A Phase I/II, Randomized, Blinded and Placebo-controlled Trial to Evaluate the Safety and Potential Efficacy of Allogeneic Human Mesenchymal Stem Cell Infusion in Patients With Aging Frailty
Phase: PHASE1
Conditions: Frailty
Sponsor: Longeveron Inc.

Interdisciplinary Stem Cell Institute
University of Miami/ Miller School of Medicine
Clinical Research Protocol
Study Title: 
A Phase I/II, Randomized, Blinded and 
Placebo-controlled Trial to Evaluate the Safety
and Potential Efficacy of Allogeneic Human 
Mesenchymal Stem Cell Infusion in Patients with 
Aging Frailty. 
AllogeneiC Human Mesenchymal Stem Cells (hMSC) 
in Patients with Aging FRAilTy via IntravenoUS 
Delivery (CRATUS)
Study Product:
Allogeneic Human Mesenchymal Stem Cells (hMSCs)
Indication:
Aging Frailty 
FDA IND No.:
BB-IND #15679
NCT No.:
NCT02065245
Principal Investigator:    Joshua M. Hare, M.D. Telephone: 305-243-5579
Protocol Version:
March 19, 2021, Version 7.5
Protocol Agreement Signature:
3/19/21
_________________________________________
______________________
Joshua M. Hare, M.D 
Date
(Sponsor-Investigator)
CONFIDENTIALITY STATEMENT
This document is confidential and proprietary to the Interdisciplinary Stem Cell Institute University of Miami/Miller School 
of Medicine 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  Acceptance of this document constitutes agreement by the recipient that no unpublished 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 without prior written 
approval of the Interdisciplinary Stem Cell Institute University of Miami or 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 Abbreviations .......................................................................................................10
Protocol Synopsis...........................................................................................................12
1.
INTRODUCTION .............................................................................................16
1.1
Background..........................................................................................................................................16
1.2
Mesenchymal Stem Cells.............................................................................................................19
1.3
Mesenchymal Stem Cells: Preclinical Experience ..........................................................20
1.4
Allogeneic Mesenchymal Stem Cells: Previous Experience in Humans.............32
1.5.
Pharmacology and Toxicology Studies of Mesenchymal Stem Cells...................38
2. 
STUDY OBJECTIVES AND ENDPOINTS.......................................................40
2.1
Study Objectives ...............................................................................................................................40
2.1.1
Primary Objective ............................................................................................40
2.1.2
Secondary Objectives......................................................................................40
2.2
Study Endpoints ................................................................................................................................40
2.2.1
Primary Endpoints (Safety)..............................................................................40
2.2.2.
Secondary Endpoints (Efficacy).......................................................................41
3.
STUDY DESIGN..............................................................................................41
3.1
Description of the Study................................................................................................................41
3.2.
RANDOMIZATION STUDY.........................................................................................................42
4. 
SUBJECT SELECTION ...................................................................................43
4.1 
Inclusion Criteria................................................................................................................................43
4.2 
Exclusion Criteria..............................................................................................................................43
4.3 
Concomitant Treatments, Procedures, and Nondrug Therapies.............................44
4.4 
Withdrawal Criteria...........................................................................................................................44
5.  
MESENCHYMAL STEM CELL DONORS .......................................................45
5.1 
Bone Marrow Aspiration for Generation of MSCs ...........................................................45
5.2 
Normal Donor Eligibility .................................................................................................................45
5.3 
Donor Consent...................................................................................................................................47
5.4 
Follow-up Schedule for Donors.................................................................................................47
5.5
Biomarker Assessment for Donors..........................................................................................47
6. 
TREATMENT OF SUBJECTS .........................................................................47
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6.1 
Study Investigational Product.....................................................................................................47
6.2 
Dosing.....................................................................................................................................................48
6.3 
Dosage Rationale.............................................................................................................................49
6.4 
Administration Rate .........................................................................................................................49
6.4.1.  
Infusion Monitoring ..........................................................................................50
6.5 
Concomitant Therapy .....................................................................................................................50
6.5.1
Permitted therapy ............................................................................................50
6.5.2
Excluded therapy .............................................................................................50
6.5.3.
Subject monitoring ...........................................................................................50
6.6
Blinding and Unblinding.................................................................................................................50
6.7
Study Investigational Therapy Management......................................................................51
6.7.1
Investigational Product Labeling and Storage...................................................................51
6.7.2
Investigational Product Accountability Procedures.........................................................51
7.
STUDY PROCEDURES ..................................................................................51
7.1.
Time and Events Schedule..........................................................................................................51
Time and Events Table Key:.......................................................................................................53
7.2.1
Screening Visit.................................................................................................54
7.2.2
Baseline Visit ...................................................................................................55
7.2.3
Day 1 Visit........................................................................................................56
7.2.4
Week 2 Visit.....................................................................................................56
7.2.5
Month 1 – Month 6 Visits .................................................................................56
7.2.6
Month 12 Visit ..................................................................................................56
7.2.7
Biomarker Assessment....................................................................................57
7.2.8
Immune Monitoring for Graft Rejection............................................................57
8.  
SAFETY...........................................................................................................58
8.1 
Safety Variables ................................................................................................................................58
8.2 
Laboratory Evaluations..................................................................................................................58
8.2.1
Pulse Oximetry ................................................................................................58
8.2.2
Pregnancy........................................................................................................59
8.2.3
Determination of Infusional Toxicity.................................................................59
8.2.4
Subject Stopping Guidelines............................................................................60
8.3
Definition of an Adverse Event ..................................................................................................61
8.4
Definition of Adverse Reaction ..................................................................................................62
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8.5
Definition of Suspected Adverse Reaction..........................................................................62
8.6
Definition of Serious ........................................................................................................................62
8.7
Definition of Unexpected...............................................................................................................63
8.8
Clinical Laboratory Assessments and Other Abnormal Assessments as 
Adverse Events and Serious Adverse Events...................................................................63
8.9
Recording of Adverse Events and Serious Adverse Events......................................63
8.10
Intensity of Adverse Events and Serious Adverse Events..........................................64
8.11
Causality of Adverse Events and Serious Adverse Events........................................64
8.12
Follow-Up of Adverse Events and Serious Adverse Events......................................65
8.13
Timeframes for Submitting SAE Reports .............................................................................65
8.14
Regulatory Aspects of Adverse Event Reporting.............................................................66
9.
STATISTICAL ANALYSIS ...............................................................................66
9.1 
Determination of Sample Size and Analysis Population..............................................67
9.2 
General Statistical Methods ........................................................................................................67
9.3
Interim Analyses................................................................................................................................67
9.4 
Data and Safety Monitoring Board (DSMB)........................................................................67
9.4.1. 
ROLE OF THE DSMB .....................................................................................67
9.4.2. 
Purpose of the DSMB ......................................................................................68
9.4.2.6 DSMB Chair Responsibilities...........................................................................70
9.4.2.7 Investigator Responsibilities ............................................................................71
9.4.3 
COMMITTEE MEETINGS ...............................................................................71
9.4.4 
DATA FLOW....................................................................................................74
9.4.5 
COMMUNICATION..........................................................................................75
10. 
STUDY ADMINISTRATION.............................................................................76
10.1
Regulatory Authority Approval...................................................................................................76
10.2 
Ethics Approval..................................................................................................................................76
10.3 
Subject Informed Consent............................................................................................................76
10.4 
Confidentiality of Information......................................................................................................77
10.5 
Payments to Subjects and Donors..........................................................................................78
APPENDIX 1: .......................................................................................................Infusion Guidelines
79
APPENDIX 2: Dobutamine Stress Echocardiogram (DSE) Guidelines..........................82
Addendum A: Pilot Subjects Optional Follow-on Phase.................................................83
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A.1 
Rationale and Description of second infusion for first 15 subjects on pilot 
phase.......................................................................................................................................................83
A.2 
Demonstrated Safety and Increased Efficacy of Multiple Infusions of 
Allogeneic Mesenchymal Stem Cells.....................................................................................83
A.3 
 STUDY OBJECTIVES AND ENDPOINTS......................................................84
A.3.1 
 Study Objectives..............................................................................................................................84
A.3.1.1
Primary Objective ............................................................................................84
A.3.1.2
Secondary Objectives......................................................................................84
A.3.2
 Study Endpoints...............................................................................................................................85
A.3.2.1
Primary Endpoints (Safety)..............................................................................85
A.3.2.2
Secondary Endpoints (Efficacy).......................................................................85
A.4
 Inclusion and Exclusion Criteria......................................................................86
A.4.1
 Inclusion Criteria for Follow-on Phase..................................................................................86
A.4.2
 Exclusion Criteria for Follow-on Phase................................................................................86
A.5
 Dosing ...................................................................................................................................................87
A.6
 Dosage Rationale............................................................................................................................88
A.7
 Administration Rate........................................................................................................................88
A.8
 Data and Safety Monitoring Board (DSMB) ......................................................................88
A.13
 Payments to Subjects and Donors in the Follow-on Phase......................................89
Time and Events Table Key:.......................................................................................................91
A.15
 Study Visits .....................................................................................................92
A.15.1 
Screening Visit for second infusion..................................................................92
A.15.2
 Baseline Visit for second infusion ...................................................................92
A.15.3
 Day 1 Visit for second infusion .......................................................................94
A.15.4
 Month 1 Visit for second infusion....................................................................94
A.15.5
Month 3 and Month 6 Visit for second infusion................................................94
A.16
 Statistical Considerations............................................................................................................94
A.17
 Safety Monitoring of 30-Day Rate of TE-SAEs................................................................94
Limitations.............................................................................................................................................96
Addendum B: Penicillin/streptomycin free cell safety study ...........................................97
B.1 
Rationale and Description for penicillin/streptomycin free cell safety study......97
B.2 
 STUDY OBJECTIVES AND ENDPOINTS......................................................97
B.2.1 
 Study Objectives..............................................................................................................................97
B.2.1.1
Primary Objective ............................................................................................97
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B.2.1.2
Secondary Objectives......................................................................................97
B.2.2
 Study Endpoints...............................................................................................................................97
B.2.2.1
Primary Endpoints (Safety)..............................................................................97
B.2.2.2
Secondary Endpoints (Efficacy).......................................................................98
B.3
 Inclusion and Exclusion Criteria......................................................................98
B.3.1
Inclusion Criteria for penicillin/streptomycin free cell safety study..........................98
B.3.2
 Exclusion Criteria for penicillin/streptomycin free cell safety....................................99
B.4
 Dosing.................................................................................................................................................100
B.5
 Dosage Rationale.........................................................................................................................100
B.6
 Administration Rate .....................................................................................................................100
B.7
 Data and Safety Monitoring Board (DSMB)....................................................................101
B.12
 Payments to Subjects and Donors in the Follow-on Phase...................................101
Time and Events Table Key:........................................................................................................................103
B.14
 Study Visits ...................................................................................................104
B.14.1 
Screening Visit...............................................................................................104
B.14.2
 Baseline Visit ................................................................................................104
B.14.3
 Day 1 Visit.....................................................................................................106
B.14.4
 Month 1 Visit .................................................................................................106
B.14.5
Month 3 and Month 6 Visit .............................................................................106
B.15
 Statistical Considerations.........................................................................................................106
B.16
 Safety Monitoring of 30-Day Rate of TE-SAEs.............................................................106
Addendum C: Pilot and Penicillin/Streptomycin Free Subjects Optional Follow-on Phase
109
C.1 
Rationale and Description of additional infusions for subjects who have 
received one or two infusions in the phase I open-label phases of this protocol.
.......................................................................................................................109
C.2 
Demonstrated Safety and Increased Efficacy of Multiple Infusions of 
Allogeneic Mesenchymal Stem Cells.............................................................109
C.3 
 STUDY OBJECTIVES AND ENDPOINTS....................................................111
C.3.1 
 Study Objectives ...........................................................................................................................111
C.3.1.1
Primary Objective ..........................................................................................111
C.3.1.2
Secondary Objectives....................................................................................111
C.3.2
 Study Endpoints ............................................................................................................................111
C.3.2.1
Primary Endpoints (Safety)............................................................................111
C.3.2.2
Secondary Endpoints (Efficacy).....................................................................112
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C.4
 Inclusion and Exclusion Criteria....................................................................112
C.4.1
 Inclusion Criteria for Follow-on Phase...............................................................................112
C.4.2
 Exclusion Criteria for Follow-on Phase .............................................................................113
C.5
 Dosing.................................................................................................................................................114
C.6
 Dosage Rationale.........................................................................................................................114
C.7
 Administration Rate .....................................................................................................................114
C.8
 Data and Safety Monitoring Board (DSMB)....................................................................115
C.13
 Payments to Subjects and Donors......................................................................................115
Time and Events Table Key:....................................................................................................117
C.15
 Study Visits ...................................................................................................119
C.15.1 
Screening Visit for additional infusion............................................................119
C.15.2
 Baseline Visit for additional infusion .............................................................119
C.15.3
 Day 1 Visit for additional infusion..................................................................120
C.15.4
 Month 1 Visit for additional infusion ..............................................................120
C.15.5
Month 3 and Month 6 Visit for additional infusion..........................................120
C.16
 Statistical Considerations.........................................................................................................121
Addendum D: Placebo Group Optional Follow-on Phase ............................................122
D.1 Rationale and Description of infusion for 10 subjects randomized to placebo group
122
D.2 STUDY OBJECTIVES AND ENDPOINTS:............................................................122
D 2.1 - 
Study Objectives.............................................................................................................................122
D.2.1.1 Primary Objective: .........................................................................................122
D.2.1.2 Secondary Objective:.....................................................................................122
D.2.2 
Study Endpoints..............................................................................................................................122
D.2.2.1 Primary Endpoints (Safety)............................................................................122
D.3
Study Design .................................................................................................123
D.4 
Inclusion and Exclusion Criteria.....................................................................124
D.4.1
 Inclusion Criteria............................................................................................................................124
D.4.2
 Exclusion Criteria..........................................................................................................................124
D.5
 Dosing...........................................................................................................125
D.6
 Dosage Rationale .........................................................................................125
D.7
 Administration Rate ......................................................................................126
D.8
 Data and Safety Monitoring Board (DSMB)..................................................126
D.9
Concomitant Treatments, Procedures, and Nondrug Therapies ...................126
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D.10
 Infusion Monitoring Guidelines .....................................................................126
D.11
 Adverse Events and Serious Adverse Events ..............................................126
D.12
 Stopping Guidelines......................................................................................126
D.13
 Payments to Subjects and Donors ...............................................................127
Time and Events Table Key:....................................................................................................129
D.15
 Study Visits ...................................................................................................130
D.15.1 
Screening Visit.................................................................................................................................130
D.15.2
Baseline Visit....................................................................................................................................130
D.15.3
Day 1 Visit..........................................................................................................................................131
D.15.4
Month 1 Visit.....................................................................................................................................131
D.15.5
Month 3 and Month 6 Visit.........................................................................................................131
D.15.6
Month 12 Visit ..................................................................................................................................131
11.
Reference List................................................................................................132
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Authorship Team (alphabetical order)
The following individuals provided substantial input during protocol development:
Darcy L. DiFede, RN, BSN
University of Miami
Joshua M. Hare, MD*
University of Miami
Marietsy V. Pujol, MBA
University of Miami
* Principal investigator
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List of Abbreviations
AE
Adverse event
ahMSCs
Allogeneic human Mesenchymal Stem Cells
Allo
Allogeneic
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BM
Bone Marrow
CBC
Complete Blood Count
CFR
Code of Federal Regulations
CHAMPS
Community Healthy Activities Model Program for Seniors 
questionnaire
CMV
Cytomegalovirus
CPF
Cell Processing Facility
CPL
Cell Processing Laboratory
CRP
C-Reactive Protein
CT
Computed tomography
DLCO
Diffusing Capacity
DMSO
Dimethyl sulfoxide
DSMB
Data Safety Monitoring Board
ECC
Eluerian Circumferential strain
EDV
End-diastolic volume
EPCs
Endothelial progenitor cells
ESR
Expedited safety report
ESV
End-systolic volume
FBS
Fetal Bovine Serum
FDA
Food and Drug Administration
FEV – 1 
Forced expiratory volume in 1 second
FSH
Follicle stimulating hormone
FVC
Forced vital capacity
GCP
Good Clinical Practice
G-CSF
Granulocyte colony stimulating factor
GFP
Green fluorescent protein
GM – CSF 
Granulocyte Macrophage Colony Stimulating Factor
GVHD
Graft versus host disease
HBcAb
Anti-Hepatitis B core antibody
HCV Ab
Anti-Hepatitis C virus antibody
HIPAA
Health Insurance Portability and Accountability Act Authorization
HIV
Human Immunodeficiency Virus
HLA
Human leukocyte antigen
Has
Human serum albumin
hMSCs
Human mesenchymal stem cell
hs-CRP
High Sensitivity C-Reactive Protein
HSCs
Hematopoietic stem cells
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HTLV
Human T-lymphotropic Virus
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IL-6
Interleukin-6
IND
Investigational new drug
INR
International Normalized Ratio
IP
Investigational Product
IRB /IEC
Institutional Review Board
IV
Intravenous Infusion
LAD
Left anterior descending
LFT
Liver Function tests
LV
Left ventricular
MFI
Multi-dimensional Fatigue Inventory
MI 
Myocardial Infarction
MMSE
Mini Mental State Examination
MNC 
Mononuclear Cell
MRI
Magnetic resonance imaging
MSCs
Mesenchymal Stem Cells
NAT
Nucleic Acid Testing
NIH
National Institute of Health
NMDP
National Marrow Donor Program
PBMC
Peripheral blood mononuclear cells
PFTs
Pulmonary function tests
PSURs
Periodic Safety Update Reports
QOL
Quality of life
RDW
Red blood cell distribution Width
RPR
Rapid Plasma Reagin
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SCA-1
Stem cell factor antigen
SF – 36 
Short Form – 36 
SGRQ
St. George’s Respiratory Questionnaire
SPPB
Standard Physical Performance Battery
TE-SAE
Treatment-emergent serious adverse event
TNF-α
Tumor necrosis factor-alpha
TTC
Triphenyltetrazolium chloride
VEGFR2
Vascular endothelial growth factor
WBC
White blood cell
WNV
West Nile virus
6MWT
Six minute walk test
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Protocol Synopsis
PRODUCT
Intravenous Allogeneic Adult Human Mesenchymal Stem Cells 
(MSCs)
PHASE OF DEVELOPMENT
I/II
MAIN CRITERIA FOR INCLUSION
Aging Frailty
STUDY OBJECTIVES
To demonstrate the safety of intravenous allogeneic hMSCs 
administered in subjects’ with Frailty and to explore 
treatment efficacy (decrease in frailty, frequency of acute 
exacerbations, change in symptom related quality of life, 
improved cardiovascular status, decrease in inflammatory 
biomarkers, endothelial function and 1 year survival).
STUDY DESIGN
A Phase I/II, Randomized, Blinded and Placebo-controlled 
INVESTIGATIONAL PLAN
Before initiating the full-randomized study, a Pilot Safety 
Phase will be performed. The randomized portion of this trial 
will be conducted after a full review of the safety data from the 
Pilot Phase by the DSMB.
Following the Pilot Phase of fifteen (15) subjects, thirty (30) 
subjects meeting all inclusion/exclusion criteria will be 
evaluated at baseline and scheduled to undergo infusion. 
Pilot Phase (15 subjects)
In the pilot phase, the first three (3) subjects in each treatment 
group will not be treated less than 5 days apart for their first 
infusion and will each undergo full evaluation for 5 days to 
demonstrate there is no evidence of treatment emergent SAE’s 
prior to proceeding with the treatment of further subjects.
Group 1 (5 subjects): 
Five (5) subjects will be treated with a single administration of 
allogeneic hMSCs: 2 x 107 (20 million) cells delivered via 
peripheral intravenous infusion.
Group 2 (5 subjects): 
Five (5) subjects will be treated with a single administration of 
allogeneic hMSCs: 1 x 108 (100 million) cells delivered via 
peripheral intravenous infusion.
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Group 3 (5 subjects):  
Five (5) subjects will be treated with a single administration of 
allogeneic hMSCs: 2 x 108 (200 million) cells delivered via 
peripheral intravenous infusion.
At completion of the one year phone call visit in the pilot 
phase, all fifteen (15) subjects will be provided with the option 
of having up to three (3) additional administrations of 
allogeneic hMSCs: 1 x 108 (100 million) cells delivered via 
peripheral intravenous infusion.
Randomized Phase (30 subjects)
In the randomized phase of allo-hMSCs or matched placebo up 
to 30 subjects will be randomized in a 1:1:1 ratio to one of two 
doses of MSCs versus placebo.
Treatment Strategies following successful completion of the 
Pilot Phase:
Group A (10 subjects) – Allogeneic hMSCs: 100 million 
cells/ml delivered via peripheral intravenous infusion.
Group B (10 subjects) – Allogeneic hMSCs: 200 million 
cells/ml delivered via peripheral intravenous infusion.
Group C (10 subjects) - Placebo delivered via peripheral 
intravenous infusion.
Subjects in the randomized phase that received placebo will 
have the option to receive one infusion of 100 million allo-
hMSCs after subjects in the randomized phase have been 
unblinded (refer to Addendum D). 
Addendum B (20 subjects)
Twenty (20) subjects will be treated with a single 
administration of allogeneic hMSCs: 1 x 108 (100 million) cells 
delivered via peripheral intravenous infusion. Subjects that 
participated in the Addendum B sub-study will then have the 
option to receive up to three (3) additional infusions 
administrations, per Addendum C, of allogeneic hMSCs: 1 x 108 
(100 million) cells delivered via peripheral intravenous 
infusion.
The Allo-hMSCs will be supplied from an allogeneic human 
mesenchymal stem cell source manufactured by the University 
of Miami or from a commercial clinical grade bone marrow 
source.
Following infusion, subjects in the pilot and randomized 
phases will be followed at 2 week’s post-infusion, and at one, 
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three, and six months to complete all safety and efficacy 
assessments. 
Subjects in the addenda will be followed at one month post-
infusion and then at three and six months to complete all 
safety and efficacy assessments. Patients participating in 
Addendum B will receive penicillin/streptomycin free cells. If 
they are participating in Addendum C or D subjects may 
receive cells with antibiotic (penicillin/streptomycin). 
All subjects, with the exception of subjects participating in 
Addendum C, will also have a final twelve-month contact for 
assessment of vital status and occurrence of hospitalization. 
ROUTE OF ADMINISTRATION
Peripheral Intravenous Infusion
DURATION OF STUDY PARTICIPATION
Pilot phase (15 subjects)
12 months (Follow-up will be at 2 weeks, 1, 3, 6, and 12 
months) for the first infusion. 
Pilot subjects will have an optional additional 12-month 
follow-up period for a second infusion (Reference Addendum 
A), and up to two (2) additional infusions with a 6 to 12-month 
follow-up period under Addendum C. The follow-up will be at 
1, 3, 6, and 12 months for Addendum A. The follow-up for 
Addendum C will be at 1, 3, and 6 and/or at 12 months.
Randomized phase (30 subjects)
12 months (Follow-up will be at 2 weeks, 1, 3, 6, and 12 
months.) 
Subjects that received placebo will have the option to receive a 
single infusion of allogeneic MSCs under Addendum D. The 
follow-up will be at 1, 3, 6, and 12 months for these subjects.
Addendum B sub-study (20 subjects)
Subjects in the penicillin/streptomycin free addendum 
(Reference Addendum B) will have up to a 12-month follow-
up schedule at 1, 3, 6, and if applicable, 12 months. Subjects 
continuing with the additional infusions in Addendum C will 
have up to a 12-month follow-up schedule at 1, 3, 6, and if 
applicable, 12 months for each additional infusion. Subjects 
will receive one initial infusion (Addendum B) and can receive 
up to three (3) additional infusions under Addendum C for a 
total of four infusions.
SUBJECT POPULATION
Forty-Five (45) subjects with frailty will be enrolled in the 
main study. 
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An additional 20 subjects will be included in a sub-study, 
(Please see Addendum B).
Definition of Endpoints
Safety (Primary): Incidence (at one month post-infusion) of 
any treatment-emergent serious adverse events (TE-SAEs), 
defined as the composite of: death, non-fatal pulmonary 
embolism, stroke, hospitalization for worsening dyspnea and 
clinically significant laboratory test abnormalities determined 
per the Investigator’s judgment.
Efficacy (Secondary): During the screening, baseline, 
Month 3 and/or Month 6 visits.
•
Difference in rate of change of frailty defined as:
- Reduced Activity (assessed via CHAMPS questionnaire)
- Slowing of Mobility (assessed via gait speed test and 
SPPB assessment)
- Weight Loss
- Diminished handgrip strength (assessed via 
dynamometer)
- Exhaustion (assessed via the MFI questionnaire)
- Decrease in subject quality of life assessment(s) 
(assessed via ICECAP, SF-36, EQ-5D Questionnaires)
•      Death from any cause.
•      Change between screening and 6 months in 
dobutamine stress echo induced ejection fraction
•     Change between screening and 6 months in the 
following panel of inflammatory markers:  CRP, IL-6,  
D-dimer, fibrinogen, CBC with differential, 
              and  TNFα
Safety (Additional)

During the 12 week follow-up period and each 
consecutive time-point up until the final visit
Inclusion Criteria 
(Applicable for Main Phase of the 
trial; reference each individual 
addendum for its inclusion 
criteria)
1.
Provide written informed consent.
2.
Subjects age >60 and <95 years at the time of 
        signing the Informed Consent Form.
3.
Show signs of frailty apart from a concomitant 
       condition as assessed by the Investigator with a  
       frailty score of 4 to 7 using the Canadian Clinical        
       Frailty Scale.
4.
Female subjects must have an FSH > 25.8 mIU/mL, if 
not currently on hormone replacement therapy.
        
