K 
Potassium 


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Kg 
Kilogram 
 
LDH 
Lactate dehydrogenase  
LV 
Left Ventricle 
LVAD 
Left Ventricular Assist Device  
LVEF 
Left Ventricular Ejection Fraction  
M 
Million 
MACE 
Major Adverse Cardiac Event 
 
Mcg 
Microgram 
 
MCH 
Mean corpuscular hemoglobin 
 
MCHC 
Mean corpuscular hemoglobin concentration 
 
MCV 
Mean corpuscular volume 
 
MedDRA 
Medical Dictionary for Regulatory Activities 
 
MI 
Myocardial Infarction 
 
Min 
Minute  
mL 
Milliliter 
MLHFQ 
Minnesota Living with Heart Failure Questionnaire 
 
Mm 
Millimeters  
mmol 
Millimole 
MRI 
Magnetic Resonance Imaging 
 
MSC 
Mesenchymal Stem Cell 
 
Na 
Sodium 
 
NHLBI 
National Heart, Lung and Blood Institute 
 
NT-proBNP 
N-terminal pro-hormone brain natriuretic peptide 
 
NYHA 
New York Heart Association 
 
OTW 
Over The Wire 
 
P 
Probability 
 
PCI 
Percutaneous Coronary Intervention 
 
PGA 
Patient Global Assessment 
 
PRA 
Panel Reactive Antibodies 


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PSP 
Patient Specific Probability 
 
PTT 
Activated Partial Thromboplastin Time 
 
RBC 
Red blood cell 
 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan  
SD 
Standard Deviation 
SF-36 
Short Form (health survey) - 36 questions  
SGOT 
Serum Glutamic Oxaloacetic Transaminase  
SGPT 
Serum Glutamic Pyruvic Transaminase  
SPRO 
Serious Procedure Related Outcome 
TIMI 
Thrombolysis In Myocardial Infarction 
 
UA 
Urinalysis 
 
VF 
Ventricular Fibrillation 
 
VGEF 
Vascular Endothelial Growth Factor 
 
VT 
Ventricular Tachycardia 
 
WBC 
White Blood Cell 
 
WPAI:SHP 
Work Productivity and Activity Impairment Questionnaire: Specific 
Health Problem 


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Amendment 8.1 
1 
INTRODUCTION 
 
The principal goal of the proposed Phase I/II study is to examine the safety of intracoronary 
administration of allogeneic cardiosphere-derived cells (CAP-1002) 4 weeks to 12 months 
following MI. 
 
 
 
 
 
 
 
1.1 
Summary of Preclinical Data 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.2 
Summary of Clinical Data 
 
1.2.1 Other Cell Therapies 
 
There have been numerous clinical studies to date in which cell therapies have been infused 
down a coronary artery. The major conclusion of those studies is that the procedure is safe. 
Efficacy has been a more confounding issue. Bone marrow mononuclear cells (BMMNCs), 
by far the cell type most extensively studied clinically, have been used repeatedly in acute MI 
(AMI) patient populations and have shown functional benefits that were marginally positive 
(Huikuri et al., 2008; Schachinger et al., 2004; Tendera et al., 2009) mixed (Janssens et al., 
2006; Roncalli et al., 2011), transient (Meyer et al., 2006; Wollert et al., 2004), or completely 
negative (Hirsch et al., 2011; Lunde et al., 2006; Wohrle et al., 2010). A meta-analysis of 10 
clinical trials involving 698 patients evaluated the overall benefit (Lipinski et al., 2007). Patients 
receiving cell therapy had an improvement of left ventricular ejection fraction (LVEF) by 3.0% 
compared to placebo-treated patients. Infarct size and end-systolic volume were significantly 
reduced in cell-treated patients by 5.6% and 7.4mL, respectively. This analysis and others 
(Martin-Rendon et al., 2008; Zhang et al., 2009) have also indicated that intracoronary BMMNC 
therapy has a positive safety profile in AMI patients: no increased incidence of arrhythmias or 
increased arrhythmia inducibility, no excess proclivity to target- vessel restenosis or repeat 
revascularization, and no evidence of increased tumorigenesis have been reported. Long-term 
follow-up data are now emerging from these early studies which also point toward unanticipated 
benefits on clinical endpoints. In the REPAIR-AMI trial (Schachinger et al., 2006) the incidence 
of the pre-specified cumulative endpoint of death, MI, or necessity for revascularization was 
significantly lower at one year. Likewise, the combined endpoint of death, recurrence of MI, and 
re-hospitalization for heart failure (HF) was reduced. These favorable clinical outcomes were 
sustained at two years (Assmus et al., 2010). Promising results have also been reported with 
transplantation of BMMNCs in small trials of patients with chronic cardiomyopathy (Bolli, 
Jneid, & Dawn, 2005; Dohmann et al., 2005; Perin et al., 2003; Perin et al., 2004; Strauer et al., 
2005). However, two rigorous, prospective, randomized, double-blinded studies where 
autologous BMMNCs were administered either 2- 3 weeks post-MI (LateTIME, (Traverse et al., 
2011)) or in a HF population (FOCUS-CCTRN, (Perin et al., 2012)), showed no significant 
benefits on cardiac function or remodeling. 
 
Mesenchymal stem cells (MSCs), or a more selected subset of mesenchymal precursor cells, 
have been utilized in several clinical studies and can be used from an allogeneic source. 
Allogeneic MSCs delivered intravenously in AMI patients have shown modest functional 
improvements (both cardiac and lung as most cells track to the lungs when given intravenously) 


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in an early phase study (Hare et al., 2009) that has led to a follow-on study. Allogeneic 
mesenchymal precursor cells have been utilized in patients with HF and shown a significant 
reduction in MACE (major adverse cardiac events) in treated patients, but inexplicably no dose-
effect in the 3 doses tested and no impact on the parameters of cardiac function examined (Perin, 
2011). Given the allogeneic nature of the product, PRAs (panel reactive antibodies) and the 
development of DSAs (donor-specific antibodies) were assessed in this study. Six of 45 patients 
(13%) developed DSAs against donor HLA class I transiently, with only 2 patients (4%) 
exhibiting DSAs beyond 1 month, and no patients exhibiting clinical symptoms. Adipose-derived 
cells (ADCs) can be isolated from autologous sources with some devices under development. 
ADCs were utilized recently to treat an AMI patient population (APOLLO) and intracoronary 
infusion led to a respectable reduction in infarct size (Houtgraaf et al., 2012). Intracoronary 
application of autologous cardiac stem cells (CSCs) in patients after coronary bypass was 
recently reported as effective in an interim analysis of an early phase study (Bolli et al., 2011). 
 
Collectively, these clinical data 1) show precedence with intracoronary cell infusion and 
establish a positive safety profile for the delivery method selected for use with CAP-1002; 2) 
give preliminary evidence that even modest functional benefits can translate into meaningful 
clinical benefits; 3) point toward a population of post-MI patients who are refractory to therapy 
with the most commonly used cell type (BMMNCs); 4) create a paradigm for testing an immune 
response to allogeneic cell products (focused on DSAs 1 month after delivery) and establish 
expectations as to the immune-related risks involved. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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1.3.1 Information on CAP -1002 
 
 
 
 
 


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1.3.2 Justification for Dose 
 
 
 
 
 
 
 
 
 
 
 
1.3.3 Risks to Human Subjects 
 
Risks associated with administration of both the study agent and placebo are similar and related 
primarily to balloon inflation following catheterization. The risks of balloon inflation are largely 
related to the balloon inflation pressure. As opposed to the usual clinical setting wherein inflation 
is performed in the setting of a stenosis and inflation pressures are usually 10-16 atmospheres or 
higher, inflation in this study is performed within a previously placed stent or area of previous 
occlusion and solely to prevent reflux of the CAP-1002 or placebo infusion with minimal 
inflation pressure required to stop blood flow. The risk of coronary dissection is estimated to be 
less than 1-4% in this setting (Assmus et al., 2006; Janssens, et al., 2006; Schachinger, et al., 
2006) and were dissection to occur in a previously unstented segment, a stent would be placed if 
clinically indicated. In CADUCEUS and ALLSTAR Phase I, no complications that necessitated 
stent placement were reported during CDC infusion or within 24 hours of infusion among the 
subjects who were randomized to CDCs. 
 
Other risks of the infusion procedure include those risks that are possible with diagnostic 
coronary angiography. These include risks related to infection, bleeding, hypotension, pain and  
hematoma at the arterial puncture site (0.4%), arrhythmia (0.38%), sensitivity or allergy to 
radiographic contrast (0.37%), exposure to radiation, thromboembolism (0.07%), contrast 
induced nephropathy, myocardial ischemia or infarction (0.05%). Overall, the risk of any 
complication is approximately 1.4%, and for death is less than 0.1% (Noto et al., 1991). 
 


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1.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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2 
STUDY OBJECTIVES 
 
2.1 
Primary Safety Objective 
 
The primary safety objective is to determine the safety profile of CAP-1002 administered by 
intracoronary infusion in subjects with ischemic left ventricular dysfunction and a previous 
myocardial infarction (MI); specifically, to test the null hypothesis that the incidence rate of the 
primary safety endpoint (a composite of peri-procedural clinical events) differs by no more than 
0.20 between treatment groups.  
 
2.2 
Primary Efficacy Objective 
The primary efficacy objective is to evaluate whether administration of CAP-1002 by 
intracoronary infusion may result in structural cardiac benefits for subjects with ischemic left 
ventricular dysfunction and a previous MI as measured by infarct size expressed as a percent of 
left ventricular mass 12 months after infusion; specifically, to test the hypothesis that CAP-1002 
is superior to placebo in reducing infarct size, expressed as a percent of left ventricular mass, 12 
months after infusion, either in all subjects combined or in subjects with recent MI ( ≤ 90 days 
before infusion). 
2.3 
Secondary Objectives 
The secondary safety objective is to compare the safety profiles of CAP-1002 and placebo over 
12 months based on pre-specified clinical events and development of increased HLA antibody 
levels.  
 
The secondary efficacy objective is to evaluate whether administration of CAP-1002 by 
intracoronary infusion may result in other left ventricular structural or functional cardiac benefits 
for subjects with ischemic left ventricular dysfunction and a previous MI.  Also evaluations will 
investigate whether administration of CAP-1002 may result in clinical or biomarker benefits for 
subjects with ischemic left ventricular dysfunction and a previous MI. 
 
2.4 
Safety Assessments 
 
The primary safety endpoint is the one-month post intracoronary infusion proportion of subjects 


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experiencing any of the following adjudicated events: 
1. Acute myocarditis possibly attributable to CAP-1002 or placebo, diagnosed with 
consideration of clinical context, with or without a clinically indicated endomyocardial 
biopsy. In order to be considered related to CAP-1002 or placebo, humoral or cellular immune 
reaction specific to CAP-1002 must also be documented for subjects treated with CAP-1002, 
or a temporal relationship with IP administration must exist for subjects administered placebo. 
2. Death due to 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. 
3. Sudden unexpected death defined as occurring within one hour of symptom onset, or un- 
witnessed death in a person previously observed to be well within the preceding 24 hours 
without an identified cause. 
4. Major adverse cardiac event (MACE), defined as the composite incidence of death, non- fatal 
recurrent MI, hospitalization for heart failure, emergency room treatment for heart failure 
(NT-proBNP >450 pg/mL or BNP>100 pg/ml, with treatment including intravenous diuretic 
administration), left ventricular assist device (LVAD) placement or heart transplant. Peri-
infusion MI will be defined as presence of troponin or CK-MB levels > 5 times the upper 
reference limit during the 24 hours following infusion. These elevations must be accompanied 
by symptoms of ischemia > 20 minutes in duration and ECG changes indicative of new 
ischemia (new ST-T changes or new left bundle branch block), development of pathological Q 
waves on the ECG, imaging evidence of new loss of viable myocardium, or new regional wall 
motion abnormality. 
 
Separate strata will be evaluated for subjects with a Recent MI and with a Chronic MI. The 
following adjudicated events will be evaluated as secondary safety endpoints during the twelve-
month follow-up period: 
1. Acute myocarditis possibly attributable to CAP-1002 or placebo, diagnosed with 
consideration of clinical context, with or without a clinically indicated endomyocardial 
biopsy. In order to be considered related to CAP-1002 or placebo, humoral or cellular 
immune reaction specific to CAP-1002 must also be documented for subjects treated with 
CAP-1002, or a temporal relationship with IP administration must exist for subjects 
administered placebo. 
2. Death due to ventricular tachycardia or ventricular fibrillation defined as occurring with prior 
ECG documentation of these arrhythmias during ambulatory ECG monitoring in an 
outpatient setting or during routine ECG monitoring while hospitalized. 
3. Sudden unexpected death defined as occurring within one hour of symptom onset, or un- 
witnessed death in a person previously observed to be well within the preceding 24 hours 
without an identified cause. 
4. Major adverse cardiac event (MACE), defined as the composite incidence of death, non- fatal 
recurrent MI, hospitalization for heart failure, emergency room treatment for heart failure 
(NT-proBNP >450 pg/mL or BNP>100 pg/ml, with treatment including intravenous diuretic 
administration), left ventricular assist device (LVAD) placement or heart transplant. Peri-
infusion MI will be defined as presence of troponin or CK-MB levels > 5 times the upper 
reference limit during the 24 hours following infusion. These elevations must be 
accompanied by symptoms of ischemia > 20 minutes in duration and ECG changes indicative 
of new ischemia (new ST-T changes or new left bundle branch block), development of 


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pathological Q waves on the ECG, imaging evidence of new loss of viable myocardium, or 
new regional wall motion abnormality. 
5. New cardiac tumor formation on MRI imaging. 
6. Any hospitalization due to a cardiovascular cause or related to CAP-1002 or placebo 
infusion. 
7. Any inter-current cardiovascular illness or one related to CAP-1002 infusion or placebo, 
which prolongs hospitalization. Evidence of myocardial injury will be assessed by a rule out 
MI cardiac enzyme protocol performed following administration of CAP-1002 or placebo. 
Troponin and CK-MB will be obtained approximately every 8 hours for the first 24 hours 
after infusion. 
8. New TIMI flow ≤1, following intracoronary infusion of CAP-1002 or placebo. 
9. Development of, or an increase in the frequency of, ventricular tachycardia with a duration of 
30 beats or longer ascertained by periodic, protocol-mandated 24 hour ambulatory ECG 
monitoring. 
10. Development of increased anti-HLA antibody levels with development of sensitization to 
HLA antigens specific to the CAP-1002 CDC donor. 
 
2.4.1 Efficacy Assessments 
 
The primary efficacy endpoint is the percent change from baseline in MRI assessment of infarct 
size as a percent of left ventricular mass 12 months after administration of treatment (either 
CAP-1002 or placebo).  The following will be evaluated as secondary efficacy endpoints during 
the six-month and twelve-month follow-up periods: 
Global LV Function Measures 
1. Percent change and change from baseline in MRI assessment of LVEF  
2. Percent change and change from baseline in MRI assessment of left ventricular 
end-diastolic and end-systolic volumes indexed to BSA  
Structural measures 
3. Change from baseline in MRI assessment of infarct size as a percent of left ventricular 
mass 
4. Percent change and change from baseline in MRI assessment of infarct size expressed in 
grams 
5. Percent change and change from baseline in MRI assessment of viable mass expressed 
in grams 
Regional measure 
6. Percent change and change from baseline in MRI assessment of function in the region 
which received CAP-1002 therapy 
Clinical function/status measures 
7. Percent change and change from baseline in distance covered in six minute walk test 
8. Change from baseline in Minnesota Living with Heart Failure Questionnaire (MLHFQ) 
scores (Total score, Physical Dimension score, and Emotional Dimension score)  
9. Change from baseline in Patient Global Assessment (PGA) score 
Biomarker 
10. Percent change and change from baseline in NT-proBNP  
11. Change from baseline in log transformed NT-proBNP 
 
Additional detail regarding secondary endpoint analyses can be found in the SAP. 


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2.5 
Exploratory Assessments 
2.5.1 Presence of DSAs (mismatched) against all donors 
 
The exploratory analysis is designed to evaluate the prevalence of mismatched subjects within 
the Randomized Cohort, as well as, the safety and efficacy profiles within the enrolled 
population.  This group of subjects will be called the Exploratory Randomized Cohort.  A review 
and descriptive comparison of safety and efficacy between the Randomized Cohort and the 
Exploratory Randomized Cohort group will be performed, which preserves the design integrity 
and statistical power of the Randomized Cohort. 
 