Exclusion Criteria
(Applicable for Main Phase of the 
trial; reference each individual 
1.
Score of <24 on the Mini Mental State Examination 
(MMSE)
2.
Be a female who is pregnant, nursing, or of 
childbearing potential while not practicing effective 
contraceptive methods. Female subjects must undergo 
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addendum for its exclusion 
criteria)
a blood or urine pregnancy test at screening and 
within 36 hours prior to infusion.
3.
Inability to perform any of the assessments required 
for endpoint analysis.
4.
Active listing (or expected future listing) for transplant 
of any organ.
5.
Clinically important abnormal screening laboratory 
values.
6.
Serious comorbid illness that, in the opinion of the 
investigator, may compromise the safety or 
compliance of the subject or preclude successful 
completion of the study.
7.
Hypersensitivity to dimethyl sulfoxide (DMSO).
8.
Be an organ transplant recipient. 
9.
Have a clinical history of malignancy within 3 years 
(i.e., subjects with prior malignancy must be disease 
free for 3 years), except curatively-treated basal cell 
carcinoma, squamous cell carcinoma, melanoma in situ 
or cervical carcinoma, if recurrence occurs.
10. Have a non-pulmonary condition that limits lifespan to 
< 1 year. 
11. Have a history of drug or alcohol abuse within the past 
24 months.
12. Be serum positive for HIV, hepatitis BsAg or Viremic 
hepatitis C.
13. Be currently participating (or participated within the 
previous 30 days) in an investigational therapeutic or 
device trial.
14. Any other condition that, in the opinion of the 
investigator, may compromise the safety or 
compliance of the subject or preclude successful 
completion of the study.
1.
INTRODUCTION
1.1
Background
Frailty in an aging population is defined as a medical syndrome “with multiple causes 
and contributors that is characterized by diminished strength, endurance, and reduced 
physiologic function that increases an individual’s vulnerability for developing increased 
dependency and/or death”1.  Of great importance is that frailty, while not characterized 
as a disability, per se, does increase the risk of death in affected individuals2-4. 
Moreover, there is a close link between a subject’s health and frailty. These subjects 
tend to show a greater risk to frailty when there are other conditions affecting their 
physical and psychological well-being, such as high blood pressure, cancer, or cognitive 
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impairment. In an aging population frailty is characterized by reduced physical activity, 
slowing of mobility, weight loss, diminished handgrip strength, and exhaustion2, 3. There 
are several well-validated models to assess frailty1For example, the FRAIL scoring 
index provides a clinical diagnosis of frailty when a subject exhibits three or more of 
these five characteristics2;5. The forward trajectory in medical advances, and a more 
health aware society, indicates that the population is living longer and requiring more 
care and services than were needed in the past. As such, the increase in frail elderly 
subjects has adversely increased the demand for healthcare services.  Currently there 
is a favorable movement in researching a novel medical therapy for frailty as this 
remains an unmet need amongst the elderly population.6  It is widely perceived that 
frailty can be favorably modified, and in this regard there is a major need for effective 
management tools and treatment strategies.   In this protocol, we will test the impact of 
a safe cell-based therapeutic on the frailty syndrome.
Frailty and Cardiovascular Performance
The aging cardiovascular system has some very specific phenotypic alterations7;8.  These 
include left ventricular hypertrophy and a diminution in exercise induced increase in 
ejection fraction9-11.  These characteristic abnormalities are hypothesized to contribute to 
specific symptoms of the frailty syndrome and to increase the morbidity and mortality from 
cardiovascular disease in elderly individuals.
Several studies document the increased risk for mortality in frail elderly subjects with 
cardiovascular events such as non-ST-segment elevation myocardial infarction 
(NSTEMI)4;12. Frail individuals have increased disease burden in and therefore more 
prolonged recuperation versus a non-frail subject1.  There are additional associations 
between frailty and other cardiovascular diagnoses including angina, myocardial 
infarction, congestive heart failure and stroke. Gait speed is one symptom of frailty that is 
associated with cardiovascular mortality and an increased risk of cardiovascular events 
specifically STEMI subjects 13;14. The Women’s Health Initiative utilized the “Frailty Index” 
by Fried and colleagues8 which was validated in the Cardiovascular Health Study15 and 
the Womens Health and Aging Study. These studies demonstrated correlations in 
functional decline, increased risk of institutionalization and mortality with the use of these 
instruments.
The strong association between frailty and cardiovascular disease and the growing data 
base documenting safety and potential favorable effects of cell-based therapy in 
cardiovascular diseases provide justification for the assessment of potential benefits of 
cell therapy in subjects with frailty.
Inflammation in frailty
In addition and of great importance, there is a growing database of studies that highlight 
a connection between frailty and inflammation.  For example, certain inflammatory 
markers, such as C-reactive protein (CRP), fibrinogen, interleukin-6 (IL-6), red blood cell 
distribution (RDW) and D-dimer are more likely to be elevated in frail as compared to non-
frail individuals8. Importantly, among frail subjects, women exhibit higher concentrations 
of inflammatory and coagulation factors than men.  CRP is an example of one marker 
studied that shows that women experiencing symptoms of frailty show a higher 
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concentration of CRP.  Differential white cell counts on the other hand exhibits an 
increased risk of frailty in both men and women.  Dysregulated inflammation is a 
considerable key physiological marker in correlation with the frailty syndrome8 . There is 
still insufficient data to show which markers specifically affect men or women5;16. It is 
believed that frailty can ultimately be prevented or attenuated, and the link between frailty 
and inflammation offers a potential therapeutic target, also addressable by cell therapy.  
Frailty is assessed with several instruments.  For example, the Clinical Frailty Scale2 is a 
clinical scale that determines the degree of a subject’s frailty based on the physician’s 
judgment and the subject’s medical information. This scale consists of 7 variables ranging 
from fit to complete functional dependence; If a subject displays three or more of the 
following symptoms: low physical activity, muscle weakness, slowed performance, 
fatigue, unintentional weight loss, then the subject is considered to be classified as frail.2;4
Stem Cells in Frailty
An individual’s endogenous stem cell production decreases with age; this decrease in an 
aging subject likely contributes to reduced ability to regenerate and repair organs and 
tissues.  Several investigators have proposed that a regenerative treatment strategy could 
ameliorate signs and symptoms of aging frailty8;16. Currently, the FDA does not have any 
specific approved treatment for frail subjects and therefore no established standard of 
care.  In many cases frailty can be masked by other physical or psychological conditions 
affecting well-being and functional status. The ultimate goal is to extend the health and 
ability of a subject to regenerate functionality.  Allogeneic Human Mesenchymal Stem 
Cells are known to hone to sites of injury, reduce inflammation, and assist in cellular 
repair.  Here we propose to study Allo-hMSCs (ahMSCs) as a novel therapy for treating 
subjects experiencing frailty. 
There are specific features of the frailty syndrome that support a potential role of ahMSCs 
to ameliorate or improve frailty.  Notably, ahMSCs are shown to improve cardiovascular 
status in subjects with acute MI17 and heart failure18.  In addition, ahMSCs are anti-
inflammatory and reduce CRP levels in a sustained manner19. Importantly, data from 
heart failure studies show that ahMSCs are safe in subjects irrespective of age18.  For 
these reasons, this protocol will test the safety of intravenous infusion (IV) of ahMSCs in 
individuals of advanced age with frailty, and will assess cardiovascular status and 
inflammatory markers in this population at increased risk for morbidity and mortality.
Cells derived from adult bone marrow
Bone marrow harbors a variety of cells that may contribute to vasculogenesis or 
cardiomyogenesis, either directly, or by facilitating endogenous repair mechanisms.  
Bone marrow cells have been prepared on the basis of being 1.) endothelial precursor 
cells that are CD34+, 2.) MSCs purified without an antigen panning technique on the basis 
of their fibroblast morphology, ability to divide in culture and to differentiate into 
mesodermal lineages20, and 3.) cells that express stem cell factor receptor, c-Kit21;22.  
Endothelial progenitor cells (EPCs) express the surface markers CD34, CD133, c-kit, and 
the vascular endothelial growth factor receptor-2 (VEGFR2; KDR; Flk-1)23-28.  
Hematopoietic stem cells (HSCs) exhibit self-renewal and differentiation.  Their cell-
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surface phenotype is CD34+, stem cell factor antigen (SCA-1)+, c-kit+, and Lin- (review29).  
While there has been controversy regarding the ability of bone marrow-derived cells to 
transdifferentiate into cardiomyocytes30, clinical trials of bone marrow therapies continue 
to suggest potential benefit in terms of improving a subject’s well-being.  
1.2
Mesenchymal Stem Cells
Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into a 
number of different cell lines.  Because of their unique combination of multipotency, 
migratory ability, and immunoprivileged state (MSCs do not express major 
histocompatibility factor-II making allogeneic transplant possible)31, interest has 
abounded regarding their potential therapeutic and regenerative applications.  In fact, 
MSCs have been shown to hold promise as a novel therapeutic agent in multiple disease 
processes.  Treatment with MSCs has been shown to ameliorate severe graft versus host 
disease31, contribute to pancreatic islet and renal glomerular repair in diabetes32, 
attenuate sepsis33, reverse fulminant hepatic failure34, protect against ischemic acute 
renal failure35, reverse remodeling36-38 and improve cardiac function after myocardial 
infarction17, to be a potential source of multiple cell types for use in tissue engineering39;40, 
and to be capable of tissue regeneration after spinal cord trauma, stroke, and connective 
tissue injury41-43.  
In the lung, MSCs have been shown to contribute to tissue regeneration after elastase-
induced emphysema44, home to sites of asbestos induced lung injury45, contribute to 
tissue remodeling in a rat monocrotaline model of pulmonary hypertension46, decrease 
chronic airway inflammation in a murine ovalbumin model of asthma47, and to restore 
alveolar fluid balance after endotoxin induced acute lung injury48.
Tracking of radioactively labeled cells shows that when administered intravenously, 
MSCs localize primarily to the lung, followed by the liver, and then other organs49.  A 
number of studies show that MSCs preferentially home to sites of injury in the lung and 
contribute to tissue regeneration and repair50-56.  Using Y-chromosome fluorescence in-
situ hybridization, Y-chromosome positive male MSCs can be found at sites of lung injury 
in transplanted female mice51;52;55.  These male MSCs appear to adopt anepithelial cell 
morphology, suggesting that they contribute to tissue regeneration either by fusion with 
resident epithelial cells or by mesenchymal to epithelial transition51.  
The ability of MSCs to differentiate towards an epithelial lineage was established by 
studies showing that they are capable of differentiation not only to cells of mesodermal 
origin, but also to cells of endodermal and ectodermal (including epithelial) origin57;58.  
MSCs cultured in airway growth media differentially express lung specific epithelial 
markers like Clara cell secretory protein, surfactant protein-C, and thyroid transcription 
factor-157;58.  In addition, in-situ hybridization studies with co-staining for green fluorescent 
protein (GFP) and epithelial markers shows that GFP-labeled MSCs assume an epithelial 
phenotype at sites of lung injury and contribute to tissue repair56;59.  It is worth noting, 
however, that not all authors agree, with some suggesting that technical difficulties 
associated with immunofluorescence microscopy have led to the false conclusion that 
MSCs contribute to alveolar epithelium60;61.
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1.3
Mesenchymal Stem Cells: Preclinical Experience
Several cell-based therapies results propose that infusion of mesenchymal stem cells is 
a safe and novel approach believed to be an effective strategy to decrease symptoms of 
frailty.  Below we review the impact of MSCs on the cardiovascular system following 
injury; this provides support for an impact of MSCs in individuals with frailty.
A porcine model of anterior myocardial infarction was used to characterize the impact of 
cellular cardiomyoplasty on cardiac structure and function using hemodynamic, imaging, 
and histological analyses.  A pig model was selected because of its anatomic similarity to 
the human heart.  The following sections describe the safety and efficacy results obtained 
with this model62.   Two distinct sets of studies were conducted, representing the early 
treatment of acute myocardial infarction, as well as the treatment of chronic ischemic 
cardiomyopathy.
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Allogeneic 
mesenchymal 
stem 
cell 
transplantation improves global cardiac 
function in a swine model of acute 
myocardial 
infarction: 
Previously 
published 
work 
demonstrated 
that 
autologous MSC transplantation in post-MI 
pigs 
improved 
cardiac 
function, 
with 
histological evidence of robust engraftment 
at 8 weeks, and differentiation to a myocyte-
like phenotype63.  Based on in vitro 
observations that MSCs lack the B-7 
costimulatory molecule and may therefore 
be 
immune-privileged, 
the 
impact 
of 
allogeneic MSC transplantation in porcine 
MI was assessed.  A 14 pig randomized, 
placebo-controlled 
study 
(MSCs 
vs. 
placebo) using the BioCardia Helical 
Infusion Catheter was performed to assess 
safety 
and 
efficacy 
of 
allogeneic 
transendocardial injections62. Farm pigs 
were chronically instrumented to measure 
left-ventricular pressure, dimension, and 
oxygen consumption, and were randomized 
to active treatment or placebo groups. 
Three days following MI, placebo (n=7) or 
2X108 allogeneic MSCs (n=7) labeled with 
Di-I and DAPI (both fluorescent dyes to aid 
histochemical identification) were injected 
percutaneously into infarcted myocardium of the left ventricular cavity using a helical 
injection needle catheter inserted through a steerable guide catheter (BioCardia, Inc.).  
All animals tolerated the catheter-based injections well.  Animals were then studied on a 
weekly basis for 8 weeks to assess hemodynamics and to examine ventricular 
architecture.  In treated animals, MSCs engrafted within the MI (Figure 1 a, b) and 
expressed several myocyte proteins, including α-actinin, phospholamban, tropomyosin, 
and troponin T (Figure 1 c, d, e, f).  In addition, there was evidence of stem-cell 
differentiation or incorporation into vascular structures within the infarct area (Figure 1 g, 
h, i).  MSCs were detected in vascular structures as they expressed VEGF and 
vonWillebrand Factor, suggesting that they are capable of differentiating into vascular 
smooth muscle and/or endothelium.  That the cells did not elicit rejection, despite the 
absence of immuno-suppressive drug therapy, was supported by the lack of a significant 
inflammatory response.  (Note that cells surrounding vessel in Figure 1g and 1i are of 
MSC origin, as indicated by DAPI positivity in Figure 1h). The number of MSCs persisting 
in the myocardium decreased over time.  Nonetheless, MSC injection produced a wide 
range of benefits, including improved regional and global ventricular function, reduced 
myocyte apoptosis, and improved tissue perfusion.
A
B
Figure 1.  MSC engraftment and differentiation.  MSC engraftment and 
muscle-specific protein-expression. DAPI and Di-I labeled MSCs (blue 
staining nuclei and red staining membranes, respectively) and fluorescent 
muscle protein-specific antibodies (green).  (A) Hematoxylin and eosin 
(H&E)–stained section and corresponding fluorescent detection of 
cellular labels (B) depicts a cluster of MSCs in proximity to host 
myocardium.  Several muscle-specific proteins are detected by 
immunoflouresence including 
-actinin (C), phospho- lamban (D), 
tropomyosin (E) and troponin T (F).  Yellow fluorescence indicates 
colocalization of immunofluorescent antibodies and DiI. (G) H&E stained 
sections of vascular structures at the border of the infarcted myocardium. 
Corresponding sections depict DAPI stained MSC nuclei (H) with 
immunofluoresecent detection of factor 8 (I).
C
D
E
F
B
A
G
H
I
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In terms of functional responses, 
anterior 
MI 
caused 
dramatic 
deterioration of systolic and diastolic 
ventricular 
function, 
and 
impaired 
cardiac energy metabolism (p<0.05 vs. 
pre-MI values). Compared with injection 
of 
placebo, 
MSC 
cardiomyoplasty 
resulted in profound improvements in 
myocardial 
function 
and 
efficiency 
(Figure 
2). 
 
Figure 
2a 
depicts 
representative examples of pressure-
dimension data from animals in either 
group.  As shown, MSC treatment led to 
a pattern of LV recovery over a 2-3 
month period marked by a substantial 
increase in stroke work (SW, the area 
within the loops).  In the placebo-treated 
group, impaired cardiac function evident 
3 days post infarction either persisted or 
worsened over 8 weeks of follow-up: 
indices of myocardial contraction fell 
and end-diastolic pressure rose (Figure 
2 a,b,c,d).  In marked contrast, LV end 
diastolic pressure increased to normal 8 
weeks after MSC treatment (*p<0.05 vs. 
placebo).  MSCs caused myocardial 
performance to recover to normal, both 
in systolic (Ees rose to 13.9±2.7 
mmHg/mm 
and 
peak 
+dP/dt 
to 
2465±575 mmHg/sec) and diastolic 
function (Tau fell to 373.8 msec).
Heart 
failure 
and 
the 
aging 
cardiovascular 
system 
are 
characterized 
by 
mechanoenergetic 
uncoupling: decreased efficiency of 
work per unit oxygen consumption.  In 
placebo-treated 
animals, 
SW 
decreased substantially during the 8-
weeks following infarction, and there 
was 
a 
paradoxical 
increase 
in 
myocardial oxygen consumption, resulting in decreased ratio of SW/MVO2.    Conversely, 
MSC-injected animals’ follow-up was marked by improving myocardial efficiency, both 
because of increasing SW (from 374.4±59.3 to 654.4±129.9 mmHg.mm at 8 weeks) and 
because of decreasing MVO2 (from10.3±2 to 3.7±1.8 J/beat), both toward normal (Figure 
2 e).  Thus, MSC therapy exerts favorable effects on the damaged heart that extend to 
0
2
4
-50
0
50
100
150
0
2
4
6
8
-40
0
40
80
120
0
2
4
6
8
-30
-20
-10
0
10
0
10
20
30
40
50
*
Dimension (mm)
28
32
36
40
44
48
52
28
32
36
40
44
48
52
20
24
28
32
36
40
44
20
24
28
32
36
40
44
Dimension (mm)
Left ventricle Pressure
mmHg
0
40
80
120
Ees
LVEDP
*† 
 Weeks
SW/ MVO2
 Ees
 MSC
 Placebo
E
D
C
B
A
*†
*†
 tau
 Day 3
 Week 8
 LVEDP 
MSC
Control
Figure 2.  Physiologic impact of MSCs delivered with the BioCardia Catheter
following anterior myocardial infarction (MI) in pigs.  (A) Pressure-dimension 
(PD) data from placebo (left) and an MSC-treated (right) pig obtained 3 days 
(black loops) and 8 weeks (red loops) following MI.  Placebo animals exhibit an
increase in left-ventricular end-diastolic pressure (LVEDP) and dimension. 
Both myocardial contractility, measured by the slope of the end systolic 
pressure-dimension relationship (ventricular elastance, Ees), and ventricular 
stroke work, pressure-dimension loop area, decline in controls.  In MSC-treated
animals, Ees and stroke work increase to normal. (B-E) Average hemodynamic
responses over 8 weeks showing divergent responses in cardiac function in 
MSC vs. placebo treated animals.  (B) Ees declines in placebo-treated pigs but 
increases in the MSC group. (C) Isovolemic ventricular relaxation (τ), reduces 
to normal in MSC pigs but remains unchanged in placebo.  (D) LVEDP increases
in placebo but remains unchanged in MSC pigs. (E) Stroke work declines in 
placebo-treated animals while myocardial oxygen consumption (MVO2) 
increases (81±10.4%), leading to reduced SW/MVO2.  In contrast, in MSC-
treated pigs, stroke work increases 89.8±15.3%, MVO2 decreases 48.9±16.7%, 
resulting in augmented SW/MVO2 and restoration of mechanoenergetic 
coupling toward normal.  *p<0.05 vs. placebo and †P<0.05 vs. 3-day following 
MI, by ANOVA.
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improvements in cellular energy metabolism.  The SW/MVO2 ratio increased from 2.5±0.6 
at 3 days post-MI to a normal ratio of 10±5.6 (p<0.05 vs. placebo) at 4 weeks.  This 
improvement in mechanoenergetics was the earliest observable benefit of MSC 
treatment, preceding changes in global cardiac function.  Improved mechanoenergetic 
coupling in the MSC group is consistent with several possible mechanisms, including 
reduced native tissue death64, new tissue formation42;65, or stimulation of endogenous 
repair mechanisms66;67.
To further investigate the mechanisms of MSC-mediated cardiac repair, both MRI and 
computed tomography (CT) were used to image and quantify myocardial infarcts in 
MSC- and placebo-injected swine. Infarct size measurement in vivo by MRI and CT  
correlated tightly to that determined by triphenyltetrazolium chloride (TTC) staining post-
mortem.  Furthermore, using a 32-slice multidetector CT, the same endocardial rim of 
viable, non-infarcted myocardium observed in the first series of post-mortem hearts 
(Figure 3, Figure 4) was identified by in vivo imaging.
Figure 4. Comparison of infarct size using MRI (A), CT (B), and TTC 
(C).  Images were obtained 8 weeks after closed-chest infarction in a pig
and 
demonstrate 
subendocardial 
myocardial 
infarction 
as 
hyperenhancing region (~7-11 o’clock).  TTC nonstaining areas (e.g., 
lack of brick red staining) in post-mortem slices (bottom) demonstrate 
concordance of infarct location and size with MRI and CT.  Infarct region
is notable for rim of noninfarctied myocardium along the endocardial
border seen with CT and TTC staining. (arrows)
A.
B.
C.
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These data not only speak to the therapeutic potential of MSC cardiomyoplasty, but also 
establish that noninvasive imaging techniques can be used to measure the effects of 
cardiomyoplasty, and to study the mechanisms underlying these effects.  These results 
in this pig model provide strong rationale for the development of MSC-based cellular 
cardiomyoplasty strategies and support ongoing human studies.
Figure 3. Myocardial infarct size 8 weeks following transient left anterior descending coronary artery occlusion.  A. 
Representative example of scar formation due to myocardial infarction in placebo (top) and MSC treated animal (bottom).  In 
placebo-treated animals the area of scar formation is transmural (arrow), while in the MSC group the scar area is barely visible 
and surrounded by non-scar tissue on both endo- and epicardial sides.  B.  Bar graph depicting scar formation as a percentage of
LV mass.  *P=0.008.
MSC
Placebo
A
B
0
6
12
18
24
*
 8 weeks Post-MI
MI size (% of LV mass)
 Placebo
 MSC
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MSCs injected intravenously home to and engraft in infarcted myocardium 
conferring functional benefit: Preliminary studies were conducted on the efficacy of 
MSCs administered intravenously (I.V.) in a rat model of permanent left anterior 
descending (LAD) artery occlusion.  Echocardiography was used to assess LV function 
at baseline, in the peri-infarct period, and four weeks after MI.  MSC injection in Wistar 
rats led to dramatic improvement in LV function, with increased myocardial thickening and 
contractility in treated animals (Figure 5A and 5B).  Labeled cells were identified within 
the infarct (Figure 6a), and were shaped like fibroblasts but expressed the cardiac protein, 
α-actinin, albeit at lower levels than native cardiomyocytes (Figure 6b). These labeled 
cells were most evident at the endocardial rim of the infarct, a finding similar to that seen 
in the porcine studies above.
MSCs delivered intravenously (I.V.) distributed to the heart in response to an injury 
signal: MSCs injected I.V. at the time of coronary reperfusion homed to the myocardium, 
while cells injected I.V. two weeks after reperfusion were more likely to engraft in the bone 
marrow (Figure 7). Determination of SDF-1 and CXCR4 levels revealed not only that both 
are expressed by MSCs, but also that serum levels are up regulated immediately post 
infarct and remain elevated for at least 2 weeks (Figure 8). 
Figure 8: Both SDF-1 and CXCR4 levels are elevated following 
myocardial infarction. P<0.05 vs pre infarct
Figure 5. A: Two-dimensional echocardiography showing end diastole 
(left column) and end systole (right column) in a treated rat 1) before 
infarction 2) after infarction and prior to treatment and 3) 4 weeks after
treatment with MSCs. B: M-Mode from same animal showing fractional 
shortening at the papillary level at the same time points as in A.
Figure 6: A: β-galactosidase positive (blue) cells are visible at 20X magnification
within the infarct in young rats.  These cells form a band along the endocardial 
surface.  B:  These cells show evidence of α-actinin expression on 
immunofluorescence, also at 20X magnification (bright appearing cells, B&W 
image).  C: Quantification demonstrates 10-fold higher engraftment in young
relative to old (p<0.001).
↑
endocardium
A.
B..
Figure 7. Confocal images of 
infarcted myocardium (top 
row) and bone marrow 
(bottom row) illustrating the 
degree of allogeneic MSC 
engraftment observed when 
5 
million 
MSCs 
were 
delivered via tail vein at 
reperfusion (left columns) or 
2 weeks post-reperfusion 
(right column).  As shown, at 
reperfusion cells home to the 
heart and not bone marrow; 
two weeks later, trafficking 
to the heart is reduced, and 
cells 
now 
migrate 
and 
engraft in the bone marrow. 
All tissues were harvested 4 
weeks post-implantation. A 
FITC-conjugated 
antibody 
directed 
against 
desmin 
(green) was used to assess 
the myogenic differentiation.
Bone 
Marrow
Infarcted 
Myocardium
Reperfusion
2-weeks post-MI
Pre-Infarct
Day-7
Pre-Infarct
Day-7
SDF
*
*
Arbitrary units
CXCR4
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Myocardial Function can be determined in vivo by MRI
The clinical research team has extensive experience using tagged MRI scanning to detect 
and quantify alterations in regional myocardial mechanics in animal models of ischemic 
heart disease68;69.  The team has also developed non-surgical, MRI-compatible animal 
models for studying cardiac mechanics, perfusion, and interventional procedures70-73. The 
team has recently developed new MR imaging and analysis methods that enable the rapid 
determination of myocardial function in infarction and ischemia70. This new technique, 
Harmonic Phase (HARP) MRI74;75 is based on tagged MRI techniques.  Computationally, 
the analysis of HARP MRI can be performed much more rapidly than traditional tag 
tracking in tagged MRI. “Real-time” HARP imaging exploits the concept that only one of 
the spectral peaks must be acquired for motion in one direction; this in turn accelerates 
the image acquisition in addition to the rapid analysis already available in HARP. An 
example of the use of real-time HARP to monitor the onset of ischemia in a canine model 
of coronary artery stenosis is depicted (Figure 9)104. Using this technique, we can identify 
abnormal regional myocardial contraction after the onset of ischemia 20 seconds earlier 
than can be done using conventional cine wall motion studies and one minute earlier than 
ECG changes. HARP MRI, similar to tagged MRI, yields quantitative motion and strain 
parameters on a regional basis that can be used for comparison across subjects or at 
serial time points after intervention.  Thus, HARP MRI and analysis represents a rapid 
and repeatable method to assess left ventricular function serially in a quantitative manner.  
HARP provides fast, accurate assessment of myocardial strains in humans with and 
without coronary artery disease76.  Similar techniques have been used to assess 
structural and functional changes after myocardial infarction in rats77;78.
Figure 9: Real-time HARP images in the short-axis plane at different time points (10 sec prior to ischemia and 0, 6, and 20 heartbeats after the 
onset of ischemia from left to right) in a canine closed-chest model of acute LAD coronary artery occlusion.  Overlaid on the tagged images is a 
pseudo-color map of circumferential shortening where green is uniform shortening, red is decreased shortening or stretching, and blue is 
increased shortening.  At 6 heartbeats after ischemic insult, stretching of the ischemic myocardium is observed in the LAD bed whereas wall 
motion abnormalities by cine MRI could not be appreciated until 30 sec post-occlusion.
Noninvasive Determination of Infarct Size
Using an intravenous injection of Gd-DTPA, the study team is able to determine infarct 
size non-invasively with T1-weighted contrast-enhanced MRI (i.e., “Delayed Contrast-
Enhanced MRI”).  Short-axis image slices, which span the entire left ventricle, can be 
obtained using multiple breath-holds to yield images with the highest spatial resolution. 
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Figure 12. Infarct circumferential extent of the LV before and 12 
weeks after injection in swine.  Infarct size was significantly 
reduced by MSC treatment.  p<0.05 MSC vs. placebo, p<0.05 MSC 
week 12 vs. week 24. [n=10]
The size of the area of hyper enhancement measured on such images has been shown 
to be within 10% of the infarct size measured by post-mortem TTC staining (Figure 10).  
Alternately, using new imaging techniques, one can obtain the entire 3D left ventricular 
volume in a single breath hold (~16 heartbeats).  It was recently shown that the 3D 
technique is in concordance with infarct size as measured by traditional 2D multi-slice 
techniques (Figure 10)89,90. Thus, infarct size and location can be accurately determined 
in less than one minute of scanning time, in order to determine the size of an infarct prior 
to therapy and over time.
Figure 10. 2D delayed CE MRI in 
short axis plane (top) acquired 
within the first 24 hrs after closed-
chest infarction demonstrating 
subendocardial myocardial 
infarction as hyperenhancing region 
(~11-1 o’clock) in a dog.  TTC 
nonstaining areas (e.g., lack of brick 
red staining) in post-mortem slices 
(bottom) demonstrate concordance 
of infarct location and size with MRI.
Autologous Mesenchymal Stem Cells Produce Reverse Remodeling in Chronic 
Ischemic Cardiomyopathy: In addition to the studies outlined above using models of 
acute MI in the pig, we have also developed a model of chronic MI in the Gottingen mini-
swine.  We have used both autologous and allogeneic MSCs, with surgical and catheter 
delivery strategies, and have developed sufficient experience to translate the therapy 
from the laboratory bench to clinical trials.  Together our results indicate that bone marrow 
derived MSCs stimulate cardiac recovery by engrafting, forming new blood vessels that 
increase tissue perfusion in hypoperfused areas, forming new cardiac myocytes, and 
importantly interacting with endogenous precursor cells to also contribute to new cardiac 
myocyte formation. From an immunologic perspective, MSCs may be safely used as an 
allogeneic graft, and have been done so extensively in clinical trials79-81.
Week 12
Week 24
Placebo
MSC
Figure 11. Myocardial regeneration in our porcine model of MI. 
Delayed gadolinium-enhanced MRI images depicting chronic 
(week 12 post MI) myocardial scar before treatment and (week 
24) 12 weeks following injection of MSCs or placebo. Infarct 
tissue appears bright white, and healthy myocardium appears 
black.  Comparable gross heart sections are shown adjacent to 
the MR images.  Infarct size is reduced by MSC treatment, and 
cardiac performance improves.
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Our experience with a 53 subject, 10-center, phase I study under the sponsorship of Osiris 
therapeutics, which demonstrated safety and provisional efficacy of allogeneic MSC 
therapy in subjects with acute infarction is outlined below17. In animal studies conducted 
in mini-swine, MSC injection via catheter into infarcted tissue reduces myocardial infarct 
size (Figs. 11 and 12), improves global and regional LV function, normalizes cardiac 
energetics, and restores tissue perfusion63;82. These results form the basis for our 
approval to conduct the CRATUS study.
Our work in large animal models with fully healed scars after MI showed that MSC 
administration can significantly improve left ventricular structural and functional indices, 
indicating meaningful repair. Using sophisticated imaging techniques, we tracked 
phenotypic improvements triggered by implantation of MSCs in a porcine model of 
chronic ischemic cardiomyopathy and quantified these changes morphometrically.  MI 
was created in swine; after 12 weeks, the infarct segment had thinned, leaving a 
transmural scar (Figure 11). Autologous MSCs were expanded from each animal83, and 
these cells or placebo were delivered to the infarct and surrounding border zone at this 
time.  During a further 12-week follow up period, cardiac MRI revealed that 
intramyocardial injections of MSCs not only reduced the scar burden (as a percentage 
of LV mass) by 21.8+3.9% (p<0.05 vs. placebo and week 12 vs. week 24) (Figure 11, 
12), but also significantly improved regional contractility, global LV function, ejection 
fraction, and myocardial blood flow.  Importantly, the therapy produced reverse 
remodeling and reduced the circumferential extent of the infarct scar (Figure 12).  This 
constellation of effects suggests highly effective repair of ischemic cardiomyopathy.  We 
subsequently confirmed reverse remodeling in a pilot study of 8 subjects with ischemic 
cardiomyopathy (Figure 21)43.  
Allogeneic Mesenchymal Stem Cells Restore Cardiac Function in Chronic Ischemic 
Cardiomyopathy Via Trilineage Differentiating Capacity:
We tested the hypothesis that MSC based cardiac repair regenerates the heart via 
mechanisms comprising long-term engraftment and by differentiation into both 
myocardial and vascular elements. We generated allogeneic MSCs from a male swine 
donor, and administered sex mismatched cells by transendocardial injection into female 
swine 12 weeks post-MI.  Animals were followed with serial MRI, and 12 weeks later the 
hearts were collected for immunohistological evaluation. The fate of the male donor cells 
was determined by co-localization of Y-chromosome (Ypos) cells with markers of cardiac, 
vascular, and endothelial lineages.  MSCs engrafted in infarct and border zones and 
differentiated into cardiomyocytes (Figure 13) as ascertained by co-localization with 
GATA-4, Nkx2.5, and α-sarcomeric actin markers. In addition, YposMSCs exhibited 
vascular smooth muscle and endothelial cell differentiation, contributing to large and small 
vessel formation.  The number of cells engrafting correlated with the functional changes 
that occurred (Figure 13F).  Thus, MSCs could engraft and repair hearts in chronic 
ischemic cardiomyopathy84.
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Ventricular remodeling is a progressive disease causing the myocardium to reorganize 
itself from an elliptical to a spherical shape. During its reorganization the heart will become 
enlarged and ventricular dimensions increase, assisting in reshaping a subject’s heart. In 
swine models, MSCs show that the reduction in scar size supports reverse remodeling, 
which show a reduction in scar size as quickly as 3 days after injection. MSCs have shown 
as a promising cell-based therapy where previously there was limited means of improving 
a subject’s heart function and survival85. 
Figure 13. Engraftment of MSCs in chronic myocardial infarction. (A) Colocalization Y chromosome and
troponin, indicative of an MSC differentiated into a cardiomyocyte. (B) Evidence of cardiac commitment in
the transplanted cardiomyocyte by the colocalization of cardiac transcription factor Nkx2.5 (green, arrow).
(C) Ypos cells also reside in the interstitial compartment (arrows) of border myocardium in a nondifferentiated
stage. (D) Ypos cells that colocalize with smooth muscle actinin (arrowheads) and factor viiirelated
antigen (white, arrows) demonstrating vascular smooth muscle and endothelial commitment, respectively. (E) 
Confirmation of Ypos cells commitment into vascular structures as depicted by colocalization with SM22-alpha (F) 
The functional outcomes (i.e. infarct size reduction, increase in contractility and increase in tissue perfusion) showed 
related interaction with the magnitude of transplanted cells detected.
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Figure 14. Merging CMR angiography and electroanatomical mapping to guide transendocardial 
mesenchymal stem cell injection.
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Figure 15: Durable and progressive scar size reduction due to intramyocardial injection of 
allogeneic bone marrow MSCs. A, Delayed-enhancement CMR scar size images show durable 
reduction in scar size with MSC therapy.
Figure 16: Allogeneic MSC therapy reverses remodeling in ischemic cardiomyopathy.
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Figure 17: Allogeneic MSC therapy improves LV sphericity index. 
Figure 18. Progressive improvement in LV function with allogeneic MSC therapy.
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1.4
Allogeneic Mesenchymal Stem Cells: Previous Experience in Humans
The use of allogeneic cellular products typically requires matching of the graft HLA to the 
donor in order to avoid graft rejection and graft versus host disease.  However, because 
MSCs do not express HLA, they represent a unique immunoprivileged cell population, 
which can be used for allogeneic cellular therapy.  In addition, MSCs fail to induce 
proliferation of allogeneic lymphocytes in vitro and suppress proliferation of T cells 
activated by allogeneic cells or mitogens.  MSCs have also been shown to exert anti-
proliferative, immunomodulatory and anti-inflammatory effects.  Many subjects have 
received allogeneic MSCs and infusions have all been well tolerated. 
A multi-center, randomized, double-blind, placebo-controlled study was performed to 
evaluate the safety and preliminary efficacy of allogeneic MSCs administered after 
myocardial infarction17.  In this study, 53 subjects were treated with one of three cell-dose 
levels of allogeneic MSCs (0.5, 1.6 and 5.0 cells/kg body weight) or placebo administered 
intravenously.  No HLA matching was performed in this study and administration was 
found to be safe and well tolerated at all dose levels (with 5.3 adverse events per subject 
in the MSC-treated group vs. 7.0 in the placebo group).  No deaths were reported and no 
serious adverse events were attributed to MSC administration.  Improvements were seen 
in subjects receiving MSCs as compared with those receiving placebo in the frequency 
of arrhythmic events and premature ventricular contractions, post-event ejection fraction 
for subjects with major anterior wall infarctions, overall clinical status, and notably post-
infusion pulmonary function as measured by FEV1 percent predicted (increased 17% in 
the MSC-treated group vs. 6% for placebo group, p < 0.05).  
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Allogeneic MSC infusion has also been studied in a phase II trial of MSCs for the 
treatment of severe acute graft versus host disease.  In this study, 55 subjects received 
1-5 intravenous infusions of 1.4 x 106 cells/kg body weight from HLA matched and mis-
matched donors.  A complete response was seen in 30 subjects and improvement was 
seen in 9 subjects.  Of note, response rates were not associated with HLA-matching.  No 
infusion related side effects were noted and no long-term adverse events were observed.      
The safety and efficacy of allogeneic MSCs for the treatment of refractory lupus has also 
been explored86.  Fifteen subjects received a single intravenous infusion of 1 x 106 cells/kg 
body weight.  MSCs were derived from family members but were not HLA-matched.  At 
12 months, all subjects had improvement in disease activity as measured by 24 hour 
proteinuria (decreased from 2505.0±1323.9 to 858.0±800.7 mg/24hr, p<0.05) and SLE 
Disease Activity Index scores (decreased from 12.2±3.3 to 3.2±2.8, p<0.05).  No serious 
adverse events were noted in any of the subjects.
The Poseidon trial (IND #13568; NCT01087996), has provided additional validity that 
MSCs reduce infarct size and reverse remodeling of the myocardium85.  Study data also 
reveal that MSCs are immunoprivileged and immunosuppressive, and do not cause acute 
immunogenic reactions.  In this regard, no subject reported symptoms or indications of a 
reaction.  Only one of 15 subjects receiving ahMSCs mounted a donor specific 
alloreaction, of low antibody titer18.  Furthermore, subjects treated with allogeneic MSCs 
suffered fewer AE’s versus autologous MSCs subjects. It is also hypothesized that the 
function of autologous MSCs could be impaired in subjects with co-mobility or advanced 
age87;88. Reverse cardiac remodeling was a prominent factor subjects showed as 
assessed by the study CT scan results18. Allogeneic MSCs were shown in this trial to be 
a safer and more effective form of cell-therapy than autologous MSCs. Figures 19 and 20 
depict functional and quality of life improvements in subjects received both allogeneic and 
autologous MSCs. 
We randomized 30 subjects in an open-label study of either allogeneic or autologous 
hMSCs at 3 doses; 20, 100, or 200 million total hMSCs.  The study was designed as a 
pilot study to compare the safety and efficacy of allogeneic versus autologous hMSCs in 
subjects with chronic ischemic left ventricular dysfunction secondary to myocardial 
infarction.  Autologous MSCs were derived from a sample of the subject’s bone marrow 
approximately 4-6 weeks prior to cardiac catheterization.  Allogeneic MSCs were supplied 
from a human MSC source manufactured by the University of Miami.  All 30 subjects 
tolerated the procedure well and have been followed-up with serial cardiac CT at 13 
months post injection.  The serious adverse event rate (SAE) was lower among subjects 
treated with allogeneic MSCs as compared to autologous MSCs (6-months: 20%-
allogeneic MSCs and 40%-autologous MSCs).  The injection of MSCs into the hearts of 
these subjects produced reverse remodeling, with reductions in EDV of ~23 ml and 
reduction in spherecity index of 0.8.   
Together, these preliminary data support our hypothesis that allogeneic MSC 
administration is a safe and successful option for cellular cardiomyoplasty.  We have 
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demonstrated long-term MSC survival, engraftment, and differentiation into myocardial, 
vascular, and endothelial lineages following transplantation into chronically scarred 
porcine myocardium. These cells’ capacity for cardiomyogenesis and vasculogenesis 
both likely contribute to their ability to repair chronically scarred myocardium.   
Figure 19: Functional Outcomes
A) Six-Minute Walk Test (meters)
B) Peak VO2 (ml/kg/min)
C) Minnesota Living with Heart Failure
D) New York Heart Association Class
Figure 20: CT Parameters Change from Baseline
A) Left Ventricular Ejection Fraction (%)
B) End Diastolic Volume (ml)
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C) End Systolic Volume (ml)
D) End Diastolic Myocardial Volume (cm3)
E) Sphericity Index
F) MI Size (Early enhancement defect; 
grams)
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G)
Before TESI 40.34 g
After TESI 26.35 g
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The study by Weiss et al, which investigated ahMSC therapy for COPD, reflected similar 
trial results indicating as the Poseidon trial that allogeneic MSCs did not cause acute 
immuogeneic reactions in subjects participating in the trial.  Importantly, ahMSCs 
produced a decrease in the inflammatory marker CRP. Systemic administration of MSCs 
appears to be safe and decrease inflammation in an older and co-morbid population of 
subjects with compromised lung function due to moderate COPD19.
Preliminary Results from the Transendocardial Autologous Cells in Ischemic Heart 
Failure Trial (TAC-HFT): We enrolled 8 subjects in an open-label run-in phase of the 
TAC-HFT trial to assess the safety and preliminary efficacy of bone marrow mononuclear 
cells (MNCs) and MSCs in subjects with ischemic cardiomyopathy24, 25. At baseline each 
subject underwent a bone marrow aspiration and transendocardial injection (Helix 
Infusion Catheter; Biocardia, Inc., CA) of bone marrow derived MNCs or MSCs to the 
infarct and border zone using biplane fluoroscopic guidance.  All 8 subjects tolerated the 
procedure well and have been followed-up with serial cardiac MRI at 3, 6, and 12 months 
post injection (Figure 21).  The injection of bone marrow derived cells into the hearts of 
these subjects produced reverse remodeling, with reductions in EDV of ~12% and 
improved regional function as measured by –Ecc, a cardiac MRI derived index (Figure 
21).  As described above, we have also treated subjects with ahMSCs in the POSEIDON 
trial and have demonstrated an outstanding safety profile.
A.
B.
C.
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D.
       E.
              