3 
INVESTIGATIONAL PLAN 
 
3.1 
Overall Study Design and Plan 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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In Phase 2, the Primary Randomized Cohort will enroll up to approximately one hundred three 
(103) subjects with a previous myocardial infarction (MI) and resultant ischemic left ventricular 
dysfunction meeting all inclusion and no exclusion criteria. The Primary Randomized Cohort 
will include the Recent and Chronic MI strata. These approximately 103 subjects will be 
randomized in a double-blind fashion to receive either CAP-1002 or placebo (collectively 
referred to as Investigational Product [IP]) in a 2:1 ratio favoring CAP-1002 to achieve 93 
subjects with complete 12 month data (assumes 10% non-completion rate).  Subjects may sign 
consent and start the screening process immediately post-MI (e.g., acute admission at hospital). 
The following assessments will be permitted within 28 days immediately following the subject’s 
MI: signing ICF, review of medical history, review of concomitant medications, and collection 
of laboratory samples required for assessment of study eligibility criteria (e.g., eGFR, HbA1c, 
hepatitis serology, HIV serology, LFTs, hematocrit, WBC, and platelet count). All other 
screening tests, including the subject’s cardiac MRI and CT (chest, abdomen, pelvis), must be 
conducted greater than 28 days post-MI. Infusion must occur within 28 days of the first 
screening procedure that is performed greater than 28 days post-MI. Relevant safety laboratory 
sample collections (e.g., chemistry, hematology, urinalysis) may need to be repeated as they 
must be obtained within 28 days of the subject’s infusion. A subject that rescreens for any reason 
may be required to repeat all protocol safety procedures (excluding CT of the chest, abdomen 
and pelvis if previously conducted) if the safety procedures were originally conducted greater 
than 28 days prior to the subject’s infusion. A subject that rescreens for any reason may be 
required to repeat all protocol efficacy procedures including the cardiac MRI unless: a) the 
subject’s efficacy procedures including baseline cardiac MRI were conducted within 28 days of 
infusion; or, b) the subject’s efficacy procedures including baseline cardiac MRI were conducted 
≥ 60 days post-MI and within 60 days of infusion. Additional instructions are included in 
protocol Section 7 and Appendix I (Schedule of Events). After completion of the screening 
procedures and meeting all inclusion and exclusion criteria, study subjects will be randomized to 
receive CAP-1002 or placebo administered via intracoronary infusion.  All subjects  in the 
Primary Randomized Cohort will be followed at week 2 and at months 1, 3, 6 and 12 after 
planned CAP-1002 or placebo infusion. Efficacy will be assessed at all specified post-infusion 
visits, with the 12 month visit being the primary efficacy endpoint. An administrative interim 
analysis of the final 6 month data will be performed when all subjects in the Primary 
Randomized Cohort have completed the 6 month visit to assist in planning Phase III studies. 
Up to approximately 103 subjects will be enrolled in the Primary Randomized Cohort. This 
maximum sample size is based on the Recent and Chronic MI strata being analyzed 
independently with a treatment effect of 15% at Month 12 for each strata, a pooled standard 
deviation of 10%, a minimum power of 80%, and a significance level (alpha) of 0.05. The 
double-blind, placebo-controlled design of the Primary Randomized Cohort will maximize the 
study’s ability to assess both safety and efficacy, as both may be subject to bias from the 
perspective of Investigators and subjects. 
The Exploratory Randomized Cohort will enroll up to 17 subjects in addition to the Primary 
Randomization Cohort.  Exploratory Randomized Cohort subjects are those subjects who are 
mismatched against all available donors. The Exploratory Randomized Cohort will also include 
Recent and Chronic subjects (up to n=8-9 per stratum). The Exploratory Randomized Cohort will 
be randomized in a double-blind fashion as described in the Primary Randomized Cohort.  The 
Exploratory Randomized Cohort will undergo the same tests as all other subjects based on the 
schedule of events (see Appendix 1 Schedule of Events Table).  This group will be analyzed 


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separately from the Primary Randomized Cohort (n=103) using descriptive analyses to assess the 
prevalence and impact on safety and efficacy, if any.  The Exploratory Randomized Cohort 
sample size was estimated based on DSA results observed in the Safety Cohort, where 
approximately 14% of the screened subjects would have been mismatched to all available 
donors, i.e., assuming at 14% rate of mismatch, approximately 120 subjects would be screened to 
achieve enrollment of 103 in the matched Primary Randomized Cohort, thus yielding up to 17 
subjects enrolled in the mismatched Exploratory Randomized Cohort. 
 
3.2 
Rationale for Study Design and Control Group 
 
The initial Safety Cohort will provide short term, open label safety data to support both dose 
escalation to the target dose of 25M cells and continuation into the larger, double-blind portion 
of the trial. Conducting the Primary Randomized Cohort as double-blind and placebo controlled 
will maximize the study’s ability to assess both safety and efficacy, as both may be subject to 
bias from the perspective of Investigators and subjects. Adverse events may occur over a 12 
month period in subjects with ischemic left ventricular dysfunction regardless of whether or not 
they receive the study agent. Scoring of these events in terms of the intensity and the relationship 
to the study therapy can be subject to Investigator bias. Quality of life measures in particular, 
such as the Six Minute Walk Test, the Minnesota Living with Heart Failure Questionnaire score, 
SF-36, WPAI-SHP and Patient Global Assessment (some designated as secondary efficacy 
endpoints), can expose subject bias. Blinding and randomization will serve to help mitigate these 
potential biases. 
 
3.3 
Study Duration and Dates 
 
After the completion of enrollment in the Safety Cohort, it is estimated that 24 months or more 
of accrual will be necessary to enroll the targeted sample size for the randomized, double- 
blinded, placebo-controlled portion after a lapse for DSMB review. All treated subjects will be 
followed for 12 months following infusion. Therefore, the total duration of the study is estimated 
to be at least 42 months. Actual overall study duration or subject recruitment period may vary.  
Subjects who sign consent to participate in the 5-year annual follow up (post-infusion) will be 
followed for an additional 48 months after completing the 12 month post-infusion primary 
efficacy endpoint visit. 


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4 
STUDY POPULATION SELECTION 
 
4.1 
Study Population 
Approximately 134 subjects with a history of MI and angioplasty that resulted in a patent infarct-
related artery, with stent placement, will be enrolled in this study. These subjects will be 
primarily recruited from subjects referred to the Principal Investigator at each study site. Of the 
134 subjects enrolled, 14 will be part of a Safety Cohort to examine safety of administration of 
CAP-1002 one month following infusion (followed for 12 months) and up to approximately 103 
will be included in the Primary Randomized Cohort. It is anticipated that up to 93 randomized 
subjects within the Primary Randomized Cohort will complete the study through the 12 month 
follow up period. The study will enlist approximately 45 sites for participation. Up to 17 
additional subjects may be treated as part of the Exploratory Randomized Cohort. However, 
since this group is exploratory in nature, enrollment of the Primary Randomized Cohort will 
define the end of the study; that is, once the Primary Randomized Cohort is fully enrolled, the 
study will be considered closed for further subject enrollment. 
 
4.2 
Inclusion Criteria 
 
Subjects meeting the following inclusion criteria may be considered for enrollment: 
 
Inclusion Criteria 
1. History of MI (STEMI or NSTEMI) within the prior 12 months due to a coronary artery 
event and evidenced by at least two of the following: typical ischemic symptoms, serial ST-T 
changes (new ST elevation or new left bundle block) and/or elevated troponin or CK-MB >5 
times the upper limit of normal. Also at least one of the following: development of 
pathological Q wave ECG changes, imaging evidence of new loss of viable myocardium, or 
new regional wall motion abnormalities. 
 The following assessments will be permitted within 28 days immediately following 
the subject’s MI: signing ICF, review of medical history, review of concomitant 
medications, and collection of laboratory samples required for assessment of study 
eligibility criteria (e.g., eGFR, HbA1c, hepatitis serology, HIV serology, LFTs, 
hematocrit, WBC, and platelet count). All other screening tests, including the 
subject’s cardiac MRI and CT (chest, abdomen, pelvis), must be conducted greater 
than 28 days post-MI. Infusion must occur within 28 days of the first screening 
procedure that is performed greater than 28 days post-MI. Relevant safety laboratory 
sample collections (e.g., chemistry, hematology, urinalysis) may need to be repeated 
as they must be obtained within 28 days of the subject’s infusion. 
2. History of percutaneous coronary intervention (PCI), with stent placement resulting in TIMI 
flow = 3, in the coronary artery supplying the infarcted, dysfunctional territory and through 
which the treatment will be infused. 
3. At least one assessment of left ventricular ejection function (LVEF) ≤0.45 as determined by 
any one of the standard modalities (echocardiography, ventriculography, nuclear imaging, 
CT and/or MRI) prior to or during the screening period.   
 For subjects that fulfill the criteria of Recent MI (i.e., within 90 days of MI) at time of 
screening visit:  assessment must be post-reperfusion after index MI and the most 


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recent test prior to or during the screening period.  
 For subjects that fulfill the criteria of Chronic MI (i.e., greater than 90 days from MI) 
at the time of screening visit: assessment must be at least 21 days post-reperfusion 
after index MI and the most recent test prior to or during the screening period.  
Note: subjects may screen as a Recent MI but be randomized into the Chronic MI strata 
if the infusion date is > 90 days post-MI. 
4. Left ventricular infarct size of ≥ 15% of left ventricular mass in the qualifying infarct-related 
region to be infused as determined by centrally read screening MRI, with associated thinning 
and/or hypokinesis, akinesis, or dyskinesis, with no large aneurysmal area in the infarcted 
regions.  
5. No further revascularization clinically indicated at the time the subject is assessed for 
participation in the clinical trial. 
6. Ability to provide informed consent and follow-up with protocol procedures. 
7. Age ≥ 18 years. 
 
4.3 
Exclusion Criteria 
 
Subjects who meet any of the following criteria will be excluded from the study: 
 
Exclusion Criteria 
1. Subjects with a history of coronary artery bypass surgery, and a patent graft (arterial or 
saphenous vein graft) attached to the coronary artery to be infused. 
2. Diagnosed or suspected myocarditis. 
3. History of cardiac tumor, or cardiac tumor demonstrated on screening MRI. 
4. History of acute coronary syndrome in the 4 weeks prior to study infusion. 
5. History of previous stem cell therapy. 
6. History of radiation treatment to the central or left side of thorax. 
7. Current or history (within the previous 5 years) of systematic auto-immune or connective 
tissue disease including, but not limited to, giant cell myocarditis, cardiac or systemic 
sarcoidosis, Dressler’s syndrome, chronic recurrent or persistent pericarditis. 
8. History of or current treatment with immunosuppressive , anti-inflammatory, or other agents 
to treat manifestations of systemic immunologic reactions, including chronic systemic 
corticosteroids, biologic agents targeting the immune system, anti-tumor and anti-neoplastic 
drugs, anti-VEGF, or chemotherapeutic agents within 3 months prior to enrollment. 
9. Prior ICD and/or pacemaker placement where study imaging site has not been trained and 
certified specifically for this protocol to conduct cardiac MRI in subjects with ICD and/or 
pacemaker placement. 
a. Presence of a pacemaker and/or ICD generator with any of the following 
limitations/conditions are excluded: 
i. Manufactured before the year 2000, 
ii. Leads implanted < 6 weeks prior to signing informed consent, 
iii. Non-transvenous epicardial, abandoned, or no-fixation leads, 
iv. Subcutaneous ICDs, 
v. Leadless pacemakers, 
vi. Any other condition that, in the judgement of device-trained staff, would 


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deem an MRI contraindicated. 
b. Pacemaker dependence with an ICD (Note: pacemaker-dependent candidates 
without an ICD are not excluded). 
c. A cardiac resynchronization therapy (CRT) device implanted < 3 months prior to 
signing informed consent. 
10. Estimated glomerular filtration rate < 30 mL/min. 
11. Participation in an on-going protocol studying an experimental drug or device, or 
participation in an interventional clinical trial within the last 30 days. 
12. Diagnosis of arrhythmogenic right ventricular cardiomyopathy. 
13. Current alcohol or drug abuse.  
14. Pregnant/nursing women and women of child-bearing potential that do not agree to use at 
least two forms of active and highly reliable method(s) of contraception. Acceptable methods 
of contraception include contraceptive pills, depo-progesterone injections, a barrier 
contraceptive such as a condom with or without spermicide cream or gel, diaphragms or 
cervical cap with or without spermicide or gel, or an intrauterine device (IUD).   
15. Human Immunodeficiency Virus (HIV) infection. 
16. Viral hepatitis. 
17. Uncontrolled diabetes (HbA1c>9%). 
18. Abnormal liver function (SGPT/ALT > 3 times the upper reference range) and/or abnormal 
hematology (hematocrit < 25%, WBC < 3000 µl, platelets < 100,000 µl) studies without a 
reversible, identifiable cause. 
19. Sustained ventricular tachycardia (VT) or non-sustained ventricular tachycardia > 30 beats, 
not associated with the acute phase of a previous MI (> 48 hours after the MI onset) or a new 
acute ischemic episode. 
20. Ventricular fibrillation not associated with a new acute ischemic episode. 
21. New York Heart Association (NYHA) Class IV congestive heart failure. 
22. Evidence of tumor on screening chest/abdominal/pelvic (body) CT scan. 
23. Any prior transplant. 
24. Known hypersensitivity to dimethyl sulfoxide (DMSO). 
25. Known hypersensitivity to bovine products. 
26. Any malignancy within 5 years (except for in-situ non-melanoma skin cancer and in-situ 
cervical cancer) of signing the ICF. 
27. Any condition or other reason that, in the opinion of the Investigator or Medical Monitor, 
would render the subject unsuitable for the study. 
 


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5 
STUDY TREATMENT(S) 
 
5.1 
Description of Treatment(s) 
 
5.1.1 Study Drug 
 
CAP-1002 CDCs will be grown from donors unrelated to the recipients. While the HLA type of 
the recipient subject and the CAP-1002 donor CDCs will be tested and known, primarily for 
product identification purposes, matching of the donors and subjects will not be performed.  
Subjects will be assessed for anti-HLA antibodies at screening, but will not be excluded from the 
study based on the presence of DSAs. Subjects, who can be matched, in the sense that no DSAs 
are present to one or more donors, will be enrolled in the Primary Randomized Cohort. Subjects, 
who are mismatched against all available donors, because they harbor one or more anti-HLA 
antibody against each donor, will be enrolled in the Exploratory Randomized Cohort.  Subjects 
who receive the Investigational Product (IP) (CAP-1002 or placebo) will be monitored during 
the course of the study for development of increased anti-HLA antibody levels with development 
of sensitization to HLA antigens specific to the CAP-1002 CDC donor (i.e. DSAs).  The IP is 
delivered to the clinical sites on an as-needed, per subject basis.
 
 
 
 
 
 
 
5.1.2 Placebo 
 
Placebo will consist of 11.1 mL of cryopreservation solution (CryoStor® CS10, BioLife 
Solutions, Inc.) containing 10% dimethyl sulfoxide (DMSO), heparin (1800 units total), and 
nitroglycerin (450 mcg total). 
 
5.1.3 Wash Solution 
 
Normal saline also containing heparin (1200 units total) and nitroglycerin (600 mcg total) will be 
used as the intermediate wash solution between boluses of CAP-1002 or placebo. A 
nitroglycerin-free wash solution may be substituted for the intermediate wash solution if, in the 
opinion of the operator, the blood pressure is too low for the subject to receive additional 
nitroglycerin. 
 
5.2 
Method of Assigning Subjects to Treatment Groups 
 
Consented subjects will be registered using an Electronic Data Capture (EDC) system.  An 
authorized user at the clinical center completes the initial screening by entering information on 
the eligibility form. If a Principal Investigator at the study site has any questions regarding 
subject eligibility, documentation may be directed to the Medical Monitor for consideration. 
 


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Subjects in the Safety Cohort received CAP-1002 in an open-label fashion (n=14). In the 
Randomized Primary and Exploratory Cohorts, all subjects meeting the inclusion and none of the 
exclusion criteria will be randomized via an interactive web-based system (IWRS) following the 
screening procedures using an institution balancing algorithm to be deployed using random 
blocks of 3 or 6 to receive either CAP-1002 or placebo in a 2:1 ratio within stratum, favoring 
CAP-1002.  Subjects that can be matched to receive one or more donors will be randomly 
assigned to CAP-1002 or placebo (2:1) under the predefined randomization scheme, then 
subsequently randomized to one of the matched donors.  If the subject is mismatched (due to the 
presence of DSAs) to all available donors, the subject will be randomized to CAP-1002 or 
placebo (2:1) under the predefined randomization scheme, then randomly assigned to one of the 
available donors. 
 
Notification of subject randomization will be received by an independent storage/distribution 
center; the storage/distribution center will have password protected access to the randomization 
in order to retrieve the treatment assignment.  The storage/distribution center will randomly 
assign an appropriate donor (or placebo) once they receive the designation of active treatment vs. 
placebo from the IWRS.  All Sponsor staff will remain blinded to treatment (CAP-1002 or 
placebo) assignments as detailed in Section 5.3. The only time other Sponsor staff will become 
aware of individual treatments is in the case of an emergency blind break resulting from an SAE. 
 
Study sites will be trained regarding the unblinding process. Should a medical event occur 
necessitating unblinding, the process will be accessible to Investigators 24 hours a day and will 
include an emergency Sponsor contact. 
 
5.3 
Blinding 
 
Subjects will be randomized 2:1 favoring CAP-1002 in a double-blind fashion, with both the 
Investigators and the subjects blind to treatment received. Central reviewers interpreting the MRI 
data and the laboratory studies will also be blinded to group assignment. 
 
During the ALLSTAR blinded Primary Randomized Cohort an independent storage/distribution 
center will be used to distribute IP (CAP-1002 and placebo) doses to the clinical sites.  The 
administration of the blinding process will occur at this independent storage/distribution center to 
remove Capricor personnel from this process.  The distribution and back-up drug product return 
will occur in validated vapor phase liquid nitrogen (N2) shipping containers allowing for 
consistent transportation and scheduling flexibility at all sites. 
 
Both CAP-1002 and the placebo will be packaged in identical cryogenic bags with similar labels.  
At the clinical site, the IP is thawed to room temperature, prepared and drawn into masked (with 
amber/transparent tape) syringes. The amber/transparent tape will allow the treating physician to 
see air bubbles but obscure the clear cellular suspension.  Specific instructions for use will be 
included with each product. 
 