         
F.
G.
Figure 21.  Cardiac MRI follow-up data of (A) end-diastolic volume, (B) end-systolic volume, and (C) peak Eulerian 
circumferential strain (Ecc) of the infarct zone from tagged imaging.  Example cardiac MRI images of change in EDV from 
(D) baseline to (E) 1 year, and change in ESV from (F) baseline to (G) 1 year after stem cell injection.  As depicted, EDV 
and ESV are reduced by 6 months following injection, and do not return towards baseline by 12 months.  Peak Ecc is 
dramatically reduced by 3 months following injection (the more negative Ecc corresponds to improving regional LV 
function). *p<0.05 in post-hoc analysis compared to baseline.  Yellow Arrow:  Note improved systolic thickening in lateral 
wall, the site of cell therapy in this example.
1.5.
Pharmacology and Toxicology Studies of Mesenchymal Stem Cells
Preclinical data suggest that MSCs may safely be used in the treatment of Frailty.  Using 
the murine bleomycin model, several groups have shown that the administration of stem 
cells ameliorates bleomycin induced lung injury with no significant adverse effects.  
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Lee et al intravenously administered 1x106 bone marrow derived MSCs to rats treated 
with bleomycin and found a decrease in bleomycin induced lung edema, neutrophil 
infiltration, collagen deposition, and overall mortality with no adverse effects reported55.  
Similarly, Ortiz et al intravenously administered 5 x 105 bone marrow derived MSCs to 
mice with no adverse effects reported.  They found that after bleomycin exposure, MSCs 
home to sites of lung injury, lead to decreased fibrosis and extracellular matrix collagen 
deposition, and contribute to tissue repair51.  Rojas et al intravenously administered 5 x 
105 allogeneic bone marrow derived MSCs to mice treated with bleomycin and observed 
that lung injury attracts bone marrow derived MSCs via the production of soluble factors 
like G-CSF and GM-CSF, which lead to MSC proliferation and migration and ultimately 
improved survival with no reported adverse effects56.  
These findings appear to extend beyond bone marrow derived MSCs.  Cargnoni et al 
administered fetal membrane derived cells (both allogeneic murine and xenogeneic 
human) to bleomycin treated mice and found that placental derived stem cells, like MSCs, 
localize to the lung and reduce tissue damage associated with bleomycin exposure 
regardless of source or route of administration (intravenous, intraperitoneal, or 
intratracheal)50.   They did find that intraperitoneal and intratracheal administration of cells 
led to mild to moderate lung inflammation but no fibrosis in the absence of bleomycin 
injury.  Importantly, this was not seen with intravenous administration of cells.  In another 
murine model, xenogeneic human umbilical cord derived MSCs were also shown to home 
to sites of bleomycin induced lung injury, inhibit the production of pro-inflammatory 
cytokines, and reduce lung injury and collagen deposition with no adverse effects 
reported52.
Table 1. Results of preclinical animal studies of mesenchymal stem cell therapy for IPF.
Study
Model
Cell Type
Cell Delivery 
and Dose
Safety Results
Efficacy Results
Lee at al, 
2006
Rat
Allogeneic
BM-MSCs
Intravenous, 1 
x 106 cells
No adverse 
effects reported.
Reduced edema, 
neutrophil 
infiltratration, 
collagen deposition.
Improved survival.
Ortiz et 
al, 2003
Mouse
Allogeneic
BM-MSCs
Intravenous, 5 
x 105 cells
No adverse 
effects reported.
Reduced 
inflammation and 
collagen deposition.
Rojas et 
al, 2005
Mouse
Allogeneic
BM-MSCs
Intravenous, 5 
x 105 cells
No adverse 
effects reported.
Reduced pro-
inflammatory 
cytokines.
Improved survival.
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Cargnoni 
et al, 
2009
Mouse
Fetal 
membrane 
derived
(Allogeneic 
murine and 
xenogeneic 
human)
Intra-
peritoneal, 
4 x 106 cells
Intratracheal, 
1 x 106 cells
Intravenous, 1 
x 106 cells
Mild to moderate 
lung 
inflammation 
but no fibrosis 
induced by 
intraperitoneal 
or intratracheal 
administration.
No adverse 
effects reported 
with I.V. 
administration.
Decreased 
neutrophil infiltration 
and fibrosis 
regardless of route 
of administration or 
source of cells.
Moodley 
et al, 
2009
Mouse
Xenogeneic 
human 
umbilical 
cord 
derived 
MSCs
Intravenous, 1 
x 106 cells
No adverse 
effects reported.
Reduced 
inflammation, pro-
inflammatory 
cytokine production, 
and collagen 
deposition.
In addition to safety data from preclinical animal studies, many subjects have received 
allogeneic MSCs in clinical trials and infusions have all been well tolerated. 
A multi-center, randomized, double-blind, placebo-controlled study was performed to 
evaluate the safety and preliminary efficacy of allogeneic MSCs administered after 
myocardial infarction17.  In this study, 53 subjects were treated with one of three cell-dose 
levels of allogeneic MSCs (0.5, 1.6 and 5.0 cells/kg body weight) or placebo administered 
intravenously.  No HLA matching was performed in this study and administration was 
found to be safe and well tolerated at all dose levels (with 5.3 adverse events per subject 
in the MSC-treated group vs. 7.0 in the placebo group).  No deaths were reported and no 
serious adverse events were attributed to MSC administration.  Improvements were seen 
in subjects receiving MSCs as compared with those receiving placebo in the frequency 
of arrhythmic events and premature ventricular contractions, post-event ejection fraction 
for subjects with major anterior wall infarctions, overall clinical status, and notably post-
infusion pulmonary function as measured by FEV1 percent predicted (increased 17% in 
the MSC-treated group vs. 6% for placebo group, p < 0.05).  
Allogeneic MSC infusion has also been studied in a phase II trial of MSCs for the 
treatment of severe acute graft versus host disease31.  In this study, 55 subjects received 
1-5 intravenous infusions of 1.4 x 106 cells/kg body weight from HLA matched and 
mismatched donors.  A complete response was seen in 30 subjects and improvement 
was seen in 9 subjects.  Of note, response rates were not associated with HLA-matching.  
No infusion related side effects were noted and no long term adverse events were 
observed.      
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The safety and efficacy of allogeneic MSCs for the treatment of refractory lupus has also 
been explored86.  Fifteen subjects received a single intravenous infusion of 1 x 106 cells/kg 
body weight.  MSCs were derived from family members but were not HLA-matched.  At 
12 months, all subjects had improvement in disease activity as measured by 24 hour 
proteinuria (decreased from 2505.0±1323.9 to 858.0±800.7 mg/24hr, p<0.05) and SLE 
Disease Activity Index scores (decreased from 12.2±3.3 to 3.2±2.8, p<0.05).  No serious 
adverse events were noted in any of the subjects.
2. 
STUDY OBJECTIVES AND ENDPOINTS
2.1
Study Objectives
2.1.1 Primary Objective
-
To demonstrate the safety of intravenous allogeneic hMSCs administered in 
subjects with Frailty and to explore treatment efficacy (decrease in frailty, 
frequency of acute exacerbations, change in symptom related quality of life, 
improved cardiovascular status, decrease in inflammatory biomarkers, 
endothelial function and 1 year survival).
2.1.2 Secondary Objectives
- To explore effects of allo-hMSCs on symptom related quality of life, 
cardiovascular performance, endothelial function and inflammation.
2.2
Study Endpoints
2.2.1 Primary Endpoints (Safety)

Safety (Primary): Incidence (at one month post infusion) of any treatment-
emergent serious adverse events (TE-SAEs), defined as the composite of: 
death, non-fatal pulmonary embolism, stroke, hospitalization for worsening 
dyspnea and clinically significant laboratory test abnormalities, determined 
per the Investigator’s judgment.
-
Serum chemistry: chloride, sodium, Carbon Dioxide, BUN, creatinine, 
glucose, calcium, AST/SGOT, ALT/SGPT, total bilirubin (fractionate if 
total >1.5 times normal), alkaline phosphatase, albumin, 
-
Hematology (CBC): hemoglobin, hematocrit, platelets, WBC, WBC 
differential
2.2.2. Secondary Endpoints (Efficacy)
The following efficacy endpoints will be evaluated in this trial (During the 
screening, baseline, Month 3 and/or Month 6 visits):
1.
Difference in rate of decline of Frailty defined as:
a.
Reduced Activity (assessed via CHAMPS questionnaire)
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b.
Slowing of Mobility (assessed via a 4 meter gait speed test and 
SPPB assessment)
c.
Weight Loss
d.
Diminished handgrip strength (assessed via dynamometer)
e.
Exhaustion (assessed via the MFI questionnaire)
f.
Decrease in subject quality of life assessment(s) (assessed via 
ICECAP, SF-36, EQ-5D Questionnaires)
2.
Death from any cause.
3.
Change between screening and 6 months in dobutamine stress echo 
induced ejection fraction.
4.
Change between screening and 6 months for the following panel of 
inflammatory markers:  CRP, IL-6, D-dimer, fibrinogen,
CBC with differential, and TNFα
3.
STUDY DESIGN
3.1
Description of the Study
A Pilot Phase will be performed to test the safety of dose and volume escalation of cells 
administered via peripheral intravenous infusion.  The randomized portion of the study 
will be conducted after a full review of the safety data from the Pilot Phase by the DSMB.  
In the pilot phase, the first three (3) subjects in each treatment group will not be treated 
less than 5 days apart for their first infusion and will each undergo full evaluation for 5 
days to demonstrate there is no evidence of treatment emergent SAE’s, defined as the 
composite of: death, non-fatal pulmonary embolism, stroke, hospitalization for worsening 
dyspnea and clinically significant laboratory test abnormalities, prior to proceeding with 
the treatment of further subjects.  
The fifteen (15) subjects that participated In the pilot phase will be able to receive up to 
an additional three (3) infusions of the study product for a total of four (4) possible 
infusions. See Addendum A and Addendum C for rationale and description. 
Following the pilot study, thirty (30) subjects meeting all inclusion/exclusion criteria will be 
evaluated at baseline and scheduled to undergo peripheral intravenous infusion.
3.2.
RANDOMIZATION STUDY
This Phase I/II, randomized, blinded, placebo-controlled study is designed to evaluate the 
safety and tolerability of allo-hMSCs in subjects with Frailty and to explore potential 
efficacy at 3 and 6 months.
Approximately fifteen (15) subjects will be enrolled in the pilot phase and thirty (30) 
subjects with Frailty will be enrolled in the randomized phase for a total of up to forty-five 
(45) subjects. In the randomized phase, subjects will then be enrolled and randomized 
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1:1:1 to an active arm or placebo.  Additional subjects may be enrolled if deemed 
appropriate.  
Eligible subjects must have a diagnosis or symptoms of frailty as defined by the Canadian 
Study on Health & Aging2. Following informed consent before or at the screening visit, 
the diagnosis of frailty will be confirmed by investigator review of medical history.
In the randomized phase of the trial, electronic randomization will be performed using the 
Advantage EDC system and communicated to cellular laboratory personnel who have no 
contact with the investigators or subjects.  At the time of administration, opaque tubing 
will be used to maintain double blinding. Treatments will be administered once and will 
consist of 1 x 108 allo-hMSCs (100 million cells), 2 x 108 allo-hMSCs (200 million cells), or 
placebo.  After each infusion, subjects will be monitored for immediate complications.  
Continued safety and tolerability with review of adverse events (AEs) will be monitored at 
each visit.  Efficacy parameters (Gait speed, handgrip strength, and QOL questionnaires) 
will be assessed following Day 0 until Month 6.  Clinical laboratory tests to assess safety 
will be performed at every clinic visit, excluding the baseline visit and month 12 visit.  
In the randomized phase of the trial, subjects who received placebo will have the option 
to receive 1 x 108 (100 million) cells of allogeneic hMSCs, if all study endpoints are met. 
If all endpoints are met then the subject will be administered the study drug and follow the 
study schedule listed in Section D.14 (Table D1) of Addendum D after subjects in the 
randomized phase have been unblinded.
4. 
SUBJECT SELECTION
4.1 
Inclusion Criteria
In order to participate in this study, a subject MUST:
1.
Provide written informed consent.
2.
Subjects age >60 and <95 years at the time of signing the Informed 
Consent Form.
3.
Show signs of frailty apart from a concomitant condition as assessed 
by the Investigator with a frailty score of 4 to 7 using the Canadian Clinical 
Frailty Scale
4.
Female subjects must have an FSH > 25.8 mIU/mL, if not currently on 
hormone replacement therapy.
4.2 
Exclusion Criteria
In order to participate in this study, a subject MUST NOT:
1.
Score of <24 on the Mini Mental State Examination (MMSE)
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2.
Inability to perform any of the assessments required for endpoint analysis 
(report safety or tolerability concerns, perform PFTs, undergo blood 
draws, read and respond to questionnaires.
3.
Active listing (or expected future listing) for transplant of any organ.
4.
Clinically important abnormal screening laboratory values, including but 
not limited to: hemoglobin <8 g/dl, white blood cell count <3000/mm3, 
platelets<80,000/mm3, INR > 1.5 not due to a reversible cause (i.e. 
Coumadin), aspartate transaminase, alanine transaminase, or alkaline 
phosphatase > 3 times upper limit of normal, total bilirubin > 1.5 mg/dl.5.
5.
Serious comorbid illness that, in the opinion of the investigator, may 
compromise the safety or compliance of the subject or preclude successful 
completion of the study.  Including, but not limited to: HIV, advanced liver or 
renal failure, class III/IV congestive heart failure, myocardial infarction, 
unstable angina, or cardiac revascularization within the last six months, or 
severe obstructive ventilatory defect. 
6.
Any other condition that, in the opinion of the investigator, may 
compromise the safety or compliance of the subject or preclude successful 
completion of the study. 
7.
Be an organ transplant recipient.
8.
Have a clinical history of malignancy within 3 years (i.e., subjects with  prior 
malignancy must be disease free for 3 years), except curatively-treated 
basal cell carcinoma, squamous cell carcinoma, melanoma in situ
or cervical carcinoma if recurrence occurs.
9.
Have a non-pulmonary condition that limits lifespan to < 1 year. 
10.
Have a history of drug or alcohol abuse within the past 24 months. 
11.
Be serum positive for HIV, hepatitis BsAg or Viremic hepatitis C.
12.
Be currently participating (or participated within the previous 30 days) in 
an investigational therapeutic or device trial.
13.
Be a female who is pregnant, nursing, or of childbearing potential while 
not practicing effective contraceptive methods. Female subjects must 
           undergo a blood or urine pregnancy test at screening and within 36 hours 
prior to infusion.
14.
Hypersensitivity to dimethyl sulfoxide (DMSO).
4.3 
Concomitant Treatments, Procedures, and Nondrug Therapies
All concomitant medications (prescription or over-the counter) as well as procedures or 
nondrug therapies (e.g. continuous positive airway pressure, pulmonary rehabilitation) 
will be recorded at the initial screening visit and updated at each subsequent visit.  Except 
for other experimental treatments or medications with putative disease modifying effects 
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in FRAILTY, subjects will continue all prior concomitant medications for comorbid 
diseases to ensure optimal general medical care. 
4.4 
Withdrawal Criteria
Subjects will be informed that they have the right to withdraw from the study at any time 
and for any reason without prejudice to future or continued medical care.   Subjects must 
be withdrawn for the following reasons:
1. Subject request.
2. Subject is unable or unwilling to comply with the protocol.
3. Medical reasons, at the discretion of the investigator.
Reason for withdrawal will be recorded in the subject’s case report form.  In order to 
adequately monitor for safety and potential efficacy outcomes, subjects who are 
withdrawn for any reason after receiving the first infusion should be encouraged to return 
for all assessments through the end of the study period.  All efforts should be made to 
continue to record safety data and lung function parameters for all withdrawn subjects.  
Subjects who withdraw for reasons unrelated to the study or study drug (e.g. withdrawal 
of consent or loss to follow-up) may be replaced if deemed necessary to meet study 
objectives.  Replacement subjects will be assigned unique identification numbers.
5.  
MESENCHYMAL STEM CELL DONORS
The availability of allogeneic hMSCs (allo-hMSC) offers the potential for an “off the shelf” 
product for subjects. Significant data has been generated to demonstrate that the 
allogeneic hMSCs are immunoprivileged and can be infused without immune rejection 
despite disparate HLA phenotypes.  
Screening of allogeneic donors will follow standard transplant practices and all allogeneic 
donors will meet allogeneic donor eligibility criteria as outlined in 21 CFR Part 1271.  
Allogeneic donor testing will include anti-HIV-1/2, anti-HTLV I/II, anti-HCV, HIV-1 nucleic 
acid testing, HCV nucleic acid testing, HBsAg, anti-HBc(IgG and IgM), CMV, West Nile 
Virus nucleic acid, T. cruzi ELISA (Chagas), Zika Virus and RPR. Potential donors testing 
positive for any of these infectious diseases with the exception of CMV, will be ineligible.  
Bone marrow (BM) aspirates will be obtained from normal individuals and allo-hMSCs will 
be isolated and expanded.
5.1 
Bone Marrow Aspiration for Generation of MSCs
A total of approximately 60mL to 120mL of BM will be obtained from each normal 
volunteer. BM will be aspirated from the posterior iliac crest into heparinized syringes.  
The mononuclear cell fraction will be isolated using a density gradient with Lymphocyte 
Separation Media (specific gravity 1.077).  The low-density cells will be collected and 
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washed with Plasma-LyteA containing 1% HSA.  The washed cells will be sampled and 
viable cell numbers determined. The MNCs will be prepared antibiotic free (ie. No 
penicillin or streptomycin). The BM mononuclear cells will be seeded into 175 cm2 tissue 
culture flasks in alpha MEM containing 20% FBS. After 14 days of culture, first passage 
(P0) cells will be harvested by trypsin treatment and expanded to passage 1, 2, and 3. At 
passage 3, cells are harvested and cryopreserved. 
5.2 
Normal Donor Eligibility
Donors (male or female) between the ages of ≥18 to ≤45 (inclusive) will be screened as 
potential BM donors. Donors will be evaluated by history and physical examination.  The 
history will include:
-
History of malignancy
-
Bleeding abnormalities
-
Prior deep venous thrombosis
-
Known cardiac or pulmonary conditions
-
Prior blood transfusions
-
Vaccinations
-
Questions to identify persons at risks of infectious disease transmission, 
including Zika virus
-
Questions to identify persons at risk of transmitting hematological or 
immunological disease
-
A physician will administer the National Marrow Donor Program (NMDP) 
Questionnaire (a donor health history screening questionnaire). 
The physical examination will include review of vital signs and evaluation for potential 
risks associated with the BM aspiration procedure.  Prospective donors will have 
infectious disease testing including:
-
Hepatitis B surface antigen (HBsAg)
-
Anti-Hepatitis B core antibody (HBcAb)
-
Anti-Hepatitis C virus antibody (HCV Ab)
-
Anti-Human Immunodeficiency Virus (HIV) antibody (HIV 1/2)
-
Cytomegalovirus antibody (CMV)
-
HCV/HIV Nucleic Acid test
-
West Nile Virus Nucleic Acid test
-
Rapid Plasma Reagin (RPR)
-
Human T-lymphotropic Virus I/II (HTLV I/II)
-
T. cruzi ELISA test (Chagas disease)
-
Zika Virus (RNA qualitative Real Time RT-PCR, Serum/Urine or Zika Virus 
Antibody (IgM), MAC-ELISA)
-
V DRL (confirmation with FTA-ABS if needed (Syphilis))
Prospective donors will also have the following blood and urine tests:
-
Complete blood count with differential
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-
Complete metabolic panel, magnesium, calcium, and uric acid
-
Urinalysis
-
Pregnancy test (Female only)
Eligibility Criteria for Normal Donors will include:
-
Male and female gender
-
No history of malignancy 
-
No active coagulopathy and/or hypocoagulable state
-
No history of cardio/pulmonary conditions
-
Negative tests for Hepatitis B, Hepatitis C, RPR, Chagas, HIV ½, HTLV I/II 
and NAT for HCV, HIV, Zika Virus, and WNV.  
-
Hemoglobin > 13.0 g/dL if male; and if female donor hemoglobin > 11.0 g/dL
-
Platelet count 140,000 to 440,000/ul
-
WBC 3.0 to 11.0 K/ul
-
No anomalies on the CBC and differential suggestive of a hematopoietic 
disorder
-
Creatinine <1.5 mg/dL
-
ALT< 112 IU/L
-
Bilirubin < 1.5 mg/dL
-
No diabetes
-
Systolic blood pressure < 170
-
Diastolic blood pressure < 90
-
No history of autoimmune disorders
-
Negative serum or urine pregnancy test for female donors
-
Body Mass Index (BMI) < 30
Female donors would need to be screened for pregnancy as the procedure may be an 
added risk to a fetus.
5.3 
Donor Consent
Informed consent will be obtained from all potential donors. The procedure will be 
explained in terms the donor can understand, and will include information about the 
significant risks of the procedure. Potential donors will have an opportunity to ask 
questions, the right to refuse or withdraw consent, and access to the results of all tests.
Donors will need to have virology’s redrawn if BMA procedure not completed 7 days 
from the initial virology results.
5.4 
Follow-up Schedule for Donors
After discharge from the hospital, the bone marrow donor will be contacted by the study 
team with a follow-up telephone call to determine the well-being, health status of the 
donor and/or if any adverse events have occurred.  Attempts should be made to follow-
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up via phone within a week of the BMA procedure. The donor will be provided with 
contact telephone numbers in the consent form for any questions or comments. 
5.5
Biomarker Assessment for Donors
A separate 7 mL blood sample for gene expression profiling will be obtained at the 
donation visit. All samples will be identified so that they can be linked to individual 
subjects.  These samples may be stored indefinitely.  Individual results will not be 
returned to the subject or the study physician. The samples will be linked to subjects, 
but there will be no recontact. Data presented in publications will not contain individual 
subjects’ clinical characteristics or outcomes; only aggregate data from the entire study 
will be disclosed.  
6. 
TREATMENT OF SUBJECTS
6.1 
Study Investigational Product
The investigational product (IP) consists of hMSCs obtained from a healthy bone marrow 
donor. Screening of allogeneic donors will follow standard transplant practices and all 
allogeneic donors will meet allogeneic donor eligibility criteria as outlined in 21 CFR Part 
1271. BM will be obtained from normal volunteers with approximately 60 ml to 120 ml 
aspirated from the posterior iliac crest. The BM will be aspirated into heparinized syringes. 
The MNC fraction will be isolated using a density gradient with Lymphocyte Separation 
Media (specific gravity 1.077). The low-density cells will be collected and washed with 
Plasma-LyteA containing 1% HSA. The MNCs will be prepared antibiotic free (ie. No 
penicillin or streptomycin). The washed cells will be samples and viable cell numbers 
determined. The BM MNC will be seeded into 175 cm2 tissue culture flasks in alpha MEM 
containing 20% FBS. After approximately 14 days of culture, passage zero (P0) cells will 
be harvested by trypsin treatment and expanded P1, P2 and P3. Cells are harvested 
using the Trypin treatment and each passage lasts approximately 7 to 10 days.  At P3, 
cells are harvested and cryopreserved. This process may or may not contain penicillin 
and/or streptomycin.  Any subject that test positive for a penicillin or streptomycin allergy 
will be provided with an antibiotic free MSC product. 
6.2 
Dosing
During the pilot phase of the study 15 subjects will receive a single infusion of hMSCs
Group 1 will consist of Five (5) subjects and will be treated with a single administration 
of allogeneic hMSCs: 2 x 107 (20 million) cells delivered via peripheral intravenous 
infusion.
Group 2 will consist of Five (5) subjects and will be treated with a single administration 
of allogeneic hMSCs: 1 x 108 (100 million) cells delivered via peripheral intravenous 
infusion.
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Group 3 will consist of Five (5) subjects and will be treated with a single administration 
of allogeneic hMSCs: 2 x 108 (200 million) cells delivered via peripheral intravenous 
infusion.
After subjects complete their Month 12 follow-up phone call visit in the pilot phase, all 15 
subjects will then have the option of receiving up to  three (3) additional infusions of 
allogeneic hMSCs: 1 x 108 (100 million) cells delivered via peripheral intravenous 
infusion. The option will be provided if subjects in the pilot phase continue to meet all 
inclusion / exclusion criteria.  See Addendum A and Addendum C for rationale and 
description for initial 15 subjects.
In the randomized phase of allo-hMSCs or matched placebo 30 subjects will be 
randomized in a 1:1:1 ratio to one of two Treatment Strategies or placebo following 
successful completion of the Pilot Phase.
Group A will consist of 10 subjects who will receive 100 million Allogeneic hMSCs 
delivered via peripheral intravenous infusion. 
Group B will consist of 10 subjects who will receive 200 million Allogeneic hMSCs 
delivered via peripheral intravenous infusion.
Group C will consist of 10 subjects who will receive placebo via peripheral intravenous 
infusion. 
The Allo-hMSCs will be derived from donors meeting criteria for allogeneic unrelated 
human bone marrow stem cell source manufactured by the University of Miami or from 
a commercial clinical grade bone marrow source.
6.3 
Dosage Rationale
A safety profile for IV infusion of hMSCs was based on results from previous completed 
toxicology results17. The results from previous studies demonstrate that the product can 
be administered intravenously without toxic events at up to 65 x 106hMSC/kg dose 
delivered in one bolus infusion or at 100 x 106hMSC/kg cumulative dose delivered by 5 
infusions (20 x 106hMSC/kg per infusion).
The evidence supports the conclusion that it is feasible to dose subjects in this study 
based on a standard dose of hMSCs rather than per kilogram of body weight. The total 
cell number corresponds to a range of 1.3 - 4.4 x 106 hMSCs per kg per infusion for 
subjects with 45 to 150kg body weight, the weight range for this study.
Therefore, results from previous trials support the rationale on the safety and potential 
efficacy of the selected maximum dose of 200 x106 allo hMSCs.
6.4 
Administration Rate
Prior clinical trials have used rates up to 30×106 hMSC/min where no infusion related 
toxicity was observed. 
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In the proposed study, the cell dose to be delivered is 20x 106, and 
100×106hMSC/infusion, and 200x106 reconstituted with the 2.5 million hMSC/ml, in the 
following total volume 
- 25 ml for 20 million dose (5 million hMSC/min)
- 40ml for 100 million dose (5 million hMSC/min)
- 80ml for 200 million dose (5 million hMSC/min)
For the randomized double blinded phase we will prepare the following doses of 
100 million, 200 million and Placebo in an 80ml bag.
Cell will be delivered at a rate of 2ml/min, and delivered at a maximum rate of 16×106 
hMSC/minute and will last approximately:
- 12.5 minutes for 25ml for 20 million dose
- 40 minutes for 40ml for 100 million dose
- 40 minutes for 80ml for 200 million dose. 
The infusion bag will be flushed with an additional 25 ml of 0.9% normal saline at the 
completion of allo-hMSC infusion and delivered at a rate of 2ml/min. 
During the randomized phase each dose will take place over approximately 40 
minutes in order to maintain the blind.
6.4.1.  Infusion Monitoring
Subjects will be monitored in the ICU for two hours prior to infusion to establish baseline 
vital signs (oxygen saturation, heart rate, respiratory rate, blood pressure, and 
temperature) every 15 minutes. Monitoring will also continue throughout the infusion. 
Once the infusion is begun, 2L/min oxygen via nasal cannula will be provided if the 
oxygen saturation drops below 90% on room air.  The infusion will be stopped if the 
oxygen saturation does not return to >93% within 3 minutes of initiating supplemental 
oxygen or if the subject requires greater than 2L/min supplemental oxygen to achieve 
the required saturation of >93%.  If a subject requires the addition of oxygen, it will be 
continued for 4 hours after the completion of the infusion.  At that time, oxygen will be 
weaned off to maintain a saturation >93% on room air.
6.5 
Concomitant Therapy
6.5.1 Permitted therapy
Concomitant medications will be recorded on the case report form (CRF), which 
includes all FDA-approved medications, therapies, and dietary supplements.
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6.5.2 Excluded therapy
Medications and therapies not approved by the FDA are prohibited for the duration of 
this trial, including participation with any investigational drug or device.
6.5.3. Subject monitoring
All aspects of the study will be conducted in accordance with Good Clinical Practice 
(GCP) as described in the ICH Guideline (CFR ICH Selected Regulations and Guidance 
for Drug Studies, CFR Title 21 Food and Drugs Revised as of April 1, 2002) all 
applicable national and local regulations. Monitoring will be conducted by a qualified 
outside source at the study site.
Monitoring of key safety endpoints will be conducted. If rates significantly exceed the 
pre-set threshold, then the DSMB will be advised.
6.6 Blinding and Unblinding
Subjects will be randomized into active groups. Only designated technicians in the ISCI 
Cell Processing Laboratory will be unblinded to treatment. The investigator, study staff, 
subject and anyone involved in the care of the subject will not be made aware of the 
assigned treatment regimen. Before dispensing the investigational product, Cell Therapy 
Lab staff will confirm the CMV status of eligible recipient. This information will be used to 
select Allo- MSC product. CMV status of the recipient and donor of the Allo-MSC product 
will be matched. CMV positive Allo-MSC product will only be infused to a CMV positive 
recipient. All CMV negative recipients will receive CMV negative Allo-MSC product91.
The designated cell-processing technicians will prepare both the allogeneic hMSCs 
infusions. The investigational agent infusions will be prepared in identical infusion bags 
and labeled with the identical investigational drug labels. A brown plastic slip cover will 
be placed over the infusion lines as well as the bags to maintain the blind. The designated 
technicians in the ISCI Cell Processing Laboratory (or designee) will be responsible for 
maintaining the investigational product records including randomized treatment 
assignments by subject identification.
If for important medical reasons unblinding is thought to be necessary, the Investigator 
may identify the treatment assignment by obtaining the randomization assignment by 
contacting the Director of the Cell Manufacturing Program at ISCI who is responsible for 
maintaining randomization records for all subjects.
6.7
Study Investigational Therapy Management
6.7.1 Investigational Product Labeling and Storage
The product label contains the elements required by the CFR and other national and local 
authorities for investigational products. ISCI GMP Cell Processing Facility (CPF) will 
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directly store and deliver the designated cell processing technologist in the CPL/CPF, and 
will be kept cryopreserved in liquid nitrogen vapor phase until shortly before 
administration must be stored in a securely locked enclosure. Access is strictly limited to 
unblinded CPL/CPF personnel prior to preparation for infusion. After preparation for 
infusion, the Investigator and his or her designees are permitted to administer the 
Investigational Product to subjects participating in this protocol.
6.7.2 Investigational Product Accountability Procedures
In accordance with all applicable regulatory requirements, the Cell Processing 
Laboratory/Cell Processing Facility will maintain a record of the investigational products 
hMSCs received, dispensed, administered, destroyed, or returned. The final disposition 
of all unused, empty, and partially used Cryocyte™ bags will be handled in accordance 
with the drug preparation manual. An independent unblinded clinical research associate 
(monitor) or auditor will perform compliance monitoring during the study.
Only unblinded personnel may access accountability records until the study blind has 
been broken.
7.
STUDY PROCEDURES
7.1.
Time and Events Schedule
The Time and Events Schedule for the conduct of this study is shown in Table 2
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 Schedule of Assessments 
Table 2: Time and Events Table for Pilot and Randomized Phases
VISIT
Screening
Day -56
+ 28 days
Baseline
(-4 weeks)
Day 
1
Week 2
(Day 14)
+/- 2 days
Month 1 
(Day 30)
(+/-2 weeks)
Month 3    
(Day 90)
 (+/-2 
weeks)
Month 6     
(Day 180)
(+/-2 weeks)
Month 12 
(Day 365)
(+/-2 weeks)
*Phone Call Follow-up
Informed Consent
x
Full Medical History 
x
Physical Exam
x
x
x
x
x
x
x
12-lead (ECG)
x
x
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
x
x
Mini Mental State Examination (MMSE)
x
x
Randomization
x
Infusion Treatment (IP)
x
Dobutamine Stress Echo Test (DSE)
x
x
Bone Density Scan (DEXA)8
x
x
FEV-1
x
x
x
6 Minute Walk Test
x
x
x
4 Meter Gait Speed Test7
x
x
x
SPPB Assessment
x
x
x
Dynamometer (handgrip)10
x
x
x
Smell Identification Test (UPSIT)
x
x
x
IIEF, SQOL-F Questionnaires
x
x
x
x
QOL Questionnaires (ICECAP, EQ-5D, SF-36,CHAMPS, MFI)
x
x
x
x
Questionnaires (Subject and Physician Global Assessment9)
x
Urinalysis
x
x
x
x
Hemat., Chem., CBC, LFTs, INR,   and other labs1
x
x
x
x
x
x
HIV 1, HIV 2, Hep. B & C, and CMV
x
Serum or Urine Pregnancy Test2
x
x
Review Adverse Events
x
x
x
x
x
x
Immune Monitoring4
x
x
x
x
x
Biomarker Assessment3
x
x
Optional: Brachial Ultrasound 5
x
x
Optional: Endothelial blood samples6
x
x

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Time and Events Table Key:
1 – The minimal laboratory requirements for hematological, liver function and renal 
function include:
Hematology Tests: white blood cell count, platelet count, hemoglobin and 
hematocrit.
Liver Function Tests: Albumin, alkaline phosphatase, alanine transaminase, 
asparate aminotransferase, prothrombin time / activated partial thromboplastin
time, and bilirubin(fractionate if total >1.5 times normal). 
Renal Function Tests: creatinine, creatinine clearance, blood urea nitrogen 
(BUN), glomerular filtration rate, sodium, potassium, chloride, calcium, carbon 
dioxide, and glucose.
Serum Uric Acid, Pro-BNP, and C-reactive protein (CRP), IL6, fibrinogen, D-
Dimer, DNA, TNFα, testosterone (males only) and estrogen (females only).
2 – A serum or urine pregnancy test will be completed within 36 hours prior to infusion  
for females of childbearing potential.
3 – The following biomarkers will be analyzed: 

Cell-surface markers: CD19, CD27, IgD, and CD5 (for Switched Memory, 
Naïve, Late/Exhausted, IgM memory B cells and regulatory B cells); CD19 
and intracellular TNF-α (to assess intracellular TNF-α); CD3, CD4, CD8, 
CCR7 and CD45RA (for Central Memory, Naïve, Effector Memory, TEMRA 
T cells and CD4 to CD8 ratio); CD3, CD25 and FOXP3 (to assess regulatory 
T cells)

Transcriptomic/Proteome: 
RNA, 
miRNA, 
protein 
samples, 
and 
telomerase, akt

Growth factors: Sdf-1, notch, 

Functional Assays: cell growth rate, VEGF, and CFU assay
4 – Immune monitoring for graft rejection.  Calculated panel reactive antibodies will be 
performed from the serum of the subjects on day 1 and 6 months post treatment. In 
addition, the following cell surface markers will be used to assess for activated T-cells 
based upon a CD3+CD25+ (late/chronic T cell activation) or CD3+CD69+ phenotype 
(early T cell activation).
5 – Optional brachial ultrasound to assess endothelial function. 
6 – Optional: An additional 5 lavender top tubes (EDTA) will be drawn to assess the 
ability of endothelial progenitor cells to form colonies.
7 – 4 meter gait speed test will be performed twice per visit and the average of the 
exams will be taken.
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8 – DEXA scan will be performed at baseline and Month 6. The scans of the hip and 
spine for bone density, and total body composition will be assessed at both visits.
9 – Subject and Physician Global Assessments are not applicable to pilot subjects in the 
initial infusion of the trial.
10 – Dynamometer will be performed at least three (3) times during each applicable visit 
for each hand. The three values collected will be averaged for each hand. (Please 
reference the instruction manual on how to administer.)
7.2 
Study Phases and Visits
7.2.1 Screening Visit
See Table 2 for the procedures and assessment to be performed during the screening 
visit of the study. Screening visit test and procedures will begin upon the subject signing 
the informed consent form (ICF). No screening exams will take place until the subject is 
fully informed of the research and signs the consent form. The tests will take place over 
several days and will need to be completed prior to the subject starting the baseline visit.
Physical exam
A complete physical examination will include general appearance, skin, head and neck,
Lymph nodes, musculoskeletal/extremities, cardiovascular, chest/lungs, abdomen, and
neurological assessment. At screening information about the physical examination and 
any significant findings must be recorded in the source documentation at the study site. 
Weight should be measured at each physical exam on a calibrated scale with the subject 
wearing only light clothing and no shoes. Height (in bare feet or wearing only thin socks) 
will be measured at the Screening visit.
Vital signs
Vital sign measurements will be performed at least once on each study visit up to time of 
discharge. These measurements will consist of respiratory rate, heart rate, blood 
pressure, and temperature. Respiratory rate, heart rate, and blood pressure should be 
measured in a sitting position after 5 minutes of rest.
Dobutamine Stress Echocardiography (DSE)
A Dobutamine Stress Echocardiography will be performed twice during the study, once 
at screening and at the Month 6 follow-up visit. This exam will assist in mimicking the 
effect of exercise on subjects to assess the heart muscle when under stress to better 
evaluate ejection fraction in frail subjects. Guidelines for completing the (DSE) are 
outlined in Appendix 2 of this protocol.
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7.2.2 Baseline Visit
See Table 2 for the procedures and assessment to be performed during the baseline visit 
of the study. Once all screening exams are completed and it has been determined that 
the subject remains eligible for the study, subjects will be enrolled into the study. The 
baseline visit will take place within four weeks from treatment. The listed procedures 
should all be performed as soon as practicable. 
Bone density Dexa scan will be performed at the baseline visit (if not done within three 
months prior to enrollment).
The Smell Identification Test (UPSIT) test will be performed once at baseline and once at 
the Month 3 and Month 6 follow-up visits. Age-related olfactory dysfunction is felt to be 
due to cumulative inflammatory damage affecting the olfactory mucosa. The Smell 
Identification Test (UPSIT) is a self-administered 40-item olfactory test. It provides an 
absolute indication of smell loss (anosmia, mild, moderate, or severe microsomia) as well 
as an index to detect malingering. 
Endothelial function (Optional Assessments) will occur upon the subject signing the 
optional section of the informed consent form (ICF). No endothelial function tests will take 
place until the subject is fully informed of the research and signs the optional portion of 
the consent form.

Brachial ultrasound testing and blood collection will be performed to assess 
endothelial function in the aging frailty population at baseline and 3 months 
post stem cell infusion. This will help provide cumulative data in assessing 
whether or not stem cell infusion improves endothelial function.  

Flow Mediated Diameter percent change (FMD%):  All measurements of the 
brachial artery diameter and FMD will be performed in the morning, in a quiet 
and dark room and at controlled ambient temperatures between 20°C and 
26°C. Studies will be conducted after an overnight fast of at least 10 hours 
(water is permitted), with the subjects supine and after 10 minutes of rest. The 
subject's right arm will be comfortably immobilized in an extending position, 
allowing for ultrasound scanning of the brachial artery 5–10 cm above the 
antecubital fossa. In each examination, recording of vessel images will be 
followed by inflation of a cuff to supra-systolic pressure (40 to 50 mmHg 
above systolic pressure) for 5 minutes. Then the cuff will be deflated and the 
brachial artery diameter will be imaged and recorded for 3 minutes. FMD% 
more than 10% is considered a normal response. Lower than 10% FMD% 
reflects endothelial dysfunction, which means a high likelihood to develop 
cardiovascular event in the future. Subjects with negative FMD% results (the 
artery is constricted after stress and not dilated as was expected) have the 
worst prognosis.
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
Blood drawn from fasting subjects will be separated and the serum will be 
frozen until processed as one batch towards the end of the study. Blood will 
be processed twice – in the beginning of the study and after 3 months.

Biochemical analysis: soluble pro inflammatory cytokines (interleukin-1, 
interleukin-6, interleukin-10, VEGFR2, TNF-a).