A central laboratory will be used to assess the sensitization to products, (i.e., DSAs, ELISpot 
assay); the results will not be shared with the Investigator or site study personnel or Sponsor staff 
to preserve blinding. 
 


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A DSMB will be utilized for this study and will have access to unblinded data. An interim 
analysis of the final 6 months data will be completed when subjects complete the 6 month 
follow-up visit. Only a statistician independent of the clinical trial team will have access to 
unblinded data and immunological test results prior to the interim analysis; this individual will 
provide the unblinded reports to the DSMB. 
 
Subjects, investigators, and Sponsor’s personnel who had direct responsibility for monitoring at 
the sites will be blinded throughout the study. The interim analysis will be considered an 
administrative interim analysis planned for the determination of efficacy at 6 months, the 
appropriate Sponsor representatives will be unblinded in order to review and make decisions 
regarding entry into Phase III clinical development. A list will be maintained in the trial master 
file to track any persons unblinded during the trial. 
Study sites will be trained regarding the emergency unblinding process. Should a medical event 
occur necessitating unblinding, the process will be accessible to Investigators 24 hours a day and 
will include an emergency Sponsor contact. 
It is not believed that unblinding would help in the treatment of the subjects participating in the 
study. However, if a medical event should occur which necessitates emergency unblinding; the 
process will be accessible to Investigators 24 hours a day. Study sites will be trained regarding 
the emergency unblinding process. 
 
 
5.4 
Concomitant Therapy 
 
All medication therapies received from the time of signing consent will be collected. These are 
considered concomitant therapies. Concomitant therapies will be recorded at each study visit, 
beginning with Screening. All subjects will receive standard-of-care for their cardiac condition 
as determined by their cardiologist. Immunosuppressive, anti-inflammatory, or other agents used 
to treat systemic immunologic reactions, including chronic systemic corticosteroids, anti-tumor 
and anti-neoplastic drugs, anti-VEGF, biologic agents targeting the immune system and 
chemotherapeutic agents are prohibited; subjects taking any of these medications within 3 
months prior to the study infusion are prohibited from participation in the study. Appendix 2 
provides a list of prohibited medications. However, if a subject is started on one of these 
medications following the IP infusion, they will be allowed to continue in the study. 
 
5.5 
Restrictions 
 
5.5.1 Prior Therapy 
 
Subjects who have had previous stem cell therapy, or central or left thorax radiation may not 
participate in this study. 
 
There are no medication restrictions except those listed in Section 5.4 and Appendix 2. 
Individual subject medication will be advised by the subject’s physician according to the usual 
practice of the study site. Warfarin (Coumadin®) discontinuation prior to catheterization will be 


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managed according to the practice and standards of the study site. 
 
5.5.2 Fluid and Food Intake 
 
There are no fluid or food intake restrictions. Subjects should follow the diet and fluid intake 
prescribed by their physician. 
 
5.5.3 Subject Activity Restrictions 
 
Subjects should follow the activity restrictions prescribed by their physician. 
 
5.6 
Treatment Compliance 
 
Since the treatment is a one-time procedure (i.e., infusion), dosing compliance is not of concern.  
Study site personnel will document use of all concomitant medications and subject compliance 
with study procedures at each study visit. 
 
5.7 
Packaging and Labeling 
 
CAP-1002 and the placebo 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 cryogenic bag and label during freezing.  Labeling will be 
attached to the cryogenic overwrap bag for quick identification.  The storage/distribution center 
will distribute the IP (which may include a back-up IP at instruction of the Sponsor) to the 
clinical sites using a validated vapor phase liquid N2 shipping containers. The unused back-up 
IP, as applicable, will be returned to the storage/distribution center using the same shipping 
container. 
 
5.8 
Storage and Accountability 
 
CAP-1002 (or placebo) will be shipped to sites as needed on an individual subject basis and only 
after a subject has (1) provided written informed consent, (2) met all eligibility criteria for entry 
into the study, (3) successfully completed all screening evaluations and 4) been randomized to 
receive either CAP-1002 or placebo treatment. The investigational products will not be stored at 
individual sites other than in the shipping materials provided by the Sponsor. 
 
Detailed instructions for storage and handling are provided in the Instructions for Use that are 
included with each individual treatment shipment. Sites are instructed to hold the IP in its 
shipping container until it is dispensed just prior to infusion. The Sponsor will time delivery of 
the IP to the clinical sites such that the time in the shipping container is less than the known 
expiration time. Once removed from the shipping container, the IP expires at 90 minutes 
post-removal. An expiration time will be noted on the product at the time of removal and 
preparation. Investigators are instructed to store the IP at room temperature (approximately 
25°C) and to administer the IP prior to the noted expiration time. 
 


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5.9 
Investigational Product Retention at Study Site 
 
Since IP will be delivered as needed on a per subject basis, there will be no IP to retain at the 
site.  Site will be instructed to retain labels and packaging materials as part of the subject records.  
Should a subject be found unsuitable for infusion after IP has been shipped, the site is instructed 
to return the IP to the Sponsor’s Manufacturing Facility per the Sponsor’s instructions. 
 
5.10 Investigational Product Accountability and Reconciliation 
 
The Sponsor is responsible for IP accountability, reconciliation, and record maintenance.  
Training will be provided regarding IP accountability. In accordance with all applicable 
regulatory requirements, the designated study center personnel must maintain accountability 
records throughout the study, and the Sponsor (or, designee) will review IP accountability and 
reconciliation. 
 
6 
STUDY PROCEDURES 
 
6.1 
Informed Consent 
 
Before being admitted to the clinical study, all subjects must consent in writing to participate. An 
Informed Consent Form (ICF) will be given to each subject, 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 
subject. The process of obtaining the informed consent will be in compliance with all federal 
regulations, International Conference on Harmonisation (ICH) requirements, and local laws.  Per 
this protocol, the subject may sign the ICF immediately post-MI (e.g., acute admission at 
hospital). The following assessments will be permitted within 28 days immediately following the 
subject’s MI: signing ICF, review of medical history, review of concomitant medications, and 
collection of laboratory samples required for assessment of study eligibility criteria (e.g., eGFR, 
HbA1c, hepatitis serology, HIV serology, LFTs, hematocrit, WBC, and platelet count). All other 
screening tests, including the subject’s cardiac MRI and CT (chest, abdomen, pelvis), must be 
conducted greater than 28 days post-MI. Infusion must occur within 28 days of the first 
screening procedure that is performed greater than 28 days post-MI. Relevant safety laboratory 
sample collections (e.g., chemistry, hematology, urinalysis) may need to be repeated as they 
must be obtained within 28 days of the subject’s infusion. Additional instructions are included in 
protocol Section 7 and Appendix I (Schedule of Events). 
 
The Investigator and/or designee must discuss the study with each subject. The discussion will 
include the nature, scope, procedures, and possible consequences of the subject's participation in 
the study. The ICF and review will be in a form understandable to the subject. The subject must 
be given adequate time to review the ICF and ask questions regarding the IP, procedures, risks 
and other treatment.  The Investigator or designee and the subject must both sign and date the 
ICF after review and before the subject can participate in the study. The subject 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 subject that study participation is entirely 


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voluntary and that consent regarding study participation may be withdrawn at any time without 
penalty or loss of benefits to which the subject 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 subjects and repeat the consent process with the amended ICF 
for any ongoing subjects. 
 
6.2 
Medical History 
 
The general and cardiac-specific medical histories (e.g., significant procedures, medications, 
therapies, allergies) of subjects enrolled in the study will be documented as part of the screening 
visit and reviewed during subsequent visits (e.g., day of infusion, follow-up visits) for any 
modifications (i.e., assessment for potential adverse events).  General and cardiac health, as well 
as concomitant medications, will be reviewed and assessed at each subject visit and new 
information will be updated in the subject’s study documentation. 
 
6.3 
Physical Examinations 
 
A qualified physician, either the Investigator or Sub-Investigator, will perform a limited 
cardiovascular physical examination at each study visit which will include angina and arrhythmia 
assessments.   
 
A limited physical examination will be conducted at the screening visit and the 12 Month follow-
up visit. Height and weight will also be collected and recorded at screening; weight will be 
collected at all subsequent visits. 
 
6.4 
Vital Signs 
 
Temperature, heart rate, blood pressure and respiration rate will be recorded at each visit on the 
case report form. 
 
6.5 
Clinical Laboratory Tests 
 
6.5.1 Laboratory Parameters 
 
Section 7 and Appendix I (Schedule of Events) list applicable clinical laboratory tests to be 
collected at study visits. Subjects will be in a seated or supine position during blood collection. 
Clinical laboratory tests will include the following:


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Table 1. List of Laboratory Tests 
 
Hematology:  
Hematocrit (Hct) 
Hemoglobin (Hgb) 
Platelet count 
White blood cell (WBC) count with differential 
 
Urinalysis: 
Appearance 
Bilirubin 
Color Glucose Ketones 
Microscopic examination of sediment 
Nitrite 
Occult blood pH 
Protein 
Specific gravity 
Urobilinogen 
 
Serum beta human chorionic gonadotropin (hCG) (only 
for females who are not diagnosed as postmenopausal) 
 
Donor Specific Antibody (DSA) monitoring and HLA 
(Human Leukocyte Antigen) typing 
ELISpot assay 
 
Serum Biomarkers (if subject provided consent) 
 
 
 
 
 
 
 
 
 
 
Serum Chemistry: 
Alanine aminotransferase (ALT; SGPT) 
Aspartate aminotransferase (AST; SGOT) 
Blood urea nitrogen (BUN) 
Creatinine 
Estimated Glomerular filtration rate (eGFR) 
Glucose 
Lactate dehydrogenase (LDH) 
Potassium (K) 
Sodium (Na) 
 
Hemoglobin A1c (HbA1c) (screening) 
Troponin I or Troponin T if Troponin I is not 
available. 
N-terminal pro-hormone brain natriuretic peptide 
(NT-proBNP) 
 
Coagulation [Infusion Visit only - for subjects taking 
warfarin (Coumadin®)]: 
 
Activated partial thromboplastin time(PTT) 
International Normalized Ratio (INR) 
 
Hepatitis B surface Antigen (HBsAg) (screening)  
Hepatitis C Virus (HCV) (screening) 
Human Immunodeficiency Virus (HIV) (screening) 


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6.5.2 Sample Collection, Storage, and Shipping 
 
Laboratory studies will be performed and reported at each individual study site, with the 
exception of the following: 
 
Serum for the donor specific antibody (DSA) monitoring, HLA typing and blood for the ELISpot 
assay will be collected and processed at each site and then shipped to a central core laboratory 
for analysis within 24 hours of obtaining the specimens (See Laboratory Manual for shipping 
instructions). Subjects will be monitored for the development of a cellular immune response 
using the ELISpot (enzyme‐linked immunosorbent spot) assay. The ELISpot assay will be 
performed at screening and at the one month study visit in a total of 50 patients treated with CAP‐
1002 (and concurrently 18 placebo subjects: 14 open‐label CDC subjects, 36 randomized CDC 
subjects, 18 randomized placebo subjects) and will be reviewed by the DSMB. If the DSMB 
determines that there is reason to believe additional value would be gained from a larger sample 
of subjects, ELISpot testing will be performed for additional subjects, followed by additional, 
subsequent DSMB review. 
 
• Serum for research purposes (biomarkers) will be collected and processed at each site then 
shipped to a central core lab that will then ship to Capricor for final storage and analysis (if 
subject has provided consent). 
 
Individual sites will be instructed regarding the processing and shipping procedures. 
 
6.6 
12-Lead ECG 
 
Beginning at the screening visit, a 12-Lead ECG will be performed at every study visit to assess 
for rhythm disturbances and new myocardial ischemia or infarction. Subsequent ECGs will be 
compared with the screening ECG for any changes in rhythm and conduction. All changes and 
any associated clinical significance will be evaluated and documented on the case report forms. 
 
6.7 
Echocardiography 
 
An echocardiogram will be performed at the screening visit as well as the 1 month visit. 
Echocardiography will be performed to measure the size and shape of the heart, its chambers and 
blood flow as well as valvular structure and function. Additionally, the echocardiogram will be 
used for detection of any wall motion abnormalities indicative of myocarditis. 
 
The quantitative echocardiographic data points must include: 
 End Diastolic Volume 
 End Systolic Volume 
 Ejection Fraction 
 LV End Systolic Diameter 
 LV End Diastolic Diameter 
 


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6.8 
24 Hour Ambulatory ECG Monitor 
 
A 24 hour ambulatory ECG monitor will be performed at the screening visit, during the 24 hours 
following release (discharge) from the hospital and also at the 1 month, 6 months and 12 months 
study visits. Subjects enrolled in the Safety Cohort will also have the test performed at the 2 
months study visit. The monitor is used to detect and record arrhythmia. All changes and any 
associated clinical significance will be evaluated and documented on the case report form. 
 
6.9 
Magnetic Resonance Imaging Protocol 
 
With the exception of those subjects who develop MRI contraindications, all subjects will 
undergo contrast-enhanced MRI at screening and the months 6 and 12 study visits. Study 
imaging sites must be trained and certified specifically for this protocol prior to conducting 
cardiac MRI in subjects with ICD and/or pacemaker placement. 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 and the site-based MRI technicians will be trained and certified in the common 
acquisition protocol prior to initiation of enrollment at each site. 
 
6.9.1 Cine Imaging Protocol 
 
A cine imaging protocol will be utilized for global ejection fraction and LV volumes and mass 
determination. Acquisition parameters and techniques will be protocoled and the site-based MRI 
technicians will be trained and certified in the common acquisition protocol prior to initiation of 
enrollment at each site. 
 
6.9.2 Delayed Contrast-Enhancement Protocol 
 
This is the most accurate assessment of infarct scar size. Subjects will receive a total bolus 
intravenous injection of 0.2 mmol/kg of gadolinium contrast as long as GFR is > 60 mL/min (for 
GFR 30-60 mL/min, 0.15 mmol/kg will be given; subjects whose GFR declines to <30 during 
the study period will be excluded from contrast injections during subsequent MRI studies). High-
resolution delayed enhancement images will be obtained using an inversion- recovery prepared 
gated fast gradient echo pulse sequence. 
 
6.9.3 Image Analysis 
 
All study images and applicable imaging data will be sent to and centrally read at an independent 
imaging core by cardiovascular radiology experts. MRI will be performed on standard phantoms 
for quality assurance and to detect any changes in system sensitivity over time. 
 
6.10 Chest, Abdomen and Pelvis CT 
 
A computerized tomography (CT) of the chest, abdomen and pelvis will be performed at the 
screening visit to ensure that there are no clinically significant pre-existing abnormalities to 
internal organs or presence of tumors or cancer. The CT will be performed with contrast. If any 


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abnormalities are found that affect the subject’s participation in the study, the subject will be 
withdrawn from the study as a screen failure and not followed further. The subject must continue 
to meet all inclusion and no exclusion criteria in order to continue in the study. 
 
6.11 Clinical Function and Quality of Life Measures 
 
At the screening, 6 month and 12 month study visits, the subject will be asked to complete the 
Minnesota Living with Heart Failure Questionnaire (MLHFQ), the Short Form-36 health survey 
(SF-36), the Work Productivity and Activity Impairment Questionnaire: Specific Health Problem 
(WPAI:SHP), and to make a global assessment of the improvement or worsening of his/her 
condition (Patient Global Assessment). 
 
In addition, subjects will perform a Six Minute Walk test at screening, and at the 6 and 12 month 
study visits. New York Heart Association (NYHA) functional status will be evaluated at 
screening, 1 month, 3 months, 6 months and 12 months study visits. 
 
7 
STUDY ACTIVITIES 
 
The Schedule of Events for the conduct of this study is shown in Appendix 1. 
 
Subjects may sign consent and start the screening process immediately post-MI (e.g., acute 
admission at hospital). The following assessments will be permitted within 28 days immediately 
following the subject’s MI: signing ICF, review of medical history, review of concomitant 
medications, and collection of laboratory samples required for assessment of study eligibility 
criteria (e.g., eGFR, HbA1c, hepatitis serology, HIV serology, LFTs, hematocrit, WBC, and 
platelet count). All other screening tests, including the subject’s cardiac MRI and CT (chest, 
abdomen, pelvis), must be conducted greater than 28 days post-MI. Infusion must occur within 
28 days of the first screening procedure that is performed greater than 28 days post-MI. Relevant 
safety laboratory sample collections (e.g., chemistry, hematology, urinalysis) may need to be 
repeated as they must be obtained within 28 days of the subject’s infusion. A subject that 
rescreens for any reason may be required to repeat all protocol safety procedures (excluding CT 
of the chest, abdomen and pelvis if previously conducted) if the safety procedures were 
originally conducted greater than 28 days prior to the subject’s infusion. A subject that rescreens 
for any reason may be required to repeat all protocol efficacy procedures including the cardiac 
MRI unless: a) the subject’s efficacy procedures including baseline cardiac MRI were conducted 
within 28 days of infusion; or, b) the subject’s efficacy procedures including baseline cardiac 
MRI were conducted ≥ 60 days post-MI and within 60 days of infusion. After completion of the 
screening procedures and meeting all inclusion and exclusion criteria, study subjects will be 
randomized to receive CAP-1002 or placebo administered via intracoronary infusion. Study 
subjects will undergo catheterization and infusion on the day of admission and will be observed 
in the hospital with continuous cardiac monitoring overnight, 20 to 24 hours afterwards. In the 
absence of serious adverse events, subjects will be discharged the day after catheterization, with 
a 24-hour ambulatory ECG monitor. 
 
 
 


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7.1 
Screening Period  
No screening exams will take place until the subject is fully informed of the research and signs 
the informed consent. Subjects may sign consent and start the screening process immediately 
post-MI (e.g., acute admission at hospital). The following assessments will be permitted within 
28 days immediately following the subject’s MI: signing ICF, review of medical history, review 
of concomitant medications, and collection of laboratory samples required for assessment of 
study eligibility criteria (e.g., eGFR, HbA1c, hepatitis serology, HIV serology, LFTs, hematocrit, 
WBC, and platelet count). All other screening tests, including the subject’s cardiac MRI and CT 
(chest, abdomen, pelvis), must be conducted greater than 28 days post-MI. Relevant safety 
laboratory sample collections (e.g., chemistry, hematology, urinalysis) may need to be repeated 
as they must be obtained within 28 days of the subject’s infusion. 
Screening tests and procedures include: 
• Medical history, limited physical examination, and cardiac physical examination 
• Medication review 
• Vital Signs 
• 12-Lead ECG 
• Laboratory tests: HLA typing, DSA evaluation 
• Echocardiography 
• Cardiac MRI 
• Laboratory tests:  hematology, chemistry, urinalysis, hemoglobin A1c (HbA1c), serum 
NT-proBNP, Serum β- HCG (only for females who are not diagnosed as 
postmenopausal), HIV and hepatitis screens, ELISpot Assay sample; refer to Table 1 for 
comprehensive list of laboratory tests 
• Serum for biomarkers (if subject has provided consent) 
• 24 hour ambulatory ECG monitoring 
• NYHA functional class assessment 
• Six Minute Walk Test 
• MLHFQ 
• SF-36 health survey 
• WPAI:SHP questionnaire 
• Patient Global Assessment 
• Adverse event assessment 
• CT of the chest, abdomen and pelvis [note: the subject’s CT of the chest, abdomen, and 
pelvis should be conducted after all other screening study eligibility criteria have been 
met, including independent imaging core confirmation of baseline (screening) MRI 
eligibility] 
A subject that rescreens for any reason may be required to repeat all protocol safety procedures 
(excluding CT of the chest, abdomen and pelvis if previously conducted) if the safety procedures 
were originally conducted greater than 28 days prior to the subject’s infusion. A subject that 
rescreens for any reason may be required to repeat all protocol efficacy procedures including the 


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cardiac MRI unless: a) the subject’s efficacy procedures including baseline cardiac MRI were 
conducted within 28 days of infusion; or, b) the subject’s efficacy procedures including baseline 
cardiac MRI were conducted ≥ 60 days post-MI and within 60 days of infusion. 
Protocol safety procedures are defined as: 
 Medical history, limited physical examination, and cardiac physical examination 
 Medication review 
 Vital signs 
 12-Lead ECG 
 Laboratory tests:  hematology, chemistry, urinalysis, hemoglobin A1c (HbA1c), serum 
NT- proBNP, Serum β- HCG (only for females who are not diagnosed as 
postmenopausal), HIV and hepatitis screens, and serum for biomarkers (if subject has 
provided consent); refer to Table 1 for comprehensive list of laboratory tests 
 24 hour ambulatory ECG monitoring 
 Adverse event assessment 
Protocol efficacy procedures are defined as: 
 Laboratory tests: serum NT- proBNP HLA typing, DSA evaluation, ELISpot Assay 
sample 
 Echocardiography 
 Cardiac MRI 
 NYHA functional class assessment 
 Six Minute Walk Test 
 MLHFQ 
 SF-36 health survey 
 WPAI:SHP questionnaire 
 Patient Global Assessment 
Randomization will occur after all of the screening examinations have been completed and only 
if the subject continues to meet all of the eligibility criteria.   After the subject is randomized, the 
subject must continue to meet eligibility criteria before proceeding to intracoronary infusion. 
Sites should randomize eligible subjects at least three (3) working days prior to a subject’s 
scheduled infusion date. The Sponsor should be notified of cases that prevent randomization at 
least three (3) working days prior to a subject’s scheduled infusion date (e.g., timing of MRI 
results). Subjects who are not randomized and do not proceed to infusion due to violation of 
eligibility criteria at screening will be withdrawn from the study as screen failures and will have 
no further follow up. 
 
7.2 
Treatment Period 
 
7.2.1 Intracoronary Infusion Visit (Day 0) 
 
Intracoronary infusion of CAP-1002 or placebo must occur within 28 days of the first screening 
procedure that is performed greater than 28 days post-MI. At the infusion visit, subjects will be 
clinically stable as judged by no evidence of infection, stable blood pressure and pulse, as well as 
over the prior four days by history no change in angina pattern, or in angina or heart failure 
medications. 
 


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As part of the infusion visit, subjects will undergo the following tests and assessments:  
 
Pre-infusion: 
• Medical history and cardiac physical examination 
• Medication review 
• Vital signs  
• 12-Lead ECG  
• Laboratory tests:  hematology, chemistry, urinalysis, serum NT-proBNP, and INR/PTT 
[as needed for subjects on warfarin (Coumadin®)]; refer to Table 1 for comprehensive list 
of laboratory tests 
• Cardiac enzymes (Serum troponin and CK-MB)  
 
Post-infusion: 
• Cardiac assessment 
• Vital signs approximately every 8 hours (from infusion time) until discharge 
• Cardiac enzymes (serum troponin and CK-MB) approximately every 8 hours x3 with last 
blood draw immediately prior to discharge (20-24 hours post infusion) 
• Urinalysis 
• 12-Lead ECG (day of discharge) 
• 24 hour ambulatory ECG monitoring (apply to subject immediately prior to discharge) 
• Adverse Event assessment 
 
Subjects must have a patent coronary artery with TIMI flow 3 in order for the IP to be infused.  
Subjects with angiographic evidence of a coronary occlusion determined to be clinically 
significant, with or without clinical symptoms during the day of IP infusion: 1) will not undergo 
intracoronary infusion of the IP, 2) will be withdrawn from the study, and 3) will not be followed 
further for either safety or efficacy. The decision to attempt opening and restoration of TIMI-3 
flow will be based on clinical grounds.  
 
Stopping criteria that would trigger halting of the CAP-1002 or placebo infusion are:  
1. Sustained hypotension unresponsive to fluids and/or medications.  
2. Evidence of acute coronary syndrome.  
3. Development of TIMI flow 0/1, after a cycle of infusion.  
4. Evidence of cerebrovascular accident.  
5. Evidence of cardiac tamponade.  
6. Hemopericardium requiring pericardiocentesis.  
7. Sustained ventricular tachycardia/ventricular fibrillation that require cardioversion or 
administration of an antiarrhythmic.  
8. Evidence of thrombus in the aorta that was not previously seen on imaging studies.  
9. Suspected or confirmed aortic dissection.  
10. Suspected or confirmed coronary dissection.  


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11. Acute onset of rigors (symptoms indicative of acute sensitivity or infection).  
12. Sustained ST-segment elevation or angina symptoms which persist longer than the time 
the balloon is deflated (> 3 minutes) with angiographic evidence of microvascular 
obstruction (i.e., no reflow).  
 
Following intracoronary infusion, subjects will be observed in the hospital for 20-24 hours with 
continuous cardiac (telemetry) monitoring. Troponin and CK-MB laboratory studies will be 
monitored every 8 hours from the end of the infusion. A total of three sets of cardiac enzymes 
will be evaluated to rule out cardiac injury during the post-infusion hospital stay through 
discharge.  If the subject is discharge prior to 24 hours, cardiac enzymes will be drawn just prior 
to discharge. 
 
Prior to discharge from the hospital, a physical assessment will be performed which will include 
chest pain assessment, review of laboratory results, ECG, and arterial puncture site as well as 
assessment of adverse events. In the absence of serious adverse events, subjects will be 
discharged the day after infusion with a 24 hour ambulatory ECG monitor. 
 
The timing of follow-up visits is based on the date of actual or planned IP administration. 
Following intracoronary infusion, a subject visit schedule listing target dates for assessments can 
be printed from the EDC system. 
 
7.2.2 Intracoronary Infusion Procedure 
 
All subjects will receive a dose of IP suspended in 11.1mL of cryopreservation solution 
(CryoStor® CS10, BioLife Solutions, Inc. containing 10% DMSO, 1800 units heparin and 450 
mcg nitroglycerin). Twelve milliliters of an intermediate wash solution containing saline, 1200 
units heparin and 600 mcg nitroglycerin is also administered to each subject between boluses of 
CAP-1002 or placebo. A nitroglycerin-free wash solution may be substituted for the 
intermediate wash solution if, in the opinion of the operator, the blood pressure is too low 
for the subject to receive additional nitroglycerin.  See Table 2 for total heparin and 
nitroglycerin for infusion/wash scenarios. 
 
Intracoronary infusion of the IP will be performed using the Abbott Trek® "over the wire" 
(OTW) balloon angioplasty catheter. A balloon catheter up to 0.5 mm larger in diameter than the 
stent diameter and shorter in length (preferably 8-12 mm) will be positioned in the stented 
segment and inflated at pressures to achieve occlusion of blood flow in the infarct- related artery; 
this is to prevent reflux of the IP infusion. The IP will then be injected through the wire lumen of 
the balloon catheter after the guide wire is removed. The balloon is kept inflated for 
approximately 2 minutes 15 seconds and deflated for approximately 3 minutes in 3 cycles for a 
total procedure time of approximately 12 minutes 45 seconds. Exact balloon inflation and 
deflation times as well as exact infusion times will be recorded during the procedure. 
 
One third of the 11.1mL total volume of IP is infused as a bolus during each balloon inflation 
cycle over the course of approximately 1 minute and 45 seconds. Two mL of the wash solution 
are infused before the IP bolus and 2 mL of the wash solution are infused after each IP bolus, 
both over the course of approximately 15 seconds, so as to wash any remaining IP solution from 


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the catheter (see Figure 1). Subjects may be given intravenous fluids and medications as 
necessary for hypotension during the procedure, per the Investigator’s discretion. 
 
Epicardial coronary flow and myocardial perfusion will be assessed quantitatively at the 
beginning and at the completion of the infusion procedure, using the validated TIMI flow score. 
However, if ST elevation or angina symptoms persist after 3 minutes with the balloon deflated, a 
diagnostic contrast injection will be performed and TIMI flow will be assessed. If ECG 
abnormalities and/or symptoms are due to impairment of blood flow at the myocardial level 
(microvascular obstruction), cell infusion will be terminated. 
 
Hemodynamics, symptoms, and electrocardiogram are continuously monitored while subjects 
are in the catheterization laboratory. If there is any evidence of infarction, the infusion protocol 
will be halted. Subjects will be monitored for 20 - 24 hours following the infusion, including a 
detailed physical examination for evidence of neurologic dysfunction and bleeding, as well as 
ECG and cardiac enzymes for arrhythmias and cardiac damage. 
 
Figure 1. Schematic of Infusion Protocol 
 


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Table 2. Infusion Scenarios for Nitroglycerin and Heparin Doses 
 
 
CAP-1002 vs. 
Placebo 
Bolus 1 
Bolus 2 
Bolus 3 
Total doses 
Heparin 
(U) 
NTG 
(mcg) 
Heparin 
(U) 
NTG 
(mcg) 
Heparin 
(U) 
NTG 
(mcg) 
Heparin 
(U) 
NTG 
(mcg) 
Heparin 
(U) 
NTG 
(mcg) 
Scenario #1 
NTG free wash with all 
bolus’ 
1800  
450  
400  
 
400 
 
400 
 
3000 
450 
Scenario #2 
NTG free wash with 2 of 
3 bolus’ 
1800  
450 
400  
200  
400 
 
400 
 
3000 
650 
Scenario #3 
NTG free wash with 1 of 
3 bolus’ 
1800  
450 
400  
200  
400 
200 
400 
 
3000 
850  
Scenario #4 
NTG Wash with all 
bolus’ 
1800  
450 
400  
200  
400 
200 
400 
200  
3000  
1050  


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7.3 
Follow-Up Period 
 
7.3.1 Week 2 Visit (Day 14 ± 3 days) Procedures 
 
The following procedures will be performed at the Week 2 visit: 
• Cardiac physical examination 
• Medication review 
• Adverse events assessment 
• Vital signs 
• 12-Lead ECG 
• Laboratory tests:  hematology, chemistry, urinalysis, DSA monitoring, serum NT-
proBNP, measurement of cardiac enzymes (serum troponin and CK-MB); refer to Table 
1 for comprehensive list of laboratory tests 
• Serum for biomarkers (if subject has provided consent) 
 
7.3.2 Month 1 Visit (Day 30 ± 3 days) Procedures 
 
The following tests and procedures will be performed at the one month visit: 
• Cardiac physical examination 
• Medication review 
• Adverse events assessment 
• Vital signs 
• 12-Lead ECG 
• Laboratory tests: hematology, chemistry, urinalysis, DSA monitoring, and ELISpot assay, 
serum NT-proBNP, measurement of cardiac enzymes (serum troponin and CK-MB); 
refer to Table 1 for comprehensive list of laboratory tests 
• 24 hour ambulatory ECG recording 
• Echocardiography 
• NYHA functional class assessment 
 
Echocardiography, as mandated in the protocol, will be performed to rule out any new regional 
or global myocardial dysfunction, possibly secondary to inflammation. Cardiac biopsy may be 
performed at any point during the study if clinically indicated by the currently accepted 
recommendations based on expert consensus (Cooper, 2009). If myocarditis is diagnosed by 
histopathologic or clinical criteria, it will be treated according to current standard-of-care. Causes 
of myocarditis that are not likely related to study therapy may include: viral infection, bacterial 
infection, protozoal infection, toxins, drugs, autoimmune diseases, giant cell myocarditis, and 
sarcoidosis (Blauwet & Cooper, 2010). 


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7.3.3 Month 2 Visit (Day 60 ± 6 days) Procedures (Phase I Safety Cohort Only) 
 
The month 2 visit will be performed for Phase I Safety Cohort subjects only.  
 
At the two-month visit the following tests and procedures will be performed: 
• History and cardiac physical examination 
• Medication review 
• Adverse events assessment 
• Vital signs 
• 12-Lead ECG 
• Laboratory tests: hematology, chemistry, urinalysis, DSA monitoring, serum NT-
proBNP; refer to Table 1 for comprehensive list of laboratory tests 
• Serum for biomarkers (if subject has provided consent) 
• 24 hour ambulatory ECG recording 
• NYHA functional class assessment 
 
7.3.4 Month 3 Visit (Day 90 ± 6 days) Procedures 
 
At the three-month visit the following tests and procedures will be performed: 
• Cardiac physical examination 
• Medication review 
• Adverse events assessment 
• Vital signs 
• 12-Lead ECG 
• Laboratory tests: hematology, chemistry, urinalysis, DSA monitoring, serum NT-
proBNP; refer to Table 1 for comprehensive list of laboratory tests 
• Serum for biomarkers (if subject has provided consent) 
• NYHA functional class assessment 
 
7.3.5 Month 6 Visit (Day 180 ± 6 days) Procedures 
 
Subjects will undergo multiple assessments 6 months after intracoronary infusion, including: 
• Cardiac physical examination 
• Medication review 
• Adverse events assessment 
• Vital signs 
• 12-Lead ECG 
• Laboratory tests: hematology, chemistry, urinalysis, DSA monitoring, serum NT-
proBNP; refer to Table 1 for comprehensive list of laboratory tests 
• Serum for biomarkers (if subject has provided consent) 


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• Cardiac MRI 
• 24 hour ambulatory ECG recording 
• NYHA functional class assessment 
• Six Minute Walk Test 
• MLHFQ 
• SF-36 health survey 
• WPAI:SHP questionnaire 
• Patient Global Assessment 
 
If subjects undergo inter-current ICD/pacemaker placement, study imaging sites must be trained 
and certified specifically for this protocol prior to conducting cardiac MRI in subjects with ICD 
and/or pacemaker placement. If subjects develop MRI contraindications, a cardiac MRI will not 
be performed. Such subjects will continue to be followed in the study and undergo all 6 month 
study procedures except MRI. Any subject whose GFR declines to <30 mL/min during a given 
MRI study will not undergo contrast administration on this and subsequent MRI studies. Such 
treated subjects will not be withdrawn but will still be followed for inclusion in safety and 
efficacy analyses for other parameters assessed during the study. 
 
7.3.6 Month 12 Visit (Day 360 ± 6 days) Procedures 
 
Subjects will undergo multiple assessments 12 months after intracoronary infusion, including: 
• Limited physical examination and cardiac physical examination 
• Medication review 
• Adverse events assessment 
• Vital signs 
• 12-Lead ECG 
• Laboratory tests: hematology, chemistry, urinalysis, DSA monitoring, serum NT-
proBNP; refer to Table 1 for comprehensive list of laboratory tests 
• Serum for biomarkers (if subject has provided consent) 
• Cardiac MRI 
• 24 hour ambulatory ECG recording 
• NYHA functional class assessment 
• Six Minute Walk Test 
• MLHFQ 
• SF-36 health survey 
• WPAI:SHP questionnaire 
• Patient Global Assessment 
 
If subjects undergo inter-current ICD/pacemaker placement, study imaging sites must be trained 
and certified specifically for this protocol prior to conducting cardiac MRI in subjects with ICD 
and/or pacemaker placement. If subjects develop MRI contraindications, a cardiac MRI will not 
be performed. Such subjects will continue to be followed in the study and undergo all 12 month 


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study procedures except MRI. Any subject whose GFR declines to <30 mL/min during a given 
MRI study will not undergo contrast administration on this and subsequent MRI studies. Such 
treated subjects will not be withdrawn but will still be followed for inclusion in safety and 
efficacy analyses for other parameters assessed during the study. 
 
7.3.7 Annual Follow-up Phone Call 
 
With consent of the subject, following completion of the 12 Month Visit or following early 
withdrawal, all enrolled subjects who completed treatment infusion will be contacted by phone 
annually on the anniversary of their infusion (± 2 weeks) through year 5 (post-infusion) to assess 
for Major Adverse Cardiac Event (MACE), defined as the composite incidence of death, non- 
fatal recurrent MI, hospitalization for heart failure, emergency room treatment for heart failure 
(NT-proBNP >450 pg/mL or BNP>100 pg/ml, with treatment including intravenous diuretic 
administration), left ventricular assist device (LVAD) placement or heart transplant.  
 
 
7.4 
Performing Adverse Events Assessments 
An Adverse Event (AE) is any untoward medical occurrence in a subject or clinical investigation 
subject temporally 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 this treatment. 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 subject’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 subject’s 
condition. 
 
The Investigator will review all documentation (e.g., hospital progress notes, laboratory, or 


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diagnostic reports) relative to the event being reported. The Investigator will then record all 
relevant information regarding an AE/SAE into the electronic data system. It is not acceptable 
for the Investigator to send photocopies of the subjects’ medical records in lieu of completion of 
the appropriate AE/SAE pages. However, there may be instances when UBC Safety requests 
copies of medical records for certain cases. In this instance, all subject identifiers will be blinded 
on the copies of the medical records prior to submission to UBC Safety. 
 
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. 
 
Adverse events classified by the Investigator as related to investigational product or the 
administration procedure, potential safety endpoints and MACEs are adjudicated by the Clinical 
Endpoints Committee (CEC). Detailed information on the CEC adjudication process can be 
found in the Clinical & Adverse Event Reporting & Adjudication Procedures Manual.  
 
7.4.1 Timing 
 
Adverse event assessment and documentation will occur at every study visit from screening 
throughout the study. On the day of treatment administration, a subject’s medical complaint will 
be considered to be a treatment-emergent adverse event if the event occurs any time after the 
time vascular access is obtained at the beginning of the catheterization for the infusion of CAP-
1002 (or placebo). 
 
7.4.2 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 subject, 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 7.4.7 Serious Adverse Events. 
 
7.4.3 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 


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therapy, other risk 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 or procedure will be defined 
according to one of the following categories: 
• Definite:  The AE/SAE is clearly related to the investigational product or procedure. 
• Probable: The AE/SAE is likely related to the investigational product or procedure. 
• Possible: The AE/SAE may be related to the investigational product or procedure. All 
AEs and SAEs that occur within 24 hours of intervention will, because of the temporal 
relationship, be considered as at least possibly related to the investigational product or 
procedure and will be reported to the DSMB. 
• Unlikely: The AE/SAE is doubtfully related to the investigational product or procedure. 
• Unrelated: The AE/SAE is clearly NOT related to the investigational product or 
procedure. 
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. 
 
7.4.4 Expectedness 
The following adverse events are considered to be expected as a result of the catheterization and 
infusion procedure: 
• Disease-related adverse events are expected 
• Some premature ventricular contractions, non-sustained ventricular tachycardia (<30 sec 
duration) 
• Hypotension (Systolic Blood Pressure <80 mmHg) and/or bradycardia (Heart Rate <50 
beats/min) that responds rapidly to fluid, atropine and possibly vasopressor 
administration, if required 
• Reduction of coronary blood flow, TIMI flow grade I or II, persisting <3 min after 
balloon deflation, during cell infusion 
• Angina, duration <10 min during cell infusion 
• ST elevations, duration <3 min during cell infusion, troponin elevations above the 99th 
percentile but not more than 3x, at any time during the first 24 hours after cell infusion 
• Coronary artery dissection 
• Other risks of the infusion procedure include those risks that are possible with the study 
procedure. These include risks related to infection, bleeding, hypotension, pain and 
hematoma at the arterial puncture site, arrhythmia, sensitivity or allergy to radiographic 
contrast, exposure to radiation, thromboembolism, contrast induced nephropathy, 
myocardial ischemia or infarction. 
• Bleeding, bruising and/or hematoma formation at the site of vascular access for the cell 
infusion procedure, at any time within the first 24 hours after cell infusion 
All adverse events expected or otherwise, should be reported in the subject data. Serious Adverse 


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Events (SAEs) should be reported to the Sponsor within 24 hours of the site learning of the 
event. 
 
7.4.5 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 will indicate whether each abnormal result is clinically significant 
(CS) or not clinically significant (NCS) on the source document and case report form.  
 
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. 
 
7.4.6 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 7.4.5 and will be recorded as AEs or SAEs if they meet the definition of an AE as 
defined in Section 7.4 or SAE, as defined in Section 7.4.7.1. 
 
Clinically significant abnormal laboratory findings that are detected during the study or are 
present at screening 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 subject’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. 
 


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7.4.7 Serious Adverse Events 
 
7.4.7.1 Definition 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a drug, and does not imply any judgment about causality. An adverse 
event can arise with any use of the drug (e.g., off-label use, use in combination with another 
drug) and with any route of administration, formulation, or dose, including an overdose. 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: Death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions, or a 
congenital anomaly/birth defect.  
 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event. For the purposes of IND safety reporting, ‘reasonable 
possibility’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event. A suspected adverse reaction implies a lesser degree of certainty about causality 
than adverse reaction, which means any adverse event caused by a drug. 
 
Within the reporting requirement under 21 CFR 312.32(c)(1)(i), the meaning of reasonable 
possibility is defined by providing the following examples of types of evidence that would 
suggest a causal relationship between the drug and the adverse event.  
 
 A single occurrence of an event that is uncommon and known to be strongly associated 
with drug exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome). 
 
 One or more occurrences of an event that is not commonly associated with drug 
exposure, but is otherwise uncommon in the population exposed to the drug (e.g., tendon 
rupture).  
 
 An aggregate analysis of specific events observed in a clinical trial (such as known 
consequences of the underlying disease or condition under investigation or other events 
that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the drug treatment group than in a concurrent or 
historical control group.  
 
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 subject 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 


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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. 
 
7.4.7.2 Reporting Serious Adverse Events 
 
All SAEs, including any fatal or life-threatening event, must be reported within 24 hours from 
the time the Investigator is made aware of the event. If the Investigator does not have all 
information regarding an SAE, he/she will not wait to receive additional information before 
recording the event in the data system and completing as much information known at the time of 
the submission. The reporting timeframes for any SAE occurring during the study are 
summarized in Table 3. 
 
All SAEs are to be reported as follows: 
 Site completes the SAE Report Form (initial and/or follow-up) and faxes the completed 
form to UBC Safety at 1-877-200-2945. 
 
 UBC Safety will review all information provided and contact the Investigator for 
additional information, as necessary. The DSMB will receive regular safety updates 
from the Sponsor. The Sponsor or designee is responsible for notifying the DSMB of all 
SAEs as described in Table 3.  
 
 Per ICH E2A and 21 CFR 312, regulatory agencies will be notified by the Sponsor by 
telephone or fax of any unexpected, SAR potentially associated with treatment as soon 
as possible, but in no event later than 15 calendar 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 7 calendar days. Follow-up information will be 
provided as required. 
 
 


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Table 3. Serious Adverse Event Reporting Requirements 
 
Serious Adverse Event Reporting Requirements  
Initial Reports 
Follow-Up Reports 
 
Type of SAE 
Serious, Unexpected, 
Reasonable Possibility 
Causality 
 
All Other SAEs 
 
Any SAE 
Reporting 
Timeframes  
(Site to Sponsor) 
24 hours 
24 hours 
72 hours 
Reporting 
Timeframes 
(Sponsor to DSMB) 
Notification will occur 
in parallel with 
applicable Regulatory 
Agencies 
Aggregate reporting 
at time of DSMB 
meetings 
 
 
All AEs and SAEs documented at a previous visit/contact that are designated as ongoing will be 
reviewed at subsequent visits/contacts. 
 
All AEs (including SAEs) will be followed until resolution, until no further changes in the event 
are expected (i.e. the point at which a subject experiencing an adverse event is treated 
successfully and stabilized even though they may continue to experience sequelae) as confirmed 
by the Investigator, until the subject is lost to follow-up, or until the subject’s 12 Month Visit. 
Subjects will be contacted by phone annually through year 5 post-infusion to assess for MACE 
as described in Protocol Section 7.3.7. If a subject dies during participation in the study or during 
a recognized follow-up period, the Medical Monitor 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 electronic data 
system. 
 
The Investigator will promptly report all SAEs within the timeframes specified in Table 3. The 
Investigator will comply with the applicable local regulatory requirements related to reporting of 
SAEs to his or her Institutional Review Board (IRB) or Independent Ethics Committee (IEC). 
 
This protocol is being filed under an investigational study with the appropriate regulatory 
agencies.  A given SAR may qualify for an Expedited Safety Report (ESR) if the SAE is serious, 
unexpected, and has a reasonable possibility that the drug caused the event. 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. 
 


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7.4.7.3 Sponsor Monitoring of Adverse Events 
 
This study will be overseen by two distinct data safety monitoring boards (DSMBs): The 
National Heart, Lung and Blood Institute (NHLBI) DSMB will review the 14 subjects in the 
Safety Cohort and an independent DSMB appointed by the Sponsor will review the Randomized 
Cohort and will have access to all Safety Cohort reports and NHLBI DSMB recommendations. 
 
The following list summarizes the Sponsor’s role in monitoring AE/SAEs: 
• All SAEs will be reviewed on a monthly basis by the Sponsor’s Medical Monitor or 
designee. 
• 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 Sponsor will prepare summary reports of all AEs/SAEs approximately every 6 
months for the NHLBI-sponsored DSMB (Safety Cohort subjects) and for the study-
sponsored DSMB (all subjects enrolled). 
 
7.4.7.4 DSMB Monitoring of Adverse Events 
 
This section generally applies to both the NHLBI and independent DSMB, but the NHLBI DSMB 
will review materials from only the fourteen subjects enrolled in the Safety Cohort. The following 
list summarizes roles of the DSMBs in monitoring AE/SAEs 
 
• The DSMBs will review all SAEs. The Sponsor will report serious, unexpected and 
potentially related SAEs to the DSMB in parallel with reporting to applicable Regulatory 
Agencies.  The DSMB chair (or designee) will be requested to acknowledge receipt of 
SAEs within 72 hours of notification. 
• Approximately every six months the DSMBs will be provided with a summary 
(aggregate) 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 DSMBs. 
• The DSMB Chair (or designee, e.g., NHLBI Project Officer) 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 regarding 
continuation of the study. 
 
7.4.8 Post-Study Adverse Events and Serious Adverse Events 
 
The Investigator should notify the Medical Monitor of any death or SAE occurring at any time 
after a subject 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. 
 
7.5 
Removal of Subjects from the Trial or Study Drug 
 
The Investigator may withdraw a subject from participation in the study for any of the following 


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reasons: 
 
• A protocol violation occurs, 
• An intolerable adverse event occurs, that affects continuation of subject’s participation in 
the study, 
• The Sponsor or Investigator terminates the study, or 
• The subject requests to be discontinued from the study. 
Subjects who become pregnant during the study following the study infusion will be followed 
during the pregnancy and through birth of the newborn. Subjects who become pregnant prior to 
receiving the study infusion will be withdrawn from the study. 
 
7.6 
Other Study Procedures 
 
For subjects who so consent, serum for clinical research into biomarkers will be collected at 
every scheduled visit and sent to the Sponsor for analysis. 
 
7.7 
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 include all MACE events, 
myocarditis, change in TIMI flow to ≤1 following infusion, troponin and CK- MB elevations, 
ventricular tachycardia events, and increases in anti-HLA antibodies as indicative of sensitization 
to CAP-1002 donor antigens. 
 
With respect to efficacy, the perfect surrogate remains elusive in terms of cardiac disease given 
the complexity of the heart failure syndrome.  Data suggest that markers of the biological process 
of left ventricular hypertrophy and enlargement (remodeling) and the factors that contribute to 
this process may be viewed as surrogates for progression of the disease as may functional 
measures and neurohormones (Anand, Florea, & Fisher, 2002). More specifically, it has been 
shown that the validity for infarct size as measured by MRI under a common imaging protocol is 
relatively high when used as a surrogate endpoint for clinical outcomes (Desch et al., 2011). In 
addition, the ability of infarct size to predict clinical endpoints has been demonstrated in 
epidemiological studies (Larose et al., 2010; Wu et al., 2008). 
 
In this trial, the primary efficacy endpoint is change in infarct size (relative to LV size). Infarct 
size represents the extent of myocardial injury sustained after an MI. Infarct size is likely the 
single most important defining factor of the remodeling process, leading to change in function, 
volume and geometry of the LV. Use of a common imaging protocol in the study ensures high 
measurement reliability for infarct size. Infarct size may prove in this study, as in prior studies, to 
be a reasonable MRI surrogate endpoint that correlates with long term subject outcome.  
 
7.8 
Payment to Subjects 
 
Subjects will be paid $100, as applicable in clinical site budgets, for the Screening, Infusion, 
Month 6, and Month 12 visits. Subjects will be paid $50 for all other visits (Week 2, and Months 


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1, 2 and 3). 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, depending on the individual circumstances. Study staff will contact the Sponsor to 
request reimbursement on a case by case basis. 
 
The total amount the subject will receive if they complete the whole study is $550. Safety Cohort 
subjects will receive up to $650 for extra testing and visits conducted in the Phase I portion of 
the study.  Subjects will only be paid for those visits and procedures that they complete. 
 
7.9 
Early Termination Procedures 
 
Every reasonable effort will be made to retain subjects in the study. In the event that a subject 
must be withdrawn from the study early, study personnel should attempt to obtain testing and 
data required for the 12 Month Visit (see Section 7.3.6) as well as the reason for withdrawal, if 
known. If the subject permits, he or she should be contacted by study personnel at the time of 
their usual study visits (and annually through 5 years post-infusion), as described in the protocol. 
 
Follow-up of adverse events that result in discontinuing the subject from the study will continue 
until resolution, until the event has stabilized as confirmed by the Investigator, or until the event 
has been determined to be caused by an agent other than the study drug. 
 
All consenting subjects, including those who discontinued early from the study, will be contacted 
by phone annually on the anniversary of their infusion through year 5 post-infusion to assess for 
MACE, defined as the composite incidence of death, non- fatal recurrent MI, hospitalization for 
heart failure, emergency room treatment for heart failure (NT-proBNP >450 pg/mL or BNP>100 
pg/ml, with treatment including intravenous diuretic administration), left ventricular assist device 
(LVAD) placement or heart transplant. 
 
A subject 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 subject is not accomplished, study personnel should follow-up with 
certified mail in the following manner: 
 
1. Mail a certified letter with return receipt requesting contact and expressing concern for the 
subject’s well-being. 
2. If the subject does not respond within seven days, mail another certified letter with return 
receipt stating that the subject’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 subject signed it. Otherwise, record the termination date as the date the second letter 
was mailed. 
8 
QUALITY CONTROL AND ASSURANCE 
 
Data will be entered using an EDC system. A detailed description of the data collection tools and 
data management process can be found in the case report form completion guidelines and other 
data management materials that will be provided to each site.  The site must ensure appropriate 
source data documentation. The Investigator or designee must enter all required subject data in 
the EDC system in a timely fashion (within 3 weeks of study visit) and an explanation must be 
documented for any missing data. 


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A site initiation visit will be conducted at each site participating in the Safety and Randomized 
Cohorts prior to subject enrollment.  During this visit, there will be a review of the study 
protocol, study procedures, the case report forms, the data collection and submission process, and 
the site’s regulatory obligations as well as any special procedures with the center personnel. A 
representative from the Sponsor will lead the site initiation visits. All training will be 
documented. A formal, centralized investigator meeting will be held prior to initiation of 
enrollment for the Randomized Cohort accompanied by site initiation visits if required/desired 
by site or Sponsor. 
 
9 
PLANNED STATISTICAL METHODS 
 
9.1 
General Considerations 
 
The Statistical Analysis Plan (SAP) for the Phase 1 Safety Cohort was drafted prior to the start of 
Phase 1 enrollment with modifications made in the analysis over time based on requests from 
DSMB during Phase 1. 
 
Pre-specified analyses will be detailed in a Statistical Analysis Plan (SAP). Descriptive 
summaries will be provided for all safety and efficacy parameters by cohort (Primary or 
Exploratory) and stratum (recent or chronic MI). Primary efficacy analyses will be performed for 
the analysis population using a modified intent-to-treat population with post-baseline outcome 
data.  Handling of missing data will be addressed in the SAP. 
 
All analyses and reports will be developed and validated per Good Clinical Practices.  An 
independent DSMB will monitor the study and make recommendations, if needed, regarding 
stopping the study due to safety concerns. 
9.2 
Determination of Sample Size 
 
In total, a maximum of approximately one hundred thirty-four (134) subjects with a MI and 
resulting ischemic left ventricular dysfunction meeting all inclusion and no exclusion criteria will 
be enrolled. The first fourteen (14) subjects (7 Recent MI and 7 Chronic MI) will receive CAP-
1002 open-label and will be designated as the Safety Cohort. The approximate maximums of one 
hundred three (103) subjects in the Primary Randomized Cohort (51-52 Recent MI and 51-52 
Chronic MI)  and the up to 17 subjects in the Exploratory Randomized Cohort will begin to 
enroll only after DSMB review of the Safety Cohort data and recommendation to proceed. These 
approximately 120 subjects in the Primary Randomized Cohort and Exploratory Randomized 
Cohort will be independently randomized in a double-blind fashion to receive either CAP-1002 
or placebo in a 2:1 ratio, favoring CAP-1002 to achieve approximately up to 93 subjects with 
complete 12 month data in the Randomized Cohort. A balancing algorithm will be used to 
ensure site-specific balancing to the 2:1 allocation after stratifying for prior MI. 
 
The Safety Cohort was evaluated once all subjects reached the primary safety endpoint assessed 
at the 1 month visit. With n=14, if no significant safety events are observed, the one-sided 95% 
upper bound for the true rate of significant events would be < 20%.  The DSMB conducted a 
review of the Safety Cohort data and made a recommendation to proceed with randomization of 
the next 120 subjects. Efficacy and safety will be assessed at all post-screening visits, although 


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MRI testing will only be completed at 6 and 12 months; the 12 month visit is the primary 
efficacy endpoint.  
 
Historical Data 
 
The CADUCEUS and ALLSTAR Safety Cohort data provide some background for planning 
sample size to test for efficacy.  The efficacy endpoints in the CADUCEUS study and in the 
ALLSTAR Safety Cohort included the relative change in the Month 6 and 12 outcomes relative 
to baseline as judged by MRI assessment of infarct size (measured in %). Assumptions used for 
power calculations are summarized below in Table 4 with the relative change displayed as a 
percent improvement from baseline. The ALLSTAR Safety Cohort was used for the assumed 
means and SDs and CADUCEUS was used for the treatment effect in Chronic MI patients 
relative to Recent MI.  
 
Table 4. Sample Size Assumptions 
 
 
 
Month 6 
Month 12 
 
Mean 
SD 
Mean 
SD 
CAP-1002 Recent 
6.20 
10.00 
14.70 
10.00 
CAP-1002 Chronic 
3.10 
10.00 
7.35 
10.00 
Placebo 
0.00 
10.00 
0.00 
10.00 
 
Power calculations using Monte Carlo simulation indicated that, under these assumptions, the 
trial will have more than 90% power to be declared successful with a total sample size of 100. 
 
Primary Randomized Cohort 
The Primary Randomized Cohort is designed to assess the efficacy of the study agent as well as 
further evaluate the safety profile of CAP-1002. Up to 103 subjects will be enrolled in the 
Primary Randomized Cohort. This maximum sample size is based on the Recent and Chronic MI 
strata being analyzed independently with a treatment effect of 15% at Month 12 for each strata, a 
pooled standard deviation of 10%, a minimum power of 80%, and a significance level (alpha) of 
0.05.   
Exploratory Randomized Cohort 
The Exploratory Randomized Cohort sample size of up to 17 subjects was estimated based on 
DSA results observed in the Safety Cohort, where approximately 14% of the screened subjects 
had pre-formed antibodies to all available donors. That is, assuming a 14% rate of pre-formed 
DSAs, approximately 120 subjects would be screened to achieve enrollment of 103 in the 
matched Primary Randomized Cohort, thus yielding up to 17 subjects enrolled in the Exploratory 
Randomized Cohort. Enrollment into the Exploratory Randomized Cohort is capped at n=17, 
with no pre-specified limit for subject counts in the Recent and Chronic stratum. Enrollment in 
the study will be complete when the Primary Randomized Cohort is fully enrolled, regardless of 
whether the Exploratory Randomized Cohort has enrolled.  
 
9.3 
Analysis Populations 
 
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months. Subjects will have study visits at 2 weeks, 1, 3, 6, and 12 months following infusion. 
Subjects enrolled in the Safety Cohort will also have a 2 month study visit. 
 
The analysis population for assessing safety will consist of all subjects in a given Cohort (Safety, 
Randomized) who received an infusion of either CAP-1002 or placebo. The primary analysis 
population for assessing efficacy will consist of all subjects in the safety population from 
Primary Randomized Cohort (Primary Modified Intent-to-Treat (mITT) Population) who had a 
baseline observation and at least one post-baseline observation. The Safety Cohort subjects will 
be summarized and analyzed distinctly from the Randomized Cohort due to the unblinded nature 
of the treatment assignment.  Similarly, the Exploratory Randomized Cohort of mismatched 
subjects will also be summarized distinctly from the Primary Randomized Cohort. Details on 
additional analysis populations will be addressed in the SAP. 
 
9.4 
Demographics and Baseline Characteristics 
 
Demographics and baseline characteristics of all accrued subjects such as race, ethnicity, sex, 
and age will be summarized and reported. The gender and minority distributions are expected to 
reflect a highly multicultural infarct subject population. There are no particular recruitment 
strategies for women or minorities. 
 
9.5 
Primary Endpoint(s) 
 
9.5.1 Primary Safety Endpoint(s) 
 
Medical Dictionary for Regulatory Activities (MedDRA) will be used for this study to code 
adverse events. 
 
The primary safety endpoint is the proportion of subjects experiencing any of the following 
adjudicated events within one month following intracoronary infusion: 
 
1.   Acute myocarditis possibly attributable to CAP-1002 or placebo, diagnosed with 
consideration of clinical context, with or without a clinically indicated endomyocardial 
biopsy. In order to be considered related to CAP-1002 or placebo, humoral or cellular 
immune reaction specific to CAP-1002 must also be documented for subjects treated with 
CAP-1002, or a temporal relationship with IP administration must exist for subjects 
administered placebo. 
2.   Death due to 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. 
3.  Sudden unexpected death defined as occurring within one hour of symptom onset, or un- 
witnessed death in a person previously observed to be well within the preceding 24 hours 
without an identified cause. 
4.   Major adverse cardiac event (MACE), defined as the composite incidence of death, non- fatal 
recurrent MI, hospitalization for heart failure, emergency room treatment for heart failure 
(NT-proBNP >450 pg/mL or BNP>100 pg/ml, with treatment including intravenous diuretic 
administration ), left ventricular assist device (LVAD) placement or heart transplant. Peri-
infusion MI will be defined as presence of troponin or CK-MB levels > 5 times the upper 
reference limit during the 24 hours following infusion. These elevations must be 


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accompanied by symptoms of ischemia >20 minutes in duration and ECG changes indicative 
of new ischemia (new ST-T changes or new left bundle branch block), development of 
pathological Q waves on the ECG, imaging evidence of new loss of viable myocardium, or 
new regional wall motion abnormality. 
 
Point estimates and two-sided 95% confidence intervals for the proportion of subjects who 
experience any of the four events will be presented. Similarly, each of the four endpoints will be 
summarized separately with point estimates and two-sided 95% confidence intervals for the 
proportion of subjects who experience each event within the first month post-infusion. Also, 
two-sided 95% confidence intervals will be constructed for the difference between CAP-1002 
and placebo and a two-sided Fisher Exact test will be used to compare the treatments for the 
Safety Analysis Set.  
 
9.5.2 Primary Efficacy  
 
The primary efficacy objective is to determine if the administration of CAP-1002 by 
intracoronary infusion may result in structural cardiac benefits for subjects with ischemic left 
ventricular dysfunction and a previous MI as measured by the percent change from baseline in 
the MRI assessment of infarct size as a percent of left ventricular mass at 12 months post 
administration. Baseline assessments are conducted during the “Screening” visit, prior to the 
administration of CAP-1002 or placebo. 
The primary efficacy hypothesis is that CAP-1002 is superior to placebo in reducing infarct size 
in either all subjects combined (“full group”) or in subjects with recent MI (“subgroup”). A 
closed testing procedure will be used so that strong control of type 1 error is maintained. 
Specifically, the following hypothesis sets will be tested: 
 
1) 
 
Ho_s:  µc_s - µp_s = 0  
        or  
Ho_f:  µc_f - µp_f = 0 
 
 
 
Ha_s:  µc_s - µp_s  <  0  
 
Ha_f:  µc_f - µp_f < 0 
 
 
 
 
 
and 
 
 
2) 
 
Ho_s ∩ Ho_f:  µc_s - µp_s = 0  and  µc_f - µp_f = 0 
 
 
 
Ha_s ∩ Ha_f:  µc_s - µp_s < 0  or  µc_f - µp_f < 0 
 
where s denotes the subgroup, f denotes the full group, µc_s and µp_s are mean percent changes in 
the CAP-1002 and placebo treatment groups, respectively, in the subgroup, and µc_f and µp_f are 
mean percent changes in the CAP-1002 and placebo treatment groups, respectively, in the full 
group.  
Therefore, both the intersection null hypothesis (Ho_s ∩ Ho_f) and either of the individual null 
hypotheses (Ho_s or Ho_f) must be rejected at the (one-sided) 0.025 significance level for the trial 
to be declared a success. In other words, the null hypothesis of “no treatment effect in the full 
group and no treatment effect in the recent MI subgroup” must be rejected at the one-side 0.025 
significance level, necessarily meaning that either the result is significant in the full group, in the 
recent MI subgroup, or both. The results of the tests of the individual hypotheses (also at the one-
sided 0.025 significance level) determines which specific comparisons are significant. 


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The primary analysis will be a longitudinal mixed effects model. The response variable of 
percent change from baseline in infarct size as a percent of left ventricular mass will be modeled 
with the fixed categorical effects of treatment group and time (6 and 12 months), as well as a 
continuous fixed covariate of baseline infarct size. Intercept and subjects will be treated as 
random in this mixed effects model. The primary hypothesis will be tested using the estimate of 
treatment effect compared to placebo at 12 months. An additional test will compare the 
treatments at 6 months and will be considered secondary. Model results will be provided for 
fixed affects and estimates for each level of each affect. A mean profile plot will be presented to 
describe the treatment response over time.  
The final primary efficacy analysis population will depend on the results of the adaptive design 
interim analysis. The final analysis will use the above model and the study result will depend on 
the result of a Dunnett intersection test p-value calculated from the final mixed model results 
similarly to the interim. The adaptive design interim analysis conducted on approximately 80 
subjects with 6 month follow-up data in the Primary Randomized Cohort across the Recent MI 
and Chronic MI strata will determine whether the analysis will be based on the strata combined 
or the Recent MI strata alone. See the Adaptive Design IAP for details. 
 
9.6 
Secondary Endpoint(s) 
 
9.6.1 Secondary Safety Endpoint(s) 
 
The following adjudicated events will be evaluated as secondary safety endpoints during the 
twelve-month follow-up period: 
 
1. Acute myocarditis possibly attributable to CAP-1002 or placebo, diagnosed with 
consideration of clinical context, with or without a clinically indicated endomyocardial 
biopsy. In order to be considered related to CAP-1002 or placebo, humoral or cellular 
immune reaction specific to CAP-1002 must also be documented for subjects treated with 
CAP-1002, or a temporal relationship with IP administration must exist for subjects 
administered placebo. 
2. Death due to ventricular tachycardia or ventricular fibrillation defined as occurring with prior 
ECG documentation of these arrhythmias during ambulatory ECG monitoring in an 
outpatient setting or during routine ECG monitoring while hospitalized. 
3. Sudden unexpected death defined as occurring within one hour of symptom onset, or un- 
witnessed death in a person previously observed to be well within the preceding 24 hours 
without an identified cause. 
4. Major adverse cardiac event (MACE), defined as the composite incidence of death, non- fatal 
recurrent MI, hospitalization for heart failure, emergency room treatment for heart failure 
(NT-proBNP >450 pg/mL or BNP>100 pg/ml, with treatment including intravenous diuretic 
administration), left ventricular assist device (LVAD) placement or heart transplant. Peri-
infusion MI will be defined as presence of troponin or CK-MB levels > 5 times the upper 
reference limit during the 24 hours following infusion. These elevations must be 
accompanied by symptoms of ischemia > 20 minutes in duration and ECG changes indicative 
of new ischemia (new ST-T changes or new left bundle branch block), development of 
pathological Q waves on the ECG, imaging evidence of new loss of viable myocardium, or 


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new regional wall motion abnormality. 
5. New cardiac tumor formation on MRI imaging. 
6. Any hospitalization due to a cardiovascular cause or related to CAP-1002 or placebo 
infusion. 
7. Any inter-current cardiovascular illness or one related to CAP-1002 or placebo infusion, 
which prolongs hospitalization. Evidence of myocardial injury will be assessed by a rule out 
MI cardiac enzyme protocol performed following administration of CAP-1002 or placebo. 
Troponin and CK-MB will be obtained approximately every 8 hours for the first 24 hours 
after infusion. 
8. New TIMI flow ≤1, following intracoronary infusion of CAP-1002 or placebo. 
9. Development of, or an increase in the frequency of, ventricular tachycardia with a duration of 
30 beats or longer ascertained by periodic, protocol-mandated 24 hour ambulatory ECG 
monitoring. 
10. Development of increased anti-HLA antibody levels with development of sensitization to 
HLA antigens specific to the CAP-1002 CDC donor. 
 
9.6.2 Secondary Efficacy 
 
All comparisons in the secondary analyses will be based on a null hypothesis of no difference in 
the endpoint between subjects administered CAP-1002 as compared to placebo and an alternate 
hypothesis of a difference in the endpoint for subjects administered CAP-1002 as compared to 
placebo. Secondary analyses will be based on a random effects model similar to the primary but 
will be based on an alpha of 0.05 without controlling for multiplicity.  
The following secondary efficacy endpoints will be evaluated during the six-month and 
twelve-month follow-up periods: 
Global LV Function measures 
1. Percent change and change from baseline in MRI assessment of LVEF  
2. Percent change and change from baseline in MRI assessment of left ventricular 
end-diastolic and end-systolic volumes indexed to BSA  
Structural measures 
3. Change from baseline in MRI assessment of infarct size as a percent of left ventricular 
mass 
4. Percent change and change from baseline in MRI assessment of infarct size expressed in 
grams 
5. Percent change and change from baseline in MRI assessment of viable mass expressed in 
grams 
Regional measure 
6. Percent change and change from baseline in MRI assessment of function in the region 
which received CAP-1002 therapy 
Clinical function/status measures 
7. Changes from baseline in distance covered in six minute walk test 


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8. Change from baseline in Minnesota Living with Heart Failure Questionnaire (MLHFQ) 
score 
9. Change from baseline in SF-36 score 
10. Change from baseline in WPAI:SPH score 
11. Change from baseline in Patient Global Assessment (PGA) score 
12. Change from baseline in NYHA Class 
Biomarker 
13. Percent change and change from baseline in NT-proBNP  
14. Change from baseline in log transformed NT-proBNP 
Additional detail regarding secondary endpoint analyses can be found in the SAP. 
 
Analyses of the secondary efficacy endpoints will be performed using the same longitudinal 
modeling approach as the primary efficacy endpoint; the baseline covariate used in the model 
will be the baseline of the endpoint being analyzed. Two-sided testing will be performed at level 
p=0.05. 
A correlational analysis will be presented (for tissue based and functional measures) with 
Pearson’s correlation coefficient for all possible pairs of efficacy endpoints and where 
appropriate the Spearman’s correlation coefficient will be presented. 
 
9.7 
Administrative Interim Analysis 
 
 
An interim safety and efficacy analysis will be performed after all Primary Randomized Cohort 
subjects have completed 6 months of follow-up. This is a pre-planned final analysis of the final 6 
month data. This analysis will be unblinded. The analysis results will be used for planning of 
Phase III activities and will have no effect on the conduct of the study. This interim analysis will 
be considered administrative and no adjustments to the study alpha will be made. 


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Subjects, investigators, and Sponsor’s personnel who had direct responsibility for monitoring at 
the sites will be blinded throughout the study. Following the interim analyses planned for the 
determination of efficacy at 6 months, the appropriate Sponsor representatives will be unblinded 
in order to review and make decisions regarding entry into Phase III clinical development. 
Sponsor personnel will be unblinded to pooled, group data but not to individual, subject level 
data. Personnel with access to the unblinded data and analysis results will be detailed in an 
unblinding memorandum to be filed in the Trial Master File. Unblinded interim data and analysis 
results will be kept confidential from other company personnel involved with trial conduct and 
from investigators, patients, and their families.  
9.8 
Study Stopping Guidelines 
 
9.8.1 Safety Cohort (Phase I) 
 
This guideline is to be used to indicate boundaries requiring discussion by the DSMB and is 
designed to assist the independent NHLBI-appointed DSMB in overseeing the study. 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 primary safety 
endpoints will be conducted. All SAEs will be reported to the DSMB for review. 
 
The proportion of subjects experiencing serious procedure-related outcomes (SPROs) will be 
monitored using a stopping guideline to be consistent with an external standard for safety in 
subjects undergoing angioplasty and stent placement. A 20% patient-specific probability (PSP) 
among CAP-1002 -treated subjects would be the upper bound of acceptability. The study may be 
stopped if two subjects experience a SPRO.  
 
9.8.2 Randomized Cohort (Phase II) 
 
Safety will continue to be assessed by the DSMB by comparing the PSP between the randomized 
CAP-1002 and placebo groups. The Sponsor will engage an independent DSMB to monitor the 
boundaries requiring discussion in overseeing the study. 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 all reports 
pertaining to the comparison of CAP-1002 to placebo, including any related literature of external 
concerns. 
 
The proportion of subjects experiencing SPROs will be monitored at pre-planned intervals set by 
the DSMB. A series of charts (n=60, 120, 180, and 234) have been created to assist with this 
oversight (see Appendix 3); the thresholds for ruling out a 10% absolute excess decreases as data 
accrue. These charts were computed using a one-sided 95% Fisher Exact test over a broad range 
of possible SPRO outcomes.  No Type I error adjustment will be made for repeated safety looks 
since the ultimate decision regarding safety represents a clinical decision involving all safety 
endpoints as an additional obligation beyond efficacy. The DSMB will also monitor efficacy but 
no futility analyses for efficacy are planned. 
 
9.8.3 Exploratory Randomized Cohort (Phase II) 
 


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There are no formal stopping guidelines for this group. In general, these subjects will be 
considered independently of the Primary Randomized Cohort, but will be reviewed in detail by 
the DSMB as are all other subjects.  Any safety concerns will be considered by the DSMB in the 
context of the greater study, including the Primary Randomized Cohort.  Should safety concerns 
arise in the Exploratory Randomized Cohort, the DSMB will make a recommendation regarding 
continuing of enrollment of mismatched subjects into the study. 
10  ADMINISTRATIVE CONSIDERATIONS 
 
10.1 Investigators and Study Administrative Structure 
 
A complete list of participating Investigators and institutions will be maintained by the Sponsor 
and 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, the staff may 
contact the ALLSTAR Sponsor staff using the current study contact information as provided on 
http:/www.clinicaltrials.gov in the listing for this study.:  
 
Contact information for the Medical Monitor for the study is provided below: 
Sponsor Medical Monitor:  
   
 
 
  
 
Study Monitors (Clinical Research Associates) will also be assigned to this study and contact 
information will be provided to the sites throughout the study. 
 
The lead Principal Investigators are 
 
 
 
 
 were responsible for 
enrolling subjects in the Safety Cohort of subjects. Approximately 45 sites will support 
enrollment. 
 
Contract research organizations (CROs) will be used, at the Sponsor’s direction, for site 
monitoring, data management, and some analyses and reporting for the study.  A core imaging 
group will be used to centrally read all MRIs and a core laboratory will be used to analyze 
samples for HLA typing, DSA monitoring and cellular immune response (ELISpot). Contact 
information for these groups will be provided to the sites prior to the start of the study. 
 
In order to ensure quality and continuance of patient care, it is highly recommended that the 
subject inform his/her primary cardiac care physician of his/her participation in ALLSTAR. 
 


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10.2 Institutional Review Board (IRB) or Independent Ethics Committee (IEC) 
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) or Independent 
Ethics Committee (IEC). The composition and conduct of this committee must conform to the 
United States CFR and ICH E6. 
 
The IRB/IEC must also review and approve the site’s informed consent form (ICF), other written 
information provided to the subject and all advertisements that may be used for subject 
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/IEC reviews and approves these amended documents. An 
IRB/IEC approval of the amended protocol and/or ICF must be obtained in writing before 
implementation of the amended procedures and before new subjects are consented to participate 
in the study using the amended version of the ICF. 
 
10.3 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 Harmonisation 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. 
 
10.4 Subject Information and Consent 
 
Before being admitted to the clinical study, all subjects must consent in writing to participate. An 
ICF will be given to each subject, 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 subject. 
 
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 subject. The review will include the nature, 
scope, procedures, and possible consequences of the subject's participation in the study. The ICF 
and review will be in a form understandable to the subject. The Investigator or designee and the 
subject must both sign and date the ICF after review and before the subject can participate in the 
study. The subject 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 subject 
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 subject 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 subjects and repeat the consent process with the amended ICF 
for any ongoing subjects. 
 
10.5 Subject Confidentiality 
 
Subjects’ names will remain confidential; only subject number and birth date will be recorded in 
the database. If the subject 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 electronic databases. The subjects 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. 
 
Subjects 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 subject 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 subject 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 subject's personal physician or to other appropriate medical personnel when required in 
connection with the subject's continued health and welfare. 
 
The Sponsor will maintain a personal subject identification list (subject and treatment numbers 
with the corresponding subject names) to enable records to be identified. 
 
10.6 Study Monitoring 
 
The Sponsor will provide study monitors and will determine the frequency of monitoring visits 
primarily based on individual site enrollment and site compliance with protocol- dictated 
procedures, with visits generally occurring once every 2-4 months.  All sites will be monitored 
shortly after the first subject at the site completes the Infusion Visit. Additionally, study monitors 
will have continuous access to the electronic data capture (EDC) system to review completion of 
study documents, data and adverse event reporting in a timely manner. 
 
 


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10.7 Case Report Forms and Study Records 
 
All CRFs will be completed in accordance with GCP guidelines and as soon as possible after 
each clinical trial visit. 
 
An electronic data capture (EDC) system will be utilized to record all of the protocol required 
information to be reported to the Sponsor on each trial subject. In the event that the EDC system 
is not functioning or accessible, a paper case report form (CRF) will be utilized in the interim 
and later entered into the EDC system.  Study personnel from each site will be trained in how to 
access and use the EDC system to enter and transmit data for the study. Study personnel will be 
given a “sign in” and password unique to them which will not be used by any other personnel.  
Study personnel will be trained regarding proper correction of data entries in the EDC system. 
 
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. CRFs will not serve as source documents. 
 
10.8 Data Monitoring Committee 
 
Safety Cohort 
 
The NHLBI Data and Safety Monitoring Board (DSMB) will oversee subjects enrolled in the 
Safety Cohort. Interim data reviews will be conducted at times coincident with regularly 
scheduled meetings of the NHLBI-appointed DSMB in accordance with reaching accrual and 
follow up milestones. The DSMB Chair will be notified each time that an SAE occurs. The 
DSMB evaluated unblinded AE data (including SAEs) in the Safety Cohort after the initial 4 
subjects were treated with 12.5 M CDCs, after the first 4 subjects were treated with 25M CDCs 
and  again when all 14 subjects completed their one month study visit (the primary endpoint) to 
trigger the initiation of the Randomized Cohort.  The NHLBI DSMB also reviewed the Safety 
Cohort after all 14 subjects competed their 2 month and their 6 month follow up visits. They 
reviewed enzyme evidence of any infarction within 24 hours of the infusion and any evidence of 
arrhythmias during the month following infusion, as well as echocardiography, anti-HLA 
antibody immunoassay, ELISpot immunoassay and  cardiac enzyme data collected at the one 
month study visit; this review occurred prior to proceeding with the Randomized Cohort. Other 
safety data, including the laboratory values were also evaluated by the DSMB as appropriate. 
Policies of the DSMB are described in the NHLBI DSMB Charter. The stopping guidelines serve 
as a trigger for consultation with the DSMB for additional review, and are not formal “stopping 
rules” that would mandate automatic closure of study enrollment. Stopping will be at the 
discretion of the Sponsor, after consideration of DSMB recommendation. 
 
Randomized Cohort 
 
An independent DSMB appointed by the Sponsor will oversee the Randomized Cohort and will 
observe the activities of the NHLBI DSMB during the Safety Cohort. The Randomized Cohort 
will begin only after the NHLBI DSMB has conducted a review of the 14 Safety Cohort 
subjects’ one-month safety data. Interim data reviews during the Randomized Cohort will be 
conducted at times coincident with regularly scheduled meetings of the DSMB at intervals not to 
exceed 6 months apart. The DSMB will evaluate unblinded safety at all meetings; this will 
include all safety datain the form of tables, figures, listings, and narratives. The DSMB Chair 


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will be notified each time that an SAE occurs. They will review MRI data collected at the six 
month study visit. Other safety data, including the laboratory values will also be evaluated by the 
DSMB as appropriate. Monitoring of key safety endpoints will be conducted as described above, 
and if rates significantly exceed preset thresholds, the Sponsor will be notified and information 
will be supplied to the DSMB. Policies of the DSMB will be described in the DSMB Charter. 
The stopping guidelines serve as a trigger for consultation with the DSMB for additional review, 
and are not formal “stopping rules” that would mandate automatic closure of study enrollment. 
Stopping will be at the discretion of the Sponsor, after consideration of DSMB recommendation. 
 
10.9 Protocol Violations/Deviations 
 
As they occur, protocol violations (i.e., events that have potential to impact interpretation of data 
for intended population, such as violations of inclusion/exclusion criteria) and deviations (i.e., 
variations from protocol-specified processes unlikely to impact interpretation of data for intended 
population) will be documented at each site and reported to the Sponsor. 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 medical director and statistician will review the circumstances 
of each violation (in a blinded fashion) to determine whether the data can reasonably be included 
in the per protocol final  analysis. 
 
10.10 Access to Source Documentation 
 
The Investigator, Sponsor’s monitor 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/IEC review, and regulatory inspection(s), with direct access to source 
data and documents. 
 
10.11 Data Generation and Analysis 
 
Contract research organizations (CROs) will provide data management and analysis and 
reporting services to the Sponsor.  A validated EDC system proprietary to the CRO will be 
utilized to collect data and generate a database. Study sites will be responsible for entering data 
collected at the site. External data sources (i.e., central labs and core imaging center) are 
expected either to provide data sets for electronic upload into the EDC database or enter the 
appropriate data directly into the EDC system.  Data queries will be generated by the EDC 
system and by CRO data managers and then forwarded to the sites for resolution.  As part of 
database quality assurance, critical fields (e.g., key efficacy and safety parameters) will be 100% 
verified between the database and e-CRFs and 10% of all other data pages will also be audited 
by the CRO. 
 


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10.12 Retention of Data 
 
In accordance with 21 CFR 312.62, an Investigator participating in this study shall retain 
records, including the case report forms 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 appropriate regulatory agencies, until 2 years after the investigation is 
discontinued and appropriate regulatory agencies are notified. In any case, the Sponsor should be 
notified prior to the destruction of any study records. 
 
10.13 Financial Disclosure 
 
In accordance with regulatory requirements, 21 CFR 54.4, the Clinical Investigators and Sub-
Investigators at each site will be required to complete a financial disclosure form provided by the 
Sponsor prior to participation in the study. Each Clinical Investigator/Sub- Investigator shall 
provide to the Sponsor of the study sufficient 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 appropriate regulatory agency regulations. Each Clinical Investigator/Sub-
Investigator shall promptly update this information if any relevant changes occur in the course of 
the study or for 1 year following completion of the study. 
 
10.14 Publication, Use and Disclosure Policy 
 
Unless the Sponsor has given its written consent in advance or unless otherwise provided in the 
Clinical Trial Agreement executed by the parties with respect to the study, neither the Institution 
where the study is being conducted nor any Clinical Investigator/Sub-Investigator or study 
personnel may publish Sponsor confidential information or study data, disclose Sponsor 
confidential information or study data to any third party, or use Sponsor confidential information 
or study data for any purpose other than the performance of the study. 
 
 


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Amendment 8.1 
11  REFERENCE LIST 
 
1.   Anand, I. S., Florea, V. G., & Fisher, L. (2002). Surrogate end points in heart failure. 
[Review]. Journal of the American College of Cardiology, 39(9), 1414-1421. 
2.   Assmus, B., Honold, J., Schachinger, V., Britten, M. B., Fischer-Rasokat, U., Lehmann, R., 
et al. (2006). Transcoronary transplantation of progenitor cells after myocardial 
infarction. The New England journal of medicine, 355(12), 1222-1232. 
3.   Assmus, B., Rolf, A., Erbs, S., Elsasser, A., Haberbosch, W., Hambrecht, R., et al. (2010). 
Clinical outcome 2 years after intracoronary administration of bone marrow- derived 
progenitor cells in acute myocardial infarction. Circulation. Heart failure, 3(1), 89-96. 
4.   Blauwet, L. A., & Cooper, L. T. (2010). Myocarditis. Prog Cardiovasc Dis, 52(4), 274-288. 
5.   Bolli, R., Chugh, A. R., D'Amario, D., Loughran, J. H., Stoddard, M. F., Ikram, S., et al. 
(2011). Cardiac stem cells in patients with ischaemic cardiomyopathy (SCIPIO): initial 
results of a randomised phase 1 trial. Lancet, 378(9806), 1847-1857. 
6.   Bolli, R., Jneid, H., & Dawn, B. (2005). Bone marrow cell-mediated cardiac regeneration a 
veritable revolution. Journal of the American College of Cardiology, 46(9), 1659-1661. 
7.   Cooper, L. T., Jr. (2009). Myocarditis. The New England journal of medicine, 360(15),1526-
1538. 
8.   Desch, S., Eitel, I., de Waha, S., Fuernau, G., Lurz, P., Gutberlet, M., et al. (2011). Cardiac 
magnetic resonance imaging parameters as surrogate endpoints in clinical trials of acute 
myocardial infarction. Trials, 12, 204. 
9.   Dillman, J. R., Ellis, J. H., Cohan, R. H., Strouse, P. J., & Jan, S. C. (2007). Frequency and 
severity of acute allergic-like reactions to gadolinium-containing i.v. contrast media in 
children and adults. AJR. American journal of roentgenology, 189(6), 1533-1538. 
10. Dohmann, H. F., Perin, E. C., Takiya, C. M., Silva, G. V., Silva, S. A., Sousa, A. L., et al. 
(2005). Transendocardial autologous bone marrow mononuclear cell injection in 
ischemic heart failure: postmortem anatomicopathologic and immunohistochemical 
findings. [Case Reports]. Circulation, 112(4), 521-526. 
11. Hare, J. M., Traverse, J. H., Henry, T. D., Dib, N., Strumpf, R. K., Schulman, S. P., et al. 
(2009). A randomized, double-blind, placebo-controlled, dose-escalation study of 
intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial 
infarction. Journal of the American College of Cardiology, 54(24), 2277-2286. 
12. Hirsch, A., Nijveldt, R., van der Vleuten, P. A., Tijssen, J. G., van der Giessen, W. J., Tio, R. 
A., et al. (2011). Intracoronary infusion of mononuclear cells from bone marrow or 
peripheral blood compared with standard therapy in patients after acute myocardial 
infarction treated by primary percutaneous coronary intervention: results of the 
randomized controlled HEBE trial. European heart journal, 32(14), 1736-1747. 
13. Houtgraaf, J. H., den Dekker, W. K., van Dalen, B. M., Springeling, T., de Jong, R., van 
Geuns, R. J., et al. (2012). First experience in humans using adipose tissue-derived 
regenerative cells in the treatment of patients with ST-segment elevation myocardial 
infarction. Journal of the American College of Cardiology, 59(5), 539-540. 
14. Huikuri, H. V., Kervinen, K., Niemela, M., Ylitalo, K., Saily, M., Koistinen, P., et al. (2008). 
Effects of intracoronary injection of mononuclear bone marrow cells on left ventricular 
function, arrhythmia risk profile, and restenosis after thrombolytic therapy of acute 
myocardial infarction. European heart journal, 29(22), 2723-2732. 


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Amendment 8.1 
15. Janssens, S., Dubois, C., Bogaert, J., Theunissen, K., Deroose, C., Desmet, W., et al. (2006). 
Autologous bone marrow-derived stem-cell transfer in patients with ST- segment 
elevation myocardial infarction: double-blind, randomised controlled trial. Lancet, 
367(9505), 113-121. 
16. Johnston, P. V., Sasano, T., Mills, K., Evers, R., Lee, S. T., Smith, R. R., et al. (2009). 
Engraftment, differentiation, and functional benefits of autologous cardiosphere- derived 
cells in porcine ischemic cardiomyopathy. Circulation, 120(12), 1075-1083, 1077 p 
following 1083. 
17. Katzberg, R. W., & Newhouse, J. H. (2010). Intravenous contrast medium-induced 
nephrotoxicity: is the medical risk really as great as we have come to believe? Radiology, 
256(1), 21-28. 
18. Larose, E., Rodes-Cabau, J., Pibarot, P., Rinfret, S., Proulx, G., Nguyen, C. M., et al. (2010). 
Predicting late myocardial recovery and outcomes in the early hours of ST- segment 
elevation myocardial infarction traditional measures compared with microvascular 
obstruction, salvaged myocardium, and necrosis characteristics by cardiovascular 
magnetic resonance. Journal of the American College of Cardiology,55(22), 2459-2469. 
19. Lipinski, M. J., Biondi-Zoccai, G. G., Abbate, A., Khianey, R., Sheiban, I., Bartunek, J., et 
al. (2007). Impact of intracoronary cell therapy on left ventricular function in the setting 
of acute myocardial infarction: a collaborative systematic review and meta- analysis of 
controlled clinical trials. Journal of the American College of Cardiology,50(18), 1761-
1767. 
20. Lunde, K., Solheim, S., Aakhus, S., Arnesen, H., Abdelnoor, M., Egeland, T., et al. (2006). 
Intracoronary injection of mononuclear bone marrow cells in acute myocardial infarction. 
The New England journal of medicine, 355(12), 1199-1209. 
21. Makkar, R. R., Smith, R. R., Cheng, K., Malliaras, K., Thomson, L. E., Berman, D., et al. 
(2012). Intracoronary cardiosphere-derived cells for heart regeneration after myocardial 
infarction (CADUCEUS): a prospective, randomised phase 1 trial. Lancet, 379(9819), 
895-904. 
22. Malliaras, K., Li, T. S., Luthringer, D., Terrovitis, J., Cheng, K., Chakravarty, T., et al. 
(2012). Safety and efficacy of allogeneic cell therapy in infarcted rats transplanted with 
mismatched cardiosphere-derived cells. Circulation, 125(1), 100-112. 
23. Martin-Rendon, E., Brunskill, S. J., Hyde, C. J., Stanworth, S. J., Mathur, A., & Watt, S.M. 
(2008). Autologous bone marrow stem cells to treat acute myocardial infarction: a 
systematic review. European heart journal, 29(15), 1807-1818. 
24. Meyer, G. P., Wollert, K. C., Lotz, J., Steffens, J., Lippolt, P., Fichtner, S., et al. (2006). 
Intracoronary bone marrow cell transfer after myocardial infarction: eighteen months' 
follow-up data from the randomized, controlled BOOST (BOne marrOw transfer to 
enhance ST-elevation infarct regeneration) trial. Circulation, 113(10), 1287-1294. 
25. Noto, T. J., Jr., Johnson, L. W., Krone, R., Weaver, W. F., Clark, D. A., Kramer, J. R., Jr., et 
al. (1991). Cardiac catheterization 1990: a report of the Registry of the Society for 
Cardiac Angiography and Interventions (SCA&I). Catheterization and cardiovascular 
diagnosis, 24(2), 75-83. 
26. Opelz, G., Daniel, V., Naujokat, C., & Dohler, B. (2009). Epidemiology of pretransplant 
EBV and CMV serostatus in relation to posttransplant non-Hodgkin lymphoma. 
Transplantation, 88(8), 962-967. 


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Amendment 8.1 
27. Perin, E. C. (2011). Clinical Science: Special Reports: A Phase II Dose-Escalation Study of 
Allogeneic Mesenchymal Precursor Cells in Patients with Ischemic and Nonischemic 
Heart Failure. Paper presented at the November 14, 2011  AHA Scientific Sessions, 
Orlando, FL. 
28. Perin, E. C., Dohmann, H. F., Borojevic, R., Silva, S. A., Sousa, A. L., Mesquita, C. T., et al. 
(2003). Transendocardial, autologous bone marrow cell transplantation for severe, 
chronic ischemic heart failure. Circulation, 107(18), 2294-2302. 
29. Perin, E. C., Dohmann, H. F., Borojevic, R., Silva, S. A., Sousa, A. L., Silva, G. V., et al. 
(2004). Improved exercise capacity and ischemia 6 and 12 months after transendocardial 
injection of autologous bone marrow mononuclear cells for ischemic cardiomyopathy. 
Circulation, 110(11 Suppl 1), II213-218. 
30. Perin, E. C., Willerson, J. T., Pepine, C. J., Henry, T. D., Ellis, S. G., Zhao, D. X., et al. 
(2012). Effect of Transendocardial Delivery of Autologous Bone Marrow Mononuclear 
Cells on Functional Capacity, Left Ventricular Function, and Perfusion in Chronic Heart 
Failure: The FOCUS-CCTRN Trial. JAMA : the journal of the American Medical 
Association. 
31. Roncalli, J., Mouquet, F., Piot, C., Trochu, J. N., Le Corvoisier, P., Neuder, Y., et al. (2011). 
Intracoronary autologous mononucleated bone marrow cell infusion for acute myocardial 
infarction: results of the randomized multicenter BONAMI trial. European heart journal, 
32(14), 1748-1757. 
32. Schachinger, V., Assmus, B., Britten, M. B., Honold, J., Lehmann, R., Teupe, C., et al. 
(2004). Transplantation of progenitor cells and regeneration enhancement in acute 
myocardial infarction: final one-year results of the TOPCARE-AMI Trial. Journal of the 
American College of Cardiology, 44(8), 1690-1699. 
33. Schachinger, V., Erbs, S., Elsasser, A., Haberbosch, W., Hambrecht, R., Holschermann, H., 
et al. (2006). Intracoronary bone marrow-derived progenitor cells in acute myocardial 
infarction. The New England journal of medicine, 355(12), 1210-1221. 
 
34. Strauer, B. E., Brehm, M., Zeus, T., Bartsch, T., Schannwell, C., Antke, C., et al. (2005) 
Regeneration of human infarcted heart muscle by intracoronary autologous bone marrow 
cell transplantation in chronic coronary artery disease: the IACT Study. Journal of the 
American College of Cardiology, 46(9), 1651-1658. 
35. Tendera, M., Wojakowski, W., Ruzyllo, W., Chojnowska, L., Kepka, C., Tracz, W., et al. 
(2009). Intracoronary infusion of bone marrow-derived selected CD34+CXCR4+cells 
and non-selected mononuclear cells in patients with acute STEMI and reduced left 
ventricular ejection fraction: results of randomized, multicentre Myocardial Regeneration 
by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial 
Infarction (REGENT) Trial. European heart journal, 30(11), 1313-1321. 
36. Traverse, J. H., Henry, T. D., Ellis, S. G., Pepine, C. J., Willerson, J. T., Zhao, D. X., et al. 
(2011). Effect of intracoronary delivery of autologous bone marrow mononuclear cells 2 
to 3 weeks following acute myocardial infarction on left ventricular function: the 
LateTIME randomized trial. JAMA : the journal of the American Medical Association, 
306(19), 2110-2119. 
37. Wohrle, J., Merkle, N., Mailander, V., Nusser, T., Schauwecker, P., von Scheidt, F., et al. 
(2010). Results of intracoronary stem cell therapy after acute myocardial infarction. The 
American journal of cardiology, 105(6), 804-812. 


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Amendment 8.1 
38. Wollert, K. C., Meyer, G. P., Lotz, J., Ringes-Lichtenberg, S., Lippolt, P., Breidenbach, C., 
et al. (2004). Intracoronary autologous bone-marrow cell transfer after myocardial 
infarction: the BOOST randomised controlled clinical trial. Lancet, 364(9429), 141-148. 
39. Wu, E., Ortiz, J. T., Tejedor, P., Lee, D. C., Bucciarelli-Ducci, C., Kansal, P., et al. (2008). 
Infarct size by contrast enhanced cardiac magnetic resonance is a stronger predictor of 
outcomes than left ventricular ejection fraction or end-systolic volume index: prospective 
cohort study. Heart, 94(6), 730-736. 
40. Zamora, M. R. (2011). DNA viruses (CMV, EBV, and the herpesviruses). [Review]. 
Seminars in respiratory and critical care medicine, 32(4), 454-470. 
41. Zhang, S., Sun, A., Xu, D., Yao, K., Huang, Z., Jin, H., et al. (2009). Impact of timing on 
efficacy and safetyof intracoronary autologous bone marrow stem cells transplantation in 
acute myocardial infarction: a pooled subgroup analysis of randomized controlled trials. 
Clinical cardiology, 32(8), 458-466.


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Amendment 8.0 
Appendix 1  
Schedule of Events8 
Study Procedure 
Screening Pre-Infusion 
Infusion 
2 Weeks 
1 Month 
2 Months 
(Phase 1 Only) 
3 Months 
6 Months 
12 Months 
/ET 
24, 36, 48, 60 
Months Follow-Up 
Study Day 
Day -28 
Day 0 
Day 0 
Day 14 3d Day 30 3d 
Day 60 6d 
Day 90 6d Day 180 6d Day 360 6d 
or ET 
Annual 2w 
Relative Timing 
Post-MI 
28d Screen 28d Screen 
Post 
Infusion 
Post 
Infusion 
Post Infusion 
Post 
Infusion 
Post 
Infusion 
Post 
Infusion 
Post Infusion 
Informed Consent 
X 1 
 
Medical History 
X 1 
X 
Limited Physical Examination 
X 2 
 
X 
 
History and Cardiac Physical 
X 2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Medication Review 
X 1 
X 
X 
X 
X 
X 
X 
X 
X 
 
Adverse Events Assessment 
X 2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Major Adverse Cardiac Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Vital Signs 
X 2 
X 
X 
X 
X 
X 
X 
X 
X 
 
12-Lead ECG 
X 2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Hematology, Chemistry, & 
Urinalysis 
X 1,2 
X 
X 
X 
X 
X 
X 
X 
X 
 
PTT / INR 
 
X 6 
 
 
 
 
 
 
 
 
Serum NT-proBNP 
X 2 
X 
X 
X 
X 
X 
X 
X 
X 
 
Serum for Biomarkers 
X 2,7 
 
X 7 
X 7 
X 7 
X 7 
X 7 
X 
 
Serum β-HCG 
X 1,2,8 
 
HIV & Hepatitis Screens; 
Hemoglobin A1c (HbA1c) 
X 1 
 
Donor Specific Antibody (DSA) 
X 2,10 
 
X 10 
X 10 
X 10 
X 10 
X 10 
X 
 
HLA Typing 
X 10 
 
 
 
 
ELISpot 
X 10 
 
X 10 
 
 
 
Cardiac MRI  
X 2 
 
X 
X 
 
Chest, Abdomen, and Pelvis CT 
X 2 
 
24 Hour Ambulatory ECG 
X 2 
 
X 11 
X 
X 
X 
X 
 
Serum troponin & CK-MB 
X 
9 
X 
9 
X 
X 
Echocardiography 
X 2 
 
X 
NYHA Functional Class 
X 2 
 
X 
X 
X 
X 
X 
 
Six Minute Walk Test 
X 2 
 
X 
X 
 
Patient Questionnaires 
X 2,12 
 
X 12 
X 12 
 
Intracoronary Infusion; 24 Hr 
Hospitalization w/ Continuous 
 
X 


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Amendment 8.0 
 
1 Permitted within 28 days immediately following index MI: signing ICF, review of medical history, review of concomitant medications, and 
collection of laboratory samples required for assessment of study eligibility criteria (e.g., eGFR, HbA1c, hepatitis serology, HIV serology, LFTs, 
hematocrit, WBC, serum -HCG and platelet count).  
2 Must be performed >28 days post-MI and 28 days of infusion. Repeat hematology, chemistry & urinalysis if initial testing to assess eligibility falls 
outside of this window. For post infusion, urinalysis only.  
3 Every 8 hours from time of infusion until discharge.  
4 On day of discharge.  
5 Urinalysis only.  
6 For subjects on anticoagulation therapy only.  
7 Only if additional consent is obtained; collection for shipment to central laboratory.  
8 Non-postmenopausal females only.  
9 Troponin and CK-MB pre-infusion and approximately every 8 hours post infusion.  
10 Collection of blood for testing at central laboratory.  
11 Starting immediately prior to discharge for 24 hours.  
12 MLHFQ, SF-36, WPAI:SHP and Patient Global Assessment. 
 


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Appendix 2  
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® 
Azathioprine 
Imuran® 
Azathioprine 
Azasan 
Basiliximab 
Simulect® 
Betamethasone 
Celestone® 
Bleomycin 
Blenoxane® 
Busulfan 
Myleran® 
Capecitabine 
Xeloda® 
Carboplatin 
Paraplatin® 
Carmustine 
BiCNU® (BCNU) 
Certolizumab pegol 
Cimzia® 
Chlorambucil 
Leukeran® 
Cidofovir 
Vistide® 
Cisplatin 
Platinol® 
Cladribine 
Leustatin® 
Cortisone 
Cortone® 
Cyclophosphamide 
Cytoxan® 
Cyclophosphamide 
Neosar® 
Cyclosporine 
Gengraf® 
Cyclosporine 
Neoral® 
Cyclosporine 
Sandimmune® 
Cytarabine 
Cytarabine 
Cytarabine 
DepoCyt® 
Dacarbazine 
DTIC-Dome® 


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Amendment 8.0 
GENERIC NAME 
TRADE NAME 
Daclizumab 
Zenopax® 
Dactinomycin 
Cosmegan® 
Darunavir 
Prezista® 
Dasatinib 
Sprycel® 
Daunorubicin 
Cerubidine® 
Delavirdine 
Rescriptor® 
Denileukin diftitox 
Ontak® 
Dexamethasone 
Dexamethasone 
Didanosine 
Videx® 
Docetaxel 
Taxotere® 
Docetaxel 
Docefrez® 
Doxorubicin 
Adriamycin® 
Doxorubicin 
Doxil® 
Efavirenz 
Sustiva® 
Efavirenz/emtricitabine/tenofovir disoproxil 
Fumarate 
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 
Hydrocortisone 
Cortef® 


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GENERIC NAME 
TRADE NAME 
Hydrocortisone 
Hydrocortone® 
Hydroxychloroquine 
Plaquenil® 
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® 
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™ 
Methylprednisolone 
Depo Medrol® 


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GENERIC NAME 
TRADE NAME 
Methylprednisolone 
Solu-Medrol® 
Methylprednisolone 
A-Methapred 
Methylprednisolone 
Medrol® 
Mitomycin 
Mutamycin® 
Mitotane 
Lysodren® 
Mitoxantrone 
Novantrone® 
Muromonab-CD3 
Orthoclone-OKT3 
Mycophenolate 
CellCept® 
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® 
Prednisolone 
Pediapred® 
Prednisolone 
Prelone® 
Prednisone 
Meticorten® 
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® 


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Amendment 8.0 
 
 
GENERIC NAME 
TRADE NAME 
Tacrolimus 
Prograf® 
Tamoxifen citrate 
Nolvadex 
Temozolomide 
Temodar® 
Temsirolimus injection 
Torisel® 
Teniposide 
Vumon® 
Tenofovir disoproxil fumarate 
Viread® 
Thalidomide 
Thalomid® 
Thioguanine 
Tabloid® 
Thiotepa 
Thiotepa 
Tipranavir 
Aptivus® 
Tocilizumab 
Actemra® 
Topotecan 
Hycamtin® 
Toremifene citrate 
Fareston® 
Trastuzumab 
Herceptin® 
Tretinoin 
Vesanoid® 
Tretinoin 
Vesanoid® 
Triamcinolone 
Kenalog® 
Triamcinolone 
Aristospan® 
Valrubicin 
Valstar® 
Vinblastine 
Vinblastine 
Vincristine 
Vincristine 
Vinorelbine 
Navelbine® 
Vorinostat 
Zolinza® 
Zalcitabine 
Hivid® 
Zidovudine 
Retrovir® 


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Amendment 8.0 
Appendix 3  
CDC Futility Boundaries 
 
The following four charts support DSMB safety monitoring of the Randomized Cohort. The 
excess for CDC-treated subjects will be of primary concern as data accrue. Charts have been 
prepared to correspond to accrual of 60, 120, 180, and 234 cases. The boundaries were computed 
using StatXact v7 (CyTel, Cambridge MA); a one-sided 95% exact test was performed assuming 
binomially distributed outcomes. The charts are illustrative and can be regenerated to correspond 
to the actual data accrued. The charts may be applied to any binary outcome pertaining to safety. 
 
 
 
 
 


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Page 92 of 93 
 
 
 
Amendment 8.0 
Appendix 4  
Sponsor Signature 
 
 
 
 
 
This clinical study protocol was subject to critical review and has been approved by the Sponsor.  
 
 
 
Signed:  
 
Date:  
 
 
 
Capricor, Inc. 
 
 
 
 
 
  
Study Title: 
Randomized, Double-Blind, Placebo-Controlled Phase I/II Study of 
the Safety and Efficacy of Intracoronary Delivery of Allogeneic 
Cardiosphere-Derived Cells in Patients with a Myocardial Infarction 
and Ischemic Left Ventricular Dysfunction (ALLogeneic Heart STem 
Cells to Achieve Myocardial Regeneration, ALLSTAR) 
Study Number:  
1002-01 
Original Protocol: 
15 May 2012 
Amendment 1: 
13 June 2012 
Amendment 2: 
26 June 2012  
Amendment 3: 
30 January 2013 
Amendment 4: 
04 May 2013 
Amendment 5: 
25 October 2013 
Amendment 6: 
01 December 2014 
Amendment 7: 
15 May 2015 
Amendment 7.1:  
05 June 2015 
Amendment 8:  
15 January 2016 


CAP-1002 Allogeneic Cardiosphere-Derived Cells 
Capricor, Inc. 
Clinical Trial Protocol:1002-01 
15-January-2016 
 
Confidential 
 
 
 
Page 93 of 93 
 
 
 
Amendment 8.0 
Appendix 5  
Investigator’s Signature 
 
 
 
 
 
I have read the protocol described above. I agree to comply with all applicable regulations and to 
conduct the study as described in the protocol. 
 
 
 
 
 
 
Signed:  
 
Date:  
 
<enter name and credentials> 
<enter title> 
<enter affiliation> 
<enter address> 
<enter phone number> 
 
 
Study Title: 
Randomized, Double-Blind, Placebo-Controlled Phase I/II Study of 
the Safety and Efficacy of Intracoronary Delivery of Allogeneic 
Cardiosphere-Derived Cells in Patients with a Myocardial Infarction 
and Ischemic Left Ventricular Dysfunction (ALLogeneic Heart STem 
Cells to Achieve Myocardial Regeneration, ALLSTAR) 
Study Number:  
1002-01 
Original Protocol: 
15 May 2012 
Amendment 1: 
13 June 2012 
Amendment 2: 
26 June 2012  
Amendment 3: 
30 January 2013 
Amendment 4: 
04 May 2013 
Amendment 5: 
25 October 2013 
Amendment 6: 
01 December 2014 
Amendment 7: 
15 May 2015 
Amendment 7.1:  
05 June 2015 
Amendment 8:  
15 January 2016 

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