Assay of colony forming units: Fresh blood will be processed for cell culture 
assays for endothelial progenitor stem cells colonies counting (a 5 days’ 
protocol). Fifty milliliter of blood will be processed; peripheral-blood 
mononuclear cells will be isolated by Ficoll density-gradient centrifugation, will 
be washed twice in phosphate buffered saline with 5% fetal bovine serum and 
re-suspended in media (EndoCult basal media with supplements; StemCell 
Technologies, Vancouver, British Columbia, Canada) for EPC colony-forming 
assay. Cells will be  planted on human fibronectin-coated plates (BIOCOAT; 
Becton Dickenson Labware, Bedford, Massachusetts) at a density of 5X106 
cells/well and incubated at 370C in humidified 5% CO2. After 48 hours, the 
non-adherent cells will be re-plated onto fibronectin-coated 24 well plates at a 
density of 1X106 cells/well. After 5 days, colony forming units (defined as a 
central core of rounded cells surrounded by elongated and spindle-shaped 
cells) will be counted manually in 8 wells out of a 24-well plate. 
7.2.3 Day 1 Visit
See Table 2 for the procedures and assessment to be performed during the Day 1 visit 
of the study. The Day 1 visit will occur after all baseline tests are completed and it has 
been determined that the subject remains eligible. Once the subject is deemed eligible 
to continue in the study the subject will be administered the investigational product.
7.2.4 Week 2 Visit
See Table 2 for the procedures and assessment to be performed for week 2 through 
month 6 visit of the study. Outpatient visits should be completed as close to the 
scheduled visit dates as possible. There will be a +/- window of 2 days for the week 2 
study visits.
7.2.5 Month 1 – Month 6 Visits
See Table 2 for the procedures and assessment to be performed for week 2 through 
month 6 visit of the study. Outpatient visits should be completed as close to the 
scheduled visit dates as possible. There will be a +/- window of 2 weeks for the Month 1 
through month 6 study visits.
7.2.6 Month 12 Visit
See Table 2 for the procedures and assessments to be performed for Month 12 visit. 
This visit will be conducted via a phone interview with the subject. A phone script will be 
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provided to the study personnel to use when interviewing the subject. There will be a +/- 
window of 2 weeks for this visit. All fifteen (15) pilot phase subjects will be informed with 
the option of having additional administrations of allogeneic hMSCs at this visit.
7.2.7 Biomarker Assessment
All samples will be identified so that they can be linked to individual subjects.  These 
samples may be stored indefinitely.  Individual results will not be returned to the subject 
or the study physician. The samples will be linked to subjects, but there will be no 
recontact. Data presented in publications will not contain individual subjects’ clinical 
characteristics or outcomes; only aggregate data from the entire study will be disclosed.  
7.2.8 Immune Monitoring for Graft Rejection
The studies planned in the CRATUS protocol will utilize allogeneic mesenchymal stem 
cells (MSC) in subjects with frailty syndrome. The use of an allogeneic graft raises the 
potential of graft rejection through immune cells resulting in failure of the therapy. MSCs 
are ideal candidates for allogeneic transplantation because they show minimal MHC class 
II and ICAM expression and lack B-7 co-stimulatory molecules necessary for T-cell 
mediated immune responses57, 58. Indeed MSCs do not stimulate a proliferative response 
from alloreactive T-cells even when the MSCs have differentiated into other lineages or 
are exposed to proinflammatory cytokines. Previous studies have demonstrated that 
MSCs have significant immunomodulatory effects, inhibiting T-cell proliferation, 
prolonging skin allograft survival, and decreasing graft-versus-host disease (GVHD). 
Recently human MSCs were shown to alter the cytokine secretion profile of dendritic cells, 
T cells, and natural killer cells in vitro, inhibiting secretion of proinflammatory cytokines 
(e.g. TNF-a, IFN-γ) and increasing expression of suppressive cytokines (e.g.IL-10), 
possibly via a prostaglandin E2 mediated pathway. 
In vivo studies of the fate of MSCs have shown that, when transplanted into fetal sheep, 
human MSCs engraft, undergo site-specific differentiation into various cell types, 
including myocytes and cardiomyocytes and persist in multiple tissues for as long as 13 
months after transplantation in non-immunosuppressed immunocompetent hosts.  
Further, in vivo studies using rodents, dogs, goats, and baboons demonstrate that 
allogeneic MSCs can be engrafted into these species without stimulating systemic 
alloantibody production or eliciting a proliferative response from recipient lymphocytes. 
These findings, coupled with our demonstration of efficacy of these cells for cardiac 
repair, solidify the notion of using MSCs as an allograft for successful tissue regeneration.
As part of the CRATUS protocol we will obtain peripheral blood samples from all 
subjects to evaluate the panel reactive antibodies (PRA) as well as the presence of 
activated T cells. Two heparinized (green top) vacutainer tubes (approx. 15 cc total 
blood) will be collected at different time points during the study: at day one prior to 
infusion of MSC and visits through month 6.  Peripheral blood mononuclear cells 
(PBMC) will be isolated from heparinized blood by ficoll sedimentation and will be viably 
cryopreserved for planned assessments of T cell activation.
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Two of the best-accepted markers of T cell activation are CD69 and CD25 (IL-2 
receptor α).  We will monitor the activation of T cells by flow cytometric analysis of 
CD3+CD25+CD69+ cells in thawed PBMC. CD69 is an immediate/early marker of 
CD3+ T cell activation while CD25 expression increases within 1-2 days of activation 
and remains sustained over the intermediate-long term during chronic immune 
activation. Given the differences in the kinetics of CD69 and CD25 up regulation, 
assessment of both activation phenotypes (CD3+CD69+ and CD3+CD25+) will 
maximize the sensitivity of detection of T cell activation following autologous or 
allogeneic MSC infusion.
8.  
SAFETY
8.1 
Safety Variables
1.
Vital signs
2.
Physical examination
3.
Clinical laboratory tests
4.
Adverse events
8.2 
Laboratory Evaluations
At screening, the HIV-1 and HIV-2 tests, CMV, hepatitis screen and β-HCG serum 
pregnancy tests (only for women of child bearing potential) will be performed locally at 
the study site. Laboratory safety tests will consist of the following:
Serum chemistry: sodium, potassium, chloride, carbon dioxide, BUN, creatinine, 
glucose, calcium, phosphate, AST/SGOT, ALT/SGPT, total bilirubin (fractionate if 
total >1.5 times normal), alkaline phosphatase, albumin, fibrinogen, IL6, D-Dimer, 
Coagulation studies
Hematology (CBC): hemoglobin, hematocrit, platelets, WBC, WBC differential
The Investigator will review all clinically relevant laboratory results requested in the 
protocol. The diagnosis associated with any clinically significant laboratory deviations 
should be recorded as an AE and should indicate the underlying abnormality or 
diagnosis (such as renal insufficiency) as opposed to the observed deviation in 
laboratory results (such as elevated creatinine). If there is no underlying abnormality 
linked to a clinically significant abnormal laboratory value, the observed deviation should 
be reported as the AE.
8.2.1 Pulse Oximetry
Pulse oximetry will be used to observe oxygen saturation when measuring vital signs at 
screening. Pulse oximetry will also be used throughout infusions and 2 hours following 
infusions. Subjects requiring oxygen, need the peripheral artery oxygen saturation 
(SaO2) to be ≥93% when given a maximum of 2L/minute supplemental O2 via nasal 
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cannula. Infusion toxicity will be assessed based on decreases in oxygen saturation 
during infusion.  The infusion will be stopped if the oxygen saturation does not return to 
>93% within 3 minutes of initiating supplemental oxygen or if the subject requires 
greater than 2L/min supplemental oxygen to achieve the required saturation of >93%. If 
this occurs then subjects will be admitted to the hospital for observation.
8.2.2 Pregnancy
There is no information allogeneic hMSCs and its effects or potential risks to a fetus or 
unborn child.  The Principal Investigator and DSMB must be notified within twenty-four 
hours of investigator’s awareness of the pregnancy via facsimile if a study subject 
becomes pregnant during the study. Males and females of childbearing potential > 60 to 
< 95 years of age at the time of signing the Informed Consent Form with documented 
FRAILTY must practice any one of the enumerated forms of contraception. Items will be 
acceptable for meeting the studies contraceptive requirements as listed in section 8.2.2. 
Females will be defined as non-childbearing potential if surgically sterilized (i.e. bilateral 
tubal litigation, bilateral oophorectomy, or complete hysterectomy) or post-menopausal 
(defined as 12 months no menses with an alternative medical cause and with a follicle 
stimulating hormone (FSH > 25.8 mIU/mL). Non-sterilized males who are sexually 
active with a female partner of childbearing potential must use any one of the 
enumerated contraceptive items as listed in section 8.2.2 throughout the study.
Acceptable forms of contraception include: 1) abstinence, 2) condoms (male or female) 
with a spermicidal agent, 3) diaphragm or cervical cap with spermicidal agent, 4) 
intrauterine device (IUD), 5) oral contraceptive, 6) injectable or transdermal hormonal 
contraceptive, 7) successful vasectomy with resulting azoospermia or azoospermia for 
any other reason, and 8) hysterectomy, bilateral oophorectomy, or tubal ligation.
Prior to study enrollment, women of childbearing potential must be advised of the 
importance of avoiding pregnancy during trial participation and the potential risk factors 
for a pregnancy. The subject must sign an informed consent and written authorization 
for use and disclosure of PHI document stating that the above-mentioned risk factors 
and the consequences were discussed with her.
8.2.3 Determination of Infusional Toxicity
Infusional toxicity will be evaluated by continuously monitoring the subject’s vital signs 
and O2 saturation by pulse oximetry from the time of allogeneic hMSCs administration 
until two hours after infusion is complete. Since there is no specific or antidotal therapy 
for AEs arising from allogeneic hMSCs, any toxicity that may arise during a subject’s 
participation in this study should be managed with supportive measures at the discretion 
of the treating physician.
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8.2.4 Subject Stopping Guidelines
This guideline is to be used to indicate boundaries requiring discussion by the Data and 
Safety Monitoring Board (DSMB) and is designed to assist the independent DSMB in 
overseeing the study. The DSMB may also request additional interim analyses and 
develop other criteria including provision for monitoring of potential late effects to 
determine when to intervene in the enrollment or treatment of subjects in the study. The 
first more conservative stopping guideline is to monitor subjects for unexpected SAEs 
where there is a reasonable possibility that the study product or administration 
procedure caused the event within 30 days of administration including subject death, 
grade 3 myocardial infarction, or grade 3 hemodynamically unstable ventricular 
tachycardia.  Study accrual and further treatment of subjects will be put on hold if any 
subjects experience one of these events.  The DSMB will be notified within 24 hours of 
the occurrence of these events and will be convened within 3 business days to review 
the event and study.
The following are subject stopping guidelines:
1. Any subject who develops persistent (that is, still existing more than 3 hours after 
the end of IP infusion) cardiorespiratory signs or symptoms (for example, 
shortness of breath, tachypnea, tachycardia, hypotension, or palpitations) will 
continue with all scheduled follow-up if such follow-up is considered safe in the 
opinion of the Investigator. A subject may still be able to receive additional 
infusions, based on the investigator’s judgement. 
2. Any subject whose infusion is stopped due to cardiorespiratory distress will not 
receive further IP infusions until it is considered safe in the opinion of the 
Investigator, but subjects will continue with all scheduled follow-up if such follow-
up is considered safe. A subject may still be able to receive additional infusions, 
based on the investigator’s judgement. 
3. The proportion of subjects experiencing TE-SAE as defined in Section 2.2.1 will 
be monitored within 30 days of infusion. This guideline is designed to assist the 
independent DSMB in overseeing the study and indicate boundaries needing 
discussion by the DSMB. The DSMB may also request additional interim 
analyses and develop other criteria including provision for monitoring of potential 
late effects to determine when to intervene in the enrollment or treatment of 
subjects in the study. 
4. Monitoring of key safety endpoints will be conducted (Please reference section 
2.2.1). If rates significantly exceed the pre-set threshold, then the DSMB will be 
advised. 
The stopping guidelines serve as a mechanism for consultation with the DSMB for 
additional review, and are not formal “stopping rules” that would mandate automatic 
closure of study enrollment. It is designed to assist the independent DSMB in 
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overseeing the study. The DSMB may also request additional interim analyses and 
develop other criteria including provision for monitoring of potential late effects to 
determine when to intervene in the enrollment or treatment of subjects in the study.   
8.2.5 Subject observation and discontinuation after IP administration
The IP administration guidelines in Appendix 1 list the study requirements for subject 
observation and discharge after IP administration.
8.3
Definition of an Adverse Event
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 to the treatment received in the study.  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:
1. Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency or intensity of the condition.
2. Significant or unexpected worsening or exacerbation of the condition/indication 
under study.
3. A new condition detected or diagnosed after study therapy administration even 
though it may have been present prior to the start of the study.
4. 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:
1. Medical or surgical procedures (e.g., colonoscopy, biopsy).  The medical 
condition that leads to the procedure is an AE.
2. Social or convenience hospital admissions where an untoward medical 
occurrence did not occur.
3. Day to day fluctuations of pre-existing disease or conditions present or detected 
at the start of the study that do not worsen.
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4. 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.
8.4
Definition of Adverse Reaction
An adverse reaction is any adverse event caused by a drug.  Adverse reactions are a 
subset of all suspected adverse reactions for which there is reason to conclude that the 
drug caused the event.
8.5
Definition of Suspected Adverse Reaction
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.
8.6 Definition of Serious
An adverse event (AE) or suspected adverse reaction is considered “serious” if it:
1. results in death
2. is life-threatening (at risk of death at the time of the event)
3. requires in inpatient hospitalization or prolongation of existing hospitalization
NOTE:  Complications that occur during hospitalization are AEs.  If a complication 
prolongs hospitalization or fulfills any other serious criteria, the event is serious.  
Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered to be an AE.
4. results in disability/incapacity
NOTE:  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.
5. Is a congenital anomaly/birth defect.  
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 the above definition.
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8.7
Definition of Unexpected
An adverse event or suspected adverse reaction is considered “unexpected” if it is not 
listed in the investigator brochure or is not listed at the specificity or severity that has been 
observed; or, if an investigator brochure is not required or available, is not consistent with 
the risk information described in the general investigational plan or elsewhere in the 
current application.
8.8
Clinical Laboratory Assessments and Other Abnormal Assessments 
as Adverse Events and Serious Adverse Events
Abnormal laboratory findings (e.g. clinical chemistry, hematology) or other abnormal 
assessments (e.g., vital signs) that are judged by the Investigator as clinically significant 
will be recorded as AEs or SAEs if they meet the definition of an AE as defined in Section 
8.3 (“Definition of an Adverse Event”) or SAE, as defined in Section 8.6 (“Definition of a 
Serious Adverse Event”).  Clinically significant abnormal laboratory findings or other 
abnormal assessments 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 or other abnormal 
assessments 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.
8.9 Recording of Adverse Events and Serious Adverse Events
The Investigator should review all documentation (e.g., hospital progress notes, 
laboratory, or 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.  
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.
SAEs will be reported to the IRB within 10 working days or within 24 hours if the event is 
life-threatening or results in death.
Pregnancies
Subject pregnancy must be reported to the Principal Investigator within 1 working day of 
knowledge of the event.  Any subject that becomes pregnant during the study must be 
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promptly withdrawn from the study.  Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be required. 
8.10
Intensity of Adverse Events and Serious Adverse Events
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 should 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.
Life-threatening: Immediate risk of death.
An AE that is assessed as severe should 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 Section 8.6, “Definition of Serious.”
8.11
Causality of Adverse Events and Serious Adverse Events
The Investigator is obligated to assess the causality 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 biological action of the study therapy was 
responsible for AE/SAE being reported.  Alternative causes such as natural history of the 
underlying diseases, concomitant therapy, other risk factors, and the temporal 
relationship of the event to the study therapy will be considered and investigated.  The 
Investigator will also consult the Clinical Investigator’s Brochure and/or Product 
Information, for marketed products, in the determination of his/her assessment.
The Investigator will use the following questions when assessing causality of an adverse 
event to study therapy. 
Is there a reasonable possibility that the study therapy caused the event? Reasonable 
possibility implies that there is evidence that the vent was caused by the study product. 
An affirmative answer designates the event as a suspected adverse reaction. 
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 always make an assessment of causality.
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The relationship between AEs and the study exposure will be classified by the 
investigator as:
1. None: 
No relationship.  Related to other known etiologies, conditions, or 
exposures.
2. Unlikely: 
Current knowledge suggests that a relationship is unlikely.
3. Possible: 
A plausible temporal sequence or response pattern exists but the 
AE may be related to other known etiologies, conditions, or 
exposures.
4. Probable: 
A plausible temporal sequence or response pattern exists and the 
AE cannot be related other known etiologies, conditions, or 
exposures.
5. Definite: 
A plausible temporal sequence or response pattern exists and the 
AE can be confirmed by re-challenge or with other supporting data.
8.12
Follow-Up of Adverse Events and Serious Adverse Events
After the initial AE/SAE report, the Investigator is required to proactively follow each 
subject and provide further information on the subject’s condition.  All AEs and SAEs 
documented at a previous visit/contact that are designated as ongoing will be reviewed 
at subsequent visits/contacts.  
Adverse events and SAEs will be followed until resolution, until no further changes in the 
event are expected (i.e. the point at which a subject experiencing a critical adverse event 
is treated successfully and stabilized even though they may continue to experience 
lingering sequelae that may never resolve), until the subject is lost to follow-up, or until it 
is agreed that further follow-up of the event is not warranted (e.g. non-serious, study 
therapy unrelated, mild or moderate adverse events ongoing at a subject’s final study 
visit).  If a subject dies during participation in the study or during a recognized follow-up 
period, the Investigator will provide 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
8.13
Timeframes for Submitting SAE Reports
Once an Investigator becomes aware that an SAE has occurred in a study subject, he/she 
will record the information in the electronic data record within 48 hours.  Any fatal or life-
threatening event must be reported within 24 hours.  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.
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TABLE 3
Serious Adverse Event Reporting Requirements
Initial Reports
Follow-Up 
Reports
Type of SAE
Fatal 
or 
Life-Threatening
Other SAEs
Any SAE
Reporting 
Timeframes
24 hours
48 hours
48 hours
Documents
Required
24 hours:
Complete as much information in the 
electronic data system that is known.
48 hours:
Fully complete all AE forms 
Fully completed 
AE forms 
Updated AE 
Forms
8.14
Regulatory Aspects of Adverse Event Reporting
The Investigator will promptly report all SAEs within the timeframes specified in Section 
8.13.  Prompt notification of SAEs by the Investigator is essential so that UMMSM can 
meet legal obligations and fulfill ethical responsibilities towards the safety of all subjects 
participating in UMMSM-sponsored investigational trials.
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 has been filed under an Investigational New Drug (IND) application with the 
FDA.  A given SAE may qualify as an Expedited Safety Report (ESR) if the SAE is both 
at least possibly attributable to study therapy and unexpected.  In this case, all 
Investigators participating in an IND study will receive an ESR.  
The ESRs are prepared according to UMMSM policy and are forwarded to the 
Investigator as necessary.  The purpose of the ESR is to fulfill specific regulatory and 
Good Clinical Practice (GCP) requirements regarding the product under investigation. 
 
Based on previous trials involving intravenous infusion of allogeneic human MSCs, no 
AEs have been attributed to treatment administration; therefore all AEs will be 
considered and documented as unexpected AEs.
All AEs occurring at any time during the trial will be collected, documented, and reported 
by the investigator.  For each AE, the investigator will provide the date of onset and 
resolution, intensity, treatment required, outcome, seriousness, and potential causality 
with regards to the study exposure.
9.
STATISTICAL ANALYSIS
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9.1 
Determination of Sample Size and Analysis Population
No formal statistical justification was performed to determine sample size in the Phase I 
study.  Cohort size was determined based on expected requirements for safety 
analyses and projected enrollment rates.  Study subject s will be randomized according 
to a fixed allocation permuted block randomization schema.  The allocation ratio will be 
1:1:1. All enrolled subject who received at least one treatment dose will be included in 
summaries of baseline characteristics, safety, and efficacy.  Reasons for study 
discontinuation will be tabulated.
9.2 
General Statistical Methods
All statistical tests will be performed at an α=0.05 level of significance, using two-sided 
tests.  Because this is a Phase I study with only exploratory efficacy outcomes, no 
adjustments will be made for multiple analyses.  Continuous variables will be presented 
by descriptive statistics.  Categorical variables will be presented by counts.  Two sided 
95% confidence intervals will be calculated and presented where appropriate.  
Analysis of AEs will include tabulation by frequency, severity, organ system affected, 
and relationship to study exposure.  Lung function data will be summarized 
descriptively.  Subject reported outcome data will be summarized according to the 
guidelines of each questionnaire.   
9.3
Interim Analyses
Interim analyses will be conducted at times coincident with regularly scheduled 
meetings of the Data and Safety Monitoring Board (DSMB), which occur at 
approximately quarterly intervals, but can be postponed at the DSMB’s discretion.  The 
DSMB Chair will be notified each time an SAE occurs. After all subjects in phase I have 
received their first infusion and been followed for 30 days, at that time an independent 
DSMB will review all available data to make an  independent recommendation to either 
keep the specified randomized dose 1:1:1 or to recommend a dose modification for the 
randomized placebo study.  
These should not be considered formal interim analyses as no hypothesis testing will be 
done. 
Policies of the DSMB will be described in the DSMB Charter, which will be prepared by 
the DSMB prior to study initiation.  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.”
9.4 
Data and Safety Monitoring Board (DSMB)
9.4.1. ROLE OF THE DSMB
This study is designed to test the safety of hMSCs in subjects with frailty. 
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The purpose of the data and safety monitoring board (DSMB) is to advise the 
investigators regarding the continuing safety of study subjects and those yet to be 
recruited to the study, as well as the continuing validity and scientific merit of the study. 
This section describes the roles, responsibilities and operating procedures of the 
DSMB, and includes guidelines for communications and interactions between the 
DSMB and the investigators to schedule and format for meetings; format for 
presentation of data; specification of who will have access to interim data and who may 
attend all or part of DSMB meetings; procedures for assessing conflict of interest of 
potential DSMB members; and the method and timing of providing interim reports to the 
DSMB. 
9.4.2. Purpose of the DSMB
The primary function of the DSMB is to review the accumulating unblinded safety data 
from each study group and using the data as the basis for recommendations concerning 
the continuation and/or modification of the study. This will be accomplished through 
regularly scheduled formal meetings and/or additional meetings to review interim 
summaries of safety and efficacy data. The DSMB will make recommendations 
regarding modification or termination of the study in the event of significant study 
conduct issues or safety concerns. The DSMB will not stop the study based on efficacy 
results favorable to hMSCs, other than for all-cause mortality as outlined below. The 
selected primary and secondary endpoints were chosen to measure major morbidity in 
subjects with FRAILTY, a fatal disease. Given the importance of mortality in FRAILTY, a 
stopping boundary based on the all-cause mortality rate will be implemented to guide 
the DSMB. This stopping boundary will not be applied until after all subjects have 
enrolled in the study. 
9.4.2.1 DSMB MEMBERSHIP
The DSMB is an independent, multidisciplinary group consisting of four members 
(inclusive of the DSMB chair). The members include a clinical trialist, a biostatistician, 
an expert gerontologist and an expert cardiologist. 
The DSMB will meet until the study’s database has been locked and a final data review 
has been completed. If a member withdraws from the DSMB, the DSMB chairperson 
will be responsible for selecting an appropriate replacement. 
9.4.2.2 Financial Disclosure and Conflict of Interest
DSMB membership is restricted to individuals without significant potential or perceived 
conflicts of interest. The source of these conflicts may be financial, scientific, or 
regulatory in nature. 
Members must disclose to the DSMB chairperson their consultancies (direct or indirect) 
in excess of $5,000 or financial interests in any pharmaceutical companies, 
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biotechnology companies, or CROs, if these relationships could lead to any conflict of 
interest or these companies’ products involve hMSCs. 
The DSMB chairperson will be responsible for deciding whether consultancies or 
financial interests of the members materially impact their objectivity. This decision is to 
be based on the reasonable belief that their objectivity is not in doubt. DSMB members 
will be responsible for advising the DSMB chairperson of any changes in financial 
interests in pharmaceutical companies, biotechnology companies, including 
consultancies, during the course of their membership. Members of the DSMB who 
develop significant potential or perceived conflicts of interest that may materially impact 
their objectivity will be asked to resign from the DSMB. 
9.4.2.3 DSMB Responsibilities
The DSMB has the responsibility to: 
1. Review the protocol
2. Review protocol amendments, as deemed necessary by the DSMB Chair. 
3. Review the statistical analysis plan with particular attention to the portions 
describing the data to be provided to the DSMB.
4. Evaluate on an ongoing basis, the accumulating unblinded safety summaries 
including AEs, SAEs, discontinuations and post-baseline laboratory results, to 
ensure the ongoing safety of study subjects.  If any potential question of safety 
arises, the DSMB will use the efficacy data to assess the possible safety risk in 
the context of the benefit-to-risk profile of study treatment.
5. Review efficacy and mortality data (although the DSMB shall not recommend 
stopping the study for efficacy because the primary objective of this study does 
not include efficacy).
6. Evaluate the conduct of the study including enrollment rates, the selection and 
retention of subjects, protocol deviations, treatment adherence and quality and 
completeness of the data.
7. Review all documents provided in the DSMB data review packets as soon as 
possible upon receipt.
8. Protect the confidentiality of the DSMB discussions and the trial data, with 
particular attention to safeguarding the confidentiality of unblinded treatment 
information to minimize the potential for premature conclusions regarding the 
study results and the potential for introducing bias into the study. 
9. Determine any safety issues, which may suggest risk to the subjects currently 
enrolled in the study or to future subjects to be enrolled
10.Ensure that the reports of the DSMB are based upon an unbiased and 
comprehensive evaluation of the data.
11.Make recommendations to modify or terminate the trial if there is a safety 
concern following review of data.
12.Make recommendations regarding study conduct as necessary to protect the 
scientific integrity of the study (the DSMB shall not make recommendations 
regarding the efficacy outcomes or associated analyses).
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13.Assure confidentiality and the scientific integrity of the study, the members will 
not disclose any data prior to the completion of the study and release of final 
results to investigators.
9.4.2.4 Confidentiality
The DSMB will be unblinded in its assessment of safety and efficacy data to ensure that 
the DSMB is fully informed in its primary mission of safeguarding the interest of 
participating subjects. The DSMB will have sole access to comparative results of safety 
data aggregated by treatment arm. The DSMB will take all necessary and appropriate 
steps to safeguard the confidentiality of unblinded treatment information it receives to 
minimize the potential for premature conclusions regarding the study results as well as 
the potential for introducing bias into the study. 
9.4.2.5 Study Conduct and Termination
The DSMB will provide recommendations following review and assessment of the 
quality of study conduct. More specifically, the DSMB will review enrollment rates, 
consistency in complying with eligibility requirements, compliance with the study 
protocol as well as the completeness of the data. In their review of the data, the DSMB 
will be responsible for protecting the safety of the enrolled subjects. If any potential 
question of safety arises, the DSMB will use the efficacy data to assess the possible 
safety risk in the context of the benefit-to-risk profile of study treatment. Based on this 
information, the DSMB may make recommendations to terminate the study if members 
believe that an undue risk (relative to benefit) would be incurred by allowing the study to 
continue to completion. Otherwise the study will be completed to allow investigators to 
complete the protocol mandated assessments to evaluate the safety of hMSCs in 
FRAILTY subjects. 
9.4.2.6 DSMB Chair Responsibilities 
The responsibilities of the DSMB Chair will include the following:
•
Serve as a voting member
•
Convene and facilitate the meetings, assist in the development of the 
agenda, and ensure that the meeting minutes and recommendation(s) are 
appropriately documented
•
Ensure that the Board is duly constituted
•
DSMB Chair (or designee) serves as the primary contact person for the 
DSMB
•
Review and approves the Charter
•
Review protocol amendments
•
Ensure that those involved in the day-to-day management of the study are 
excluded from DSMB voting procedures
•
Will be responsible for deciding whether consultancies of financial interests 
of the members materially impact their objectivity
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•
DSMB Chair (or designee) will be responsible for presenting requests to 
University of Miami/ISCI for unscheduled (not planned) meetings
•
DSMB Chair (or designee) will be responsible for discussing DSMB 
recommendations with University of Miami/ISCI and appropriate members of 
the project team via teleconference.  These discussions will be conducted in 
a manner that preserves the study blind.
•
Will have the authority to ask for the resignation of a member of the DSMB 
who exhibits poor attendance, inadequate demonstration of effort, 
unprofessional conduct, or failure to act consistently with the DSMB 
objectives
•
Will be responsible for selecting an appropriate replacement for any DSMB 
member that withdraws from the committee
9.4.2.7 Investigator Responsibilities
　The investigator has the responsibility to: 
1. Make decisions based on DSMB recommendations in a timely fashion. 
2. Notify study centers of the outcome of the DSMB meetings, and any DSMB 
recommendations addressing actions to be taken to ensure the integrity of the 
study. 
3. Notify regulatory agencies of DSMB recommendations addressing any emerging 
safety concern not recognized at the start of the study. 
4. Ensure that the unblinded DSMB support team is provided with the data 
necessary for the chosen analyses and reports. 
5. Provide DSMB members with the current protocols and Investigator’s Brochure.
6. Provide DSMB members with PSURs as published 
7. Attend the open session of each DSMB data review meeting. 
9.4.3 COMMITTEE MEETINGS 
9.4.3.1 Organizational Meeting
At an organizational meeting the DSMB will discuss the operational aspects of the 
committee. This meeting will include DSMB members and the clinical monitor. The 
documents to be provided before this meeting are: 
1. Study protocol 
2. Preliminary DSMB Statistical Analysis Plan (SAP) 
3. Preliminary list of tables and listings to be provided for interim assessments 
4. Investigator’s Brochure 
5. Food and Drug Administration Guidance: Establishment and Operation of Clinical 
Trial Data Monitoring Committees. 
For all DSMB meetings, a quorum is defined as at least two members of the DSMB in 
addition to the DSMB chairperson. 
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9.4.3.2 Review of Safety /SAE Reports
As part of ongoing safety review and obligation to regulatory agencies, cumulative 
safety and SAE reports will be furnished for each DSMB meeting. These reports will be 
available to the DSMB, who shall review them in the context of providing additional 
information to assist the committee’s consideration of subject safety. 
9.4.3.3 Data Review Meetings
After all subjects enrolled in the Pilot Phase have received the study therapy infusion 
and been followed for 30 days, the DSMB will conduct a full review of all cumulative 
safety data before the trial proceeds to the Randomized Phase.  As part of the 
cumulative safety data review meeting for the pilot phase, the DSMB will recommend 
that the trial proceed to the protocol-specified randomized phase or recommend a dose 
modification for the randomized placebo study.
Ongoing Monitoring During Randomized Phase
Formal data review meetings that include the entire DSMB will be conducted via 
teleconference approximately every three months.  The timeline for the quarterly DSMB 
data review meetings will begin after approximately 25% of subjects are enrolled in the 
randomized phase.  Meetings may be postponed due to accrual rates or to coincide with 
study milestones (e.g. after all subject s’ Day 30 data are entered) at the DSMB’s 
discretion.  The purpose of the data review is for safety evaluation, and the study may 
be stopped because of significant safety concerns.  SAEs which are related to stopping 
rules will be continuously evaluated and the full DSMB will be informed of any extra risk.
Other safety data obtained at protocol-specified follow-up visits, including but not limited 
to data from the assessments listed below, will also be evaluated by the DSMB as 
appropriate:

12-lead ECGs

Hematology, clinical chemistry, and urinalysis data

Serum or Urine Pregnancy test

Medical history

Physical Exam

Vital Signs

FEV-1

6 – Minute Walk Test

QOL Questionnaire

Adverse Events
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The DSMB will evaluate all safety data available for each subject as appropriate.  In 
addition to those assessments listed above, data for DEXA scan, Dobutamine stress 
echocardiogram test, dynamometer test, and specific biomarkers may be available.  
The EMMES Corporation will coordinate the scheduling of the teleconferences to review 
safety data during the randomized phase.
Open session
Blinded data will be provided to the DSMB approximately 1 week before each data 
review meeting. The report will contain: 
1. Protocol status including any protocol changes 
2. Data sources and cutoff dates 
3. Analysis methods applied specifically to the open session report 
4. Subject enrollment by month 
5. Protocol deviations 
6. Early treatment discontinuations and study withdrawals 
7. Demographic and baseline characteristics 
8. Duration of follow-up at time of data cutoff 
 Closed Session 
Only the DSMB members will participate in closed sessions. Unblinded data will be 
presented to the DSMB in closed session and discussed by the DSMB. "Unblinded" 
means that the name of actual treatment arm is associated with individual subject data 
listings and summaries of data. At the chairperson’s discretion, the DSMB may discuss 
or vote on potential study conduct recommendations at closed session.
The closed session report will contain data separated and identified by treatment group. 
This report (hard copy) will be provided to the DSMB approximately 1 week before each 
data review meeting and will include: 
1. Data sources and cutoff dates 
2. Analysis methods applied specifically to the closed session report 
3. Subject enrollment 
4. Protocol deviations 
5. Early treatment discontinuations and study withdrawals 
6. Demographic and baseline characteristics 
7. Primary and secondary efficacy outcome measures
8. Prohibited concomitant medications 
9. Adverse events
10.Serious adverse events 
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During the closed session, the DSMB chairperson will issue one of the following 
recommendations as determined by the DSMB and will be reported in the meeting 
minutes: 
1. Continue the study, with or without modifications. 
2. Terminate the study for safety concerns. 
Separate meeting minutes for the open and closed sessions will be prepared by the 
DSMB support team, then reviewed and issued by the DSMB chairperson. The DSMB 
support team will distribute the finalized minutes. The DSMB support team will maintain 
copies of the meeting minutes for both the open and closed meetings. To preserve the 
integrity of the study, the detailed rationale and discussion of comparative unblinded 
data will be included only in the closed meeting minutes
 Follow-Up Open Session 
Immediately following the closed session, the DSMB will meet with the investigators to 
discuss any study conduct concerns. This follow-up open session may be attended by 
DSMB Members, clinical monitor, and study staff. Potential recommendations from the 
DSMB regarding study discontinuation or continuation, with or without modification, will 
not be communicated in this open session.
 Closed Executive Session 
At the discretion of the DSMB chairperson, a closed executive session may be held. 
Closed executive sessions will include only DSMB members. Discussion of unblinded 
study data and potential DSMB recommendations and voting may take place in closed 
executive session. The DSMB may choose whether to write minutes of the closed 
executive sessions. 
9.4.4 DATA FLOW
9.4.4.1 Communications and Reports
For each DSMB meeting, the open session and closed session reports will be prepared 
by the DSMB support team. Open session reports will be circulated to all attendees of 
the open session. The closed session reports will be circulated to DSMB members only. 
The closed session reports will be retrieved from the DSMB members by the DSMB 
support team and destroyed after the closed session. The DSMB support team will 
maintain copies of all reports from the open and closed sessions. 
9.4.4.2 Review of Unblinding Requests
Except as required by regulatory authorities for safety reporting, individual subjects’ 
treatment assignments will not be unblinded during the conduct of the study, unless a 
subject safety issue arises in which unblinding is necessary to ensure optimal subject 
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management. It is not anticipated that unblinding will be necessary, given the hMSCs 
can be safely discontinued at any time a safety concern arises. The DSMB will be 
informed in a timely manner of any case for which unblinding was requested and 
performed. 
9.4.4.3 DSMB Additional Analysis Requests 
The DSMB may request additional analyses from the statistician if deemed necessary to 
fulfill the mission of the DSMB. If based on the additional data the DSMB feels there is a 
need for an unscheduled formal meeting, the DSMB chairperson will arrange.
9.4.4.4 Confidentiality 
All documents will be held in strict confidence by the DSMB, and all documents 
provided to the DSMB will be collected and destroyed at the end of all DSMB meetings 
by the DSMB support team. 
9.4.5 COMMUNICATION
9.4.5.1 DSMB Minutes
The DSMB chairperson is responsible for issuing minutes of the open and closed 
sessions. Minutes of the open session will be distributed to all open meeting attendees 
within two weeks of the meeting. Minutes of the closed session will be distributed to the 
members of the DSMB within two weeks of the meeting. At the conclusion of the study, 
the DSMB support team will send a complete set of the open and closed reports, 
minutes of the open and closed sessions with the tables and listings, all presentations 
and copies of the recommendation forms to the investigators. 
9.4.5.2 DSMB Recommendations
Written recommendations will be forwarded to University of Miami/ISCI in the finalized 
open session meeting minutes within two weeks of the DSMB meeting.
All recommendations of the DSMB, such as a change in the study protocol or early 
termination of the study, must be documented in the DSMB meeting minutes.  If the 
DSMB recommends modification to, or termination of, the study, the CRO will contact 
the investigators within 24 hours of the DSMB making the decision. 
Recommendations for modifications other than termination should be accompanied by 
the rationale for the recommendation and the minimum amount of data required to 
make a decision. The investigator will be responsible for promptly reviewing the DSMB 
recommendations and determining whether amendments to the protocol or changes 
regarding the study conduct are required and if reporting to regulatory authorities is 
warranted (FDA, 2006). 
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Should there be disagreement between the DSMB and the investigators around the 
decision to stop or modify the study a separate compliance committee will be appointed. 
This committee is comprised of individuals who have extensive experience in the 
pharmaceutical industry and a deep appreciation of the ethical issues surrounding the 
conduct of clinical studies and are responsible for the investigator’s code of ethics. The 
Compliance Committee is charged with independently evaluating differing opinions that 
may arise between the investigator and DSMB and applying the highest ethical 
standards with respect to determining the best interests of subjects enrolled in the 
study. 
10. 
STUDY ADMINISTRATION
10.1
Regulatory Authority Approval
This study will be conducted in accordance with Good Clinical Practice (GCP) 
requirements described in the current revision of International Conference on 
Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) 
Guidelines and all applicable regulations, including current United States Code of 
Federal Regulations (CFR), Title 21, Parts 11, 50, 54, 56, and 312 and Title 45, Part 
164.  Compliance with these regulations and guidelines also constitutes compliance 
with the ethical principles described in the current revision of the Declaration of Helsinki.  
This study will also be carried out in accordance with local legal requirements.
10.2 Ethics Approval
It is the Investigator’s responsibility to ensure that prior to initiating this study; this 
protocol is reviewed and approved by the appropriate local IRB.  The composition and 
conduct of this committee must conform to the United States CFR.  
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 Subject Informed 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 Authorization (HIPAA) information in language that is 
understandable to the subject. 
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The process of obtaining the informed consent will be in compliance with all federal 
regulations, ICH requirements, and local laws.  
The investigator or designee 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 must 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 must 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.
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.
In cases where a new ICF is issued between the Month 6 (Office Visit) and Month 12 
(Telephone visit) the subject will be contacted and informed of the changes. The subject 
will be asked if they are available to come to the site. If the subject is unable to come to 
the site the subject may be reconsented via phone. 
10.4 
Confidentiality of Information
Subjects’ names will remain confidential and will not be included in the database.  Only 
subject number, subject initials, and birth date will be recorded in the data system.  If 
the subject name appears on any other document collected (e.g., hospital discharge 
summary), the name must be deleted before the document is transmitted.  All study 
findings will be stored in electronic databases.  The subjects will give explicit permission 
for representatives of 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.
Subject s will be asked to voluntarily provide written authorization prior to requesting or 
disclosing private health information either as part of the written ICF or as a separate 
authorization form. The authorization will contain all required elements specified by 45 
CFR 164, and will allow the site to access 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 two years after the study therapy 
is approved for the indication being studied, or (2) the expiration of two 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 
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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 investigator will maintain a personal subject identification list (subject and treatment 
numbers with the corresponding subject names) to enable records to be identified.  
10.5 
Payments to Subjects and Donors
Subjects will be reimbursed $25 at the end of each follow-up visit (Month 1 – Month 6) 
for a total remuneration of $75.  These disbursements are meant to cover the time 
required to complete these study visits and all necessary travel and parking expenses. 
Normal donors for generation of allo-MSC will be reimbursed $500 at the end of BM 
aspiration. This payment will compensate donors for lost time, parking, and travel 
expenses. 
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APPENDIX 1: 
Infusion Guidelines
Prior to the start of the infusion the following procedures and assessments will be 
conducted on the study subject:
1.
Vital Signs: Blood pressure, heart rate, respiratory rate, and temperature, will 
be measured within 15 minutes prior to the initiation of the infusion.
2.
Oxygen saturation will be continuously monitored by pulse oximetry for at 
least 30 minutes prior to initiation of IP infusion.
3.
Confirm that IV access is established and that the IV catheter is no smaller 
than 20 gauge
4.
Study personnel needs to verify that the following pre-medications have 
been administered 30 minutes to an hour prior to infusion, unless otherwise 
determined by the physician:

Hydrocortisone 25 – 50 mg IV

Diphenhydramine (Benadryl) 25 – 50 mg IV
Note: No other medications should be given during the infusion unless 
determined medically necessary by the Investigator.
5.
Document pre-medications given prior to infusion on the source documents
6.
Required IV Infusion materials as follows:

0.9 % normal saline IV infusion bag

IV Pump tubing

IV extension tubing (unless using a central line)

Volumetric infusion pump

Gloves
7.
Remove 0.9% normal saline infusion bag and connect IV tubing to the 
volumetric infusion pump
8.
Cover the IV tubing with the blinding material provided with the infusion bag 
by the drug preparation technician. 
During the IP infusion the following procedures and assessments will be conducted on the 
study subject:
1.
Monitor the subject continuously with pulse oximetry
2.
Hang the blinded infusion bag. Investigational product (IP) should not be 
“piggybacked” through another line
3.
Intravenously administer the IP at a rate of 2ml/min. 
Note: Study personnel administering the IP must be present throughout 
the infusion process. The Investigator must be available at the site during the 
infusion process in case an emergency should arise. 
4.
Record the start time of the infusion bag 
5.
Gently squeeze the infusion bag several times every 15 minutes to assure 
uniform dispersion of contents
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6.
Vital signs and O2 saturation will be measured every 15 minutes until the 
end of IP infusion
7.
Record the total volume infused from the IP bag
8.
At the end of the IP infusion, close the line and flush 25ml of 0.9% normal 
saline into the luer lock connector on the bottom of the IP bag, reopen line 
and allow to infuse at a rate of 2mL/min until completion.
9.
Discard IV tubing according to established guidelines
10.
Return the blinded IP infusion bag to the cell-processing technician.
Procedures post-infusion:
1.
Vital signs will be monitored at 15 minutes, 30 minutes, 1 hour, and 2 hours 
post IP infusion
2.
The subject will be monitored for a minimum of 2 hours post IP infusion with 
continuous pulse oximetry
3.
If the O2 saturation decreases to < 90% over a continual period of 3 – 5 
minutes then supplemental oxygen may be added or increased during the 
two-three hours post-infusion observation period. 
4.
If at the end of the 2 hour observation period, if a subject’s O2 saturation 
stays below 90% then the subject will be provided additional oxygen to 
maintain a saturation of >90% at room air up to 4 hours post infusion. 
5.
After the minimum two hour observation period, the subject will be 
continuously monitored and discharged, if no complaints are experienced, 
such as shortness of breath or other objective signs of cardiorespiratory 
compromise. 
6.
Subjects not meeting criteria for discharge will be assessed by the 
Investigator during the observation period to further determine 
hospitalization otherwise not specified in the protocol.
Subject Stopping Guidelines:
1. Any subject who develops persistent (that is, still existing more than 3 hours after 
the end of IP infusion) cardiorespiratory signs or symptoms including hypoxemia 
(defined per oxygenation criteria of 93% on room air at rest, or shortness of breath, 
tachypnea, tachycardia, hypotension, or palpitations) will continue with all 
scheduled follow-up if such follow-up is considered safe in the opinion of the 
Investigator. The infusion will be stopped if the oxygen saturation does not return to 
>93% within 3 minutes of initiating supplemental oxygen or if the subject requires 
greater than 2L/min supplemental oxygen to achieve the required saturation of 
>93%.  If a subject requires the addition of oxygen, it will be continued for 4 hours 
after the completion of the infusion.  At that time, oxygen will be weaned off to 
maintain a saturation >93% on room air.
2. Any subject whose infusion is stopped due to cardiorespiratory distress will receive 
no further IP infusions but will continue with all scheduled follow-up if such follow-
up is considered safe in the opinion of the Investigator.
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3. Any subject who develops any sign or symptom that, at the discretion of the 
Investigator, warrants the discontinuation of infusion will receive no further IP 
infusions but will continue with all scheduled follow-up if such follow-up is 
considered safe in the opinion of the Investigator.
4. Infusion of the IP may be stopped if there is an adverse event that the Investigator 
believes is related to the IP or if there is an issue with the IP infusion.
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APPENDIX 2: Dobutamine Stress Echocardiogram (DSE) Guidelines 
A Dobutamine Stress Echocardiogram (DSE) will be performed at screening and at the 
Month 6 follow-up visit. Dobutamine is a chemical, which can assist in mimicking the effect 
of exercise on subjects in order to assess the heart muscle and ejection fraction when 
under stress. 
Procedure Details:
1. Obtain baseline heart rate, blood pressure, Electrocardiogram (ECG), physical 
exam, and echocardiographic images on the study participant.
2. Place an Intravenous (IV) line to administer Dobutamine.
3. Administer progressively increasing doses of Dobutamine (5, 10, 20, and 30 
mcg/kg/min) in 3-minute intervals.
4. Obtain Heart rate, Blood Pressure, ECG, and echocardiographic images at each 
dosage.
5. After completing measurements at 30mcg/kg/min dosage, discontinue 
Dobutamine and allow heart rate to recover to baseline and obtain repeat 
echocardiographic images.
Required Data Points:
6. Right Ventricular end-diastolic dimension (RVDd)
7. Interventricular Septal end-diastolic dimension (IVSd)
8. Left Ventricular Internal end-diastolic dimension (LVIDd)
9. Left Ventricular Internal end-systolic dimension (LVIDs)
10.Left Ventricular Posterior Wall end-diastolic dimension (LVPWd)
11.End-Diastolic Volume (EDV)
12.End-Systolic Volume (ESV)
13.Left Atrial (LA) dimension
14.Peak infusion rate
15.Peak heart rate 
16.Peak blood pressure (systolic/diastolic)
17.Resting biplane ejection fraction
•
Ejection fraction at 5 mcg/kg/min
•
Ejection fraction at 10 mcg/kg/min
•
Ejection fraction at 20 mcg/kg/min
•
Ejection fraction at 30 mcg/kg/min
18.Evidence of Mitral Valve Regurgitation (MR)
19.Evidence of Pericardial Effusion (PE)
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Addendum A: Pilot Subjects Optional Follow-on Phase
A.1 
Rationale and Description of second infusion for first 15 subjects on 
pilot phase
This addendum protocol is designed to test the safety of a second infusion of allogeneic 
mesenchymal stem cells 12 to 18 months following a first infusion.  
Subjects in the pilot phase that received one (1) infusion of allogeneic MSCs are eligible 
to participate in this optional follow-on phase for a second dose.  Because several 
studies, reviewed below, have now shown safety of repeat doses of MSCs in a variety 
of medical conditions, additional safety testing in the subject population of aging frailty 
enrolled in the CRATUS trial is required92. All study specific processes and procedures 
included in the pilot phase of the protocol apply in this addendum unless otherwise 
noted.
A.2 
Demonstrated Safety and Increased Efficacy of Multiple Infusions of 
Allogeneic Mesenchymal Stem Cells
Active clinical trials and ongoing preclinical work provide an accumulating data set 
supporting the safety and, in some cases, therapeutic efficacy of allogeneic 
mesenchymal stem cells (MSCs).  Allogeneic mesenchymal stem cells are both 
immunoprivileged and immunosuppressive, thereby enabling their use as an allograft93.  
Cellular therapy with allogeneic MSCs has abundant support from both animal studies 
and human clinical trials for a wide range of disorders (Table 1).  For example, the 
POSEIDON study addressed the major issue of the use of allogeneic MSCs as a cell-
based therapeutic18.  In this study, subjects with cardiac failure were randomized to 
receive either autologous MSCs or identically prepared allogeneic MSCs from healthy 
donors.
Accumulating evidence also supports the concept that repeated doses and/or co-
administration of allogeneic MSCs could further enhance therapeutic outcomes. This is 
an extremely important area for medical investigation, since repeat dosing could 
potentially have an additive effect and/or reverse disease pathology, depending on the 
disorder.
Recently, several clinical studies have demonstrated that multiple infusions of 
allogeneic MSCs are well tolerated with minimal side-effects.  Importantly, repeat dosing 
has no increased level of side effects compared with single doses.  For example, results 
from Franco Locatelli’s group92 clearly demonstrate the safety and efficacy of multiple 
allogeneic MSC infusions in children with steroid-refractory acute graft versus host 
disease (aGvHD).  Doses in these studies were 1-2x106 MSCs/kg recipient body mass, 
and each child received on average 2 doses (range was 1-13 doses) separated on 
average by 15 days (range 3-43 days).  The results of this study indicated increased 
effectiveness when the therapy was commenced early in the disease.  Furthermore, the 
study indicated the therapeutic benefits of repeat doses to subjects who did not achieve 
complete remission after a single dose. 
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Koc et al94; further investigated Hurler syndrome (mucopolysaccharidosis type-IH) and 
metachromatic leukodystrophy (MLD) and studied allogeneic MSCs based on their 
potential to differentiate into cells of bone, cartilage, tendon, muscle and other 
adventitial tissues and offer potential for corrective cellular therapy95. Their results 
demonstrated no infusion-related toxicity, improvement in nerve conduction, and bone 
mineral density was either maintained or improved in all subjects.
A Phase II study on the 3-year efficacy of allogeneic MSCs in the treatment of system 
lupus erythrematosus (SLE) was reported by Lingyun Sun’s group96.  The results of this 
study demonstrated the therapeutic efficacy of allogeneic MSCs in treating SLE.  
However, no advantage was found by administering a second or higher dose of 
allogeneic MSCs.  Despite this lack of additional efficacy over a single dose, the results 
of this study confirmed the safety of multiple infusions of allogeneic MSCs.  The doses 
(1x106 MSCs/kg body mass) were administered 1 week apart.   Another study reported 
on the use of repeated dosing of allogeneic MSCs in subjects with chronic obstructive 
pulmonary disease.  The study showed minimal therapeutic efficacy after 2 years19.  
Importantly, in this subject population repeated allogeneic MSC infusions, which were 
given 4 times at 30 day intervals (1x108 MSCs/infusion) were safe.
Taken together, these various clinical studies provide a solid rationale for repeat 
allogeneic MSC infusions.  In no case did the administration of multiple doses lead to a 
significant increase in the frequency of adverse effects, or to a decrease in therapeutic 
efficacy over a single dose.  In many cases, repeated infusions indeed improved clinical 
outcomes, demonstrating an additive effect of allogeneic MSC therapy.  Given these 
promising results, investigations are now warranted to determine optimal dosing 
frequency and total doses of allogeneic MSCs to administer.  
It is particularly important to establish safety of repeat doses of allogeneic MSCs in the 
subject population enrolled in the CRATUS study.  These individuals are of older age 
and are not represented in the previous studies described.   In this follow-on study 
subject s in an earlier open label pilot study will be asked to participate in this repeat 
dosing protocol.
A.3 
STUDY OBJECTIVES AND ENDPOINTS
A.3.1 
Study Objectives
A.3.1.1
Primary Objective
1. Demonstrate the safety and tolerability of a second intravenous 
infusion of allo-hMSCs in subjects with aging frailty who had 
previously received an infusion of allogeneic MSCs as part of the 
pilot phase of the protocol.
A.3.1.2
Secondary Objectives
1. To explore treatment efficacy (decrease in frailty, frequency of 
acute exacerbations, change in symptom related quality of life, 
improved cardiovascular status, decrease in inflammatory 
biomarkers, endothelial function and 1 year survival).
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A.3.2
Study Endpoints
A.3.2.1
Primary Endpoints (Safety)
1. Safety (Primary): Incidence (at one-month post second infusion) of 
any treatment-emergent serious adverse events (TE-SAEs), 
defined as the composite of: death, non-fatal pulmonary embolism, 
stroke, hospitalization for worsening dyspnea and clinically 
significant laboratory test abnormalities, determined per the 
Investigator’s judgment. 
Laboratory tests included in the primary endpoint include the 
following:

Serum chemistry: chloride, sodium, Carbon Dioxide, BUN, 
creatinine, glucose, calcium, AST/SGOT, ALT/SGPT, total 
bilirubin (fractionate if total >1.5 times normal), alkaline 
phosphatase, albumin, 

Hematology (CBC): hemoglobin, hematocrit, platelets, WBC, 
WBC differential
A.3.2.2
Secondary Endpoints (Efficacy)
The following efficacy endpoints will be evaluated in this trial (During the 
screening, baseline, Month 3 and/or Month 6 visits):
1. Difference in rate of decline of Frailty defined as:

Reduced Activity (assessed via CHAMPS questionnaire)

Slowing of Mobility (assessed via a 4 meter gait speed test 
and SPPB assessment)

Weight Loss

Diminished handgrip strength (assessed via dynamometer)

Exhaustion (assessed via the MFI questionnaire)

Decrease in subject quality of life assessment(s) (assessed 
via ICECAP, SF-36, EQ-5D Questionnaires)
2. Death from any cause.
3. Change between screening and 6 months in dobutamine stress echo 
induced ejection fraction.
4. Change between screening and 6 months for the following panel of  
inflammatory markers:  CRP, IL-6, D-dimer, fibrinogen,
CBC with differential, and TNFα.
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5. The incidence of each component of the primary endpoint including 
non-fatal pulmonary embolism, stroke, hospitalization for worsening 
dyspnea and clinically significant laboratory test abnormalities
6. Change in Smell Identification Test (UPSIT)
A.4
Inclusion and Exclusion Criteria
A.4.1
Inclusion Criteria for Follow-on Phase
In order to participate in this study, a subject MUST:
1.
Provide written informed consent.
2.
Subjects age >60 and <95 years at the time of signing the Informed 
Consent Form for the second infusion.
3.
Have previously participated in the pilot phase of this trial
4.
Female subjects must have an FSH > 25.8 mIU/mL, if not currently on 
hormone replacement therapy.
A.4.2
Exclusion Criteria for Follow-on Phase
In order to participate in this study, a subject MUST NOT have any of the following:
1.
Score of <24 on the Mini Mental State Examination (MMSE)
2.
Inability to perform any of the assessments required for endpoint analysis 
(report safety or tolerability concerns, perform PFTs, undergo blood 
draws, read and respond to questionnaires.
3.
Active listing (or expected future listing) for transplant of any organ.
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4.
Clinically important abnormal screening laboratory values, including but 
not limited to: hemoglobin <8 g/dl, white blood cell count <3000/mm3, 
platelets<80,000/mm3, INR > 1.5 not due to a reversible cause (i.e. 
Coumadin), aspartate transaminase, alanine transaminase, or alkaline 
phosphatase > 3 times upper limit of normal, total bilirubin > 1.5 mg/dl.
5.
Serious comorbid illness that, in the opinion of the investigator, may 
compromise the safety or compliance of the subject or preclude 
successful completion of the study.  Including, but not limited to: HIV, 
advanced liver or renal failure, class III/IV congestive heart failure, 
myocardial infarction, unstable angina, or cardiac revascularization within 
the last six months, or severe obstructive ventilatory defect.
6.
Any other condition that, in the opinion of the investigator, may 
compromise the safety or compliance of the subject or preclude successful 
completion of the study. 
7.
Be an organ transplant recipient.
8.
Have a clinical history of malignancy within 3 years (i.e., subjects with prior 
malignancy must be disease free for 3 years), except curatively-treated 
basal cell carcinoma, squamous cell carcinoma, melanoma in situ or 
cervical carcinoma if recurrence occurs.
9.
Have a non-pulmonary condition that limits lifespan to < 1 year. 
10.
Have a history of drug or alcohol abuse within the past 24 months. 
11.
Be serum positive for HIV, hepatitis BsAg or Viremic hepatitis C.
12.
Be currently participating (or participated within the previous 30 days) in an 
investigational therapeutic or device trial. This does not exclude subjects 
that participated in the pilot phase.  
 
13.
Be a female who is pregnant, nursing, or of childbearing potential while 
not practicing effective contraceptive methods. Female subjects must 
undergo a blood or urine pregnancy test at screening and within 36 hours 
prior to infusion.
14.
Have hypersensitivity to dimethyl sulfoxide (DMSO)
A.5
Dosing
After subjects complete their Month 12 follow-up phone call visit in the pilot phase (first 
infusion), all 15 subjects will then have the option of receiving additional infusions of 
allogeneic hMSCs: 1 x 108 (100 million) cells delivered via peripheral intravenous 
infusion.
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The Allo-hMSCs will be derived from donors meeting criteria for allogeneic unrelated 
human bone marrow stem cell source manufactured by the University of Miami.
A.6
Dosage Rationale
A safety profile for IV infusion of hMSCs was based on results from previous completed 
toxicology results (Hare et al. 2277-86). The results from previous studies demonstrate that the 
product can be administered intravenously without toxic events at up to 65 x 
106hMSC/kg dose delivered in one bolus infusion or at 100 x 106hMSC/kg cumulative 
dose delivered by 5 infusions (20 x 106hMSC/kg per infusion).
The evidence supports the conclusion that it is feasible to dose subjects in this study 
based on a standard dose of hMSCs rather than per kilogram of body weight. The total 
cell number corresponds to a range of 1.3 - 4.4 x 106 hMSCs per kg per infusion for 
subjects with 45 to 150kg body weight, the weight range for this study.
Therefore, results from previous trials support the rationale on the safety and potential 
efficacy of a second infusion of the selected maximum dose of 100 x106 allo-hMSCs.
A.7
Administration Rate
Prior clinical trials have used rates up to 30×106 hMSC/min where no infusion related 
toxicity was observed. 
In the proposed study addendum, the cell dose to be delivered is 1 x 108 (100 million), in 
the following total volume: 
-   40ml for 100 million dose (5 million hMSC/min)
Cells are placed in an 80ml bag and will be delivered at a rate of 2ml/min, and delivered 
at a maximum rate of 16×106 hMSC/minute and will last approximately:
40 minutes for delivery of 40ml of 100 million dose in an 80 ml bag 
A.8
Data and Safety Monitoring Board (DSMB)
DSMB will continue to provide the same oversight as noted in Section 9.4 of the Main 
protocol.
A.9
Concomitant Treatments, Procedures, and Nondrug Therapies
Refer to section 4.3 of the main study protocol
A.10
Infusion Monitoring Guidelines
Refer to section 6.4.1 and Appendix 1 of the main protocol.
A.11
Adverse Events and Serious Adverse Events
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Refer to section 8.9 through 8.15 of the main study protocol.
A.12
Stopping Guidelines
Refer to section 8.2.4 of the main study protocol for further stopping guidelines.
A.13
Payments to Subjects and Donors in the Follow-on Phase
Subjects will be reimbursed $25 at the end of each follow-up visit (Month 1 – Month 6 
for a total remuneration of $75.  These disbursements are meant to cover the time 
required to complete these study visits and all necessary travel and parking expenses. 
Normal donors for generation of allo-MSC will be reimbursed $500 at the end of BM 
aspiration. This payment will compensate donors for lost time, parking, and travel 
expenses.
A.14
Study Procedures for Pilot Phase Optional Second Infusion
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Table A1: Time and Events Table for Optional Pilot Phase Second Infusion Schedule
Visit Schedule for Second Infusion
Screening
+ 6 
Months
Baseline
(-4 weeks)
Day 
1
Month 1
(Day 30)
(+/- 2 
weeks)
Month 3 
(Day 90)
(+/- 30 days)
Month 6 
(Day 180)
(+/-30 days)
Month 12 
(Day 365) 
(+/-2 weeks) 
*Phone Call 
Follow-up
Informed Consent
x
Full Medical History 
x
Physical Exam
x
x
x
x
x
x
12-lead (ECG)
x
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
x
Mini Mental State Examination (MMSE)
x
x
Infusion Treatment (IP)
x
Dobutamine Stress Echo Test (DSE)
x
x
Bone Density Scan (DEXA)8
x
x
FEV-1
x
x
6 Minute Walk Test
x
x
4 Meter Gait Speed Test7
x
x
SPPB Assessment
x
x
Dynamometer (handgrip)9
x
x
Smell Identification Test (UPSIT)
x
x
IIEF, SQOL-F Questionnaires
x
x
x
x
QOL Questionnaires (ICECAP, EQ-5D, SF-36,CHAMPS, MFI)
x
x
x
x
Urinalysis
x
x
x
x
Hemat., Chem., CBC, LFTs, INR,   and other labs1
x
x
x
x
x
HIV 1, HIV 2, Hep. B & C, and CMV
x
Serum or Urine Pregnancy Test2
x
x
Review Adverse Events
x
x
x
x
x
Immune Monitoring4
x
x
x
x
Biomarker Assessment3
x
x
Optional: Brachial Ultrasound 5
x
x
Optional: Endothelial blood samples6
x
x

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Time and Events Table Key:
1 – The minimal laboratory requirements for hematological, liver function and renal 
function include:
Hematology Tests: white blood cell count, platelet count, hemoglobin and 
hematocrit, red blood cell count, CBC with Differential: neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils.
Liver Function Tests: Albumin, alkaline phosphatase, alanine transaminase, 
asparate aminotransferase, prothrombin time / activated partial thromboplastin
time, and bilirubin(fractionate if total >1.5 times normal). 
Renal Function Tests: creatinine, creatinine clearance, blood urea nitrogen 
(BUN), glomerular filtration rate, sodium, potassium, chloride, calcium, carbon 
dioxide, total protein, glomerular filtration rate (GFR), and glucose, (HbA1c) will 
be collected at every follow-up visit only for subjects diagnosed with diabetes 
mellitus (DM).
Serum Uric Acid, Pro-BNP, and high sensitivity C-reactive protein (hs-CRP), 
IL6, fibrinogen, D-Dimer, DNA**, TNFα, testosterone (males only) and 
estrogen (females only).
- Laboratory work may be completed at a diagnostic center or home health 
agency should the subject be unable to come to the site.
** Deoxyribonucleic acid (DNA) will only be collected once during the subject’s 
participation. There is no specific point DNA needs to be collected as it can 
occur at any time point. 
2 – A serum or urine pregnancy test will be completed within 36 hours prior to infusion  
for females of childbearing potential.
3 – The following biomarkers will be analyzed (Approximately 10mL blood samples will 
be collected): 

Cell-surface markers: CD19, CD27, IgD, and CD5 (for Switched Memory, 
Naïve, Late/Exhausted, IgM memory B cells and regulatory B cells); CD19 
and intracellular TNF-α (to assess intracellular TNF-α); CD3, CD4, CD8, 
CCR7 and CD45RA (for Central Memory, Naïve, Effector Memory, TEMRA 
T cells and CD4 to CD8 ratio); CD3, CD25 and FOXP3 (to assess regulatory 
T cells)

Transcriptomic/Proteome: 
RNA, 
miRNA, 
protein 
samples, 
and 
telomerase, akt

Growth factors: Sdf-1, notch, 

Functional Assays: cell growth rate, VEGF, and CFU assay
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4 – Immune monitoring for graft rejection.  Calculated panel reactive antibodies (cPRA) 
will be performed on day 1 and 6 months post treatment to assess for donor specific 
antibodies. In addition, the following markers will be used for analysis to assess for 
activated T-cells based upon a CD3+CD25+ (late/chronic T cell activation) or 
CD3+CD69+ phenotype (early T cell activation).
5 – Optional brachial ultrasound to assess endothelial function. 
6 – Optional: An additional five (5) lavender top tubes (EDTA) will be drawn of 
approximately 8ml per tube.
7 – 4 meter gait speed test will be performed twice per visit and the average of the 
exams will be taken.
8 – DEXA scan will be performed at baseline and Month 6. The scans of the hip and 
spine for bone density, and total body composition will be assessed at both visits.
9 – Dynamometer will be performed at least three (3) times during each applicable visit 
for each hand. The three values collected will be averaged for each hand. (Please 
reference the instruction manual on how to administer.)
10– Infectious disease tests – HIV, HIV 2, Hep B (HBsAG, Anti-HBs, Anti-HBc), and 
Hep C (Anti-HCV), VDRL, Syphilis, West Nile Virus, and CMV. (Conducted within 30 
days of infusion, if test expire prior infusion, they must be performed again)
A.15
Study Visits
A.15.1 
Screening Visit for second infusion
See Table A1 for the procedures and assessments to be performed during the 
screening visit of the study for the 15 pilot subjects that consent to participate in a 
second infusion. All screening visit test and procedures will occur upon signing the 
informed consent form (ICF). No screening exams will take place until the subject is fully 
informed of the research and signs the consent form. The tests may take place over 
several days and will need to be completed prior to the start of the baseline visit. There 
will be up to a 6 month window from the subjects Month 12 follow-up visit to the 
subject’s additional infusion. 
A.15.2
Baseline Visit for second infusion
See Table A1 for the procedures and assessment to be performed during the baseline 
visit of the study. Once all screening exams are completed and it has been determined 
that the subject remains eligible for the study, subjects will be enrolled into the study. 
The baseline visit will take place within four weeks of the infusion. The listed procedures 
should all be performed as soon as practicable.
Endothelial function (Optional Assessments) will occur upon the subject signing the 
optional section of the informed consent form (ICF). No endothelial function tests will take 
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place until the subject is fully informed of the research and signs the optional portion of 
the consent form.

Brachial ultrasound testing and blood collection will be performed to assess 
endothelial function in the aging frailty population at baseline and 3 months 
post stem cell infusion. This will help provide cumulative data in assessing 
whether or not stem cell infusion improves endothelial function.  

Flow Mediated Diameter percent change (FMD%):  All measurements of the 
brachial artery diameter and FMD will be performed in the morning, in a quiet 
and dark room and at controlled ambient temperatures between 20°C and 
26°C. Studies will be conducted after an overnight fast of at least 10 hours 
(water is permitted), with the subjects supine and after 10 minutes of rest. The 
subject's right arm will be comfortably immobilized in an extending position, 
allowing for ultrasound scanning of the brachial artery 5–10 cm above the 
antecubital fossa. In each examination, recording of vessel images will be 
followed by inflation of a cuff to supra-systolic pressure (40 to 50 mmHg 
above systolic pressure) for 5 minutes. Then the cuff will be deflated and the 
brachial artery diameter will be imaged and recorded for 3 minutes. FMD% 
more than 10% is considered a normal response. Lower than 10% FMD% 
reflects endothelial dysfunction, which means a high likelihood to develop 
cardiovascular event in the future. Subjects with negative FMD% results (the 
artery is constricted after stress and not dilated as was expected) have the 
worst prognosis.

Blood drawn from fasting subjects will be separated and the serum will be 
frozen until processed as one batch towards the end of the study. Blood will 
be processed twice – in the beginning of the study and after 3 months.

Biochemical analysis: soluble pro inflammatory cytokines (interleukin-1, 
interleukin-6, interleukin-10, VEGFR2, TNF-a).

Assay of colony forming units: Fresh blood will be processed for cell culture 
assays for endothelial progenitor stem cells colonies counting (a 5 days’ 
protocol). Fifty milliliter of blood will be processed; peripheral-blood 
mononuclear cells will be isolated by Ficoll density-gradient centrifugation, will 
be washed twice in phosphate buffered saline with 5% fetal bovine serum and 
re-suspended in media (EndoCult basal media with supplements; StemCell 
Technologies, Vancouver, British Columbia, Canada) for EPC colony-forming 
assay. Cells will be planted on human fibronectin-coated plates (BIOCOAT; 
Becton Dickenson Labware, Bedford, Massachusetts) at a density of 5X106 
cells/well and incubated at 370C in humidified 5% CO2. After 48 hours, the 
non-adherent cells will be re-plated onto fibronectin-coated 24 well plates at a 
density of 1X106 cells/well. After 5 days, colony forming units (defined as a 
central core of rounded cells surrounded by elongated and spindle-shaped 
cells) will be counted manually in 8 wells out of a 24-well plate. 
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A.15.3
Day 1 Visit for second infusion
See Table A1 for the procedures and assessment to be performed during the Day 1 visit 
of the study. The Day 1 visit will occur after all baseline tests are completed and it has 
been determined that the subject remains eligible. Once the subject is deemed eligible 
to continue in the study the subject will be administered the investigational product. The 
subject will be monitored for 2-3 hours, following administration of the investigational 
product, and will be sent home the same day.
A.15.4
Month 1 Visit for second infusion
See Table A1 for the procedures and assessment to be performed for the Month 1 visit 
of the study. Subject visits should be completed as close to the scheduled visit dates as 
possible. There will be a +/- window of 2 weeks for the month 1 study visit.
A.15.5
Month 3 and Month 6 Visit for second infusion
See Table A1 for the procedures and assessment to be performed for month 3 and 6 
visit of the study. Subject visit should be completed as close to the scheduled visit dates 
as possible. There will be a +/- window of 30 days for the month 3 and 6 study visit.
A.15.6
Month 12 Visit
See Table A1 for the procedures and assessments to be performed for Month 12 visit. 
This visit will be conducted via a phone interview with the subject. A phone script will be 
provided to the study personnel to use when interviewing the subject. There will be a +/- 
window of 2 weeks for this visit.
A.16
Statistical Considerations
All subjects will be offered the re-infusion and formal statistical considerations regarding 
sample size and power are not provided.  Based on prior studies, a second infusion of 
stem cells are safe but strict safety monitoring will be employed to continue the safety 
assessment of allogeneic infusion of MSCs.  Detailed analyses will be described in the 
separate statistical analysis plan.  
A.17
Safety Monitoring of 30-Day Rate of TE-SAEs
Monitoring of the rate of TE-SAEs by 30-days post-second infusion among subjects who 
received the infusion of allogeneic MSCs will be employed to assist the DSMB in 
prospective monitoring of this study.  The guideline is to be used to indicate boundaries 
requiring discussion by the DSMB and is designed to assist the independent DSMB in 
overseeing the study. The DSMB may also request additional interim analyses and 
develop other criteria including provision for monitoring of potential late effects to 
determine when to intervene in the enrollment or treatment of subjects in the study. 
Monitoring of key safety endpoints will be conducted. If rates significantly exceed the pre-
set threshold, then the DSMB will be notified.  
A Bayesian motivated safety stopping guideline for monitoring the 30-day TE-SAE rate 
will be used for this trial.  The expected underlying rate of TE-SAE at 30 days post-second 
infusion is assumed to be 13.3% based on the assumption that 2 out of 15 subjects 
experience a TE-SAE.  It would then be assumed that a rate of greater than 40.0% is 
unacceptable. 
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A Beta distribution can be used as the prior distribution of ; where  is the proportion of 
subjects who experience an TE-SAE by 30-days post-second infusion.  The stopping rule 
is based on the beta-binomial methodology and assumes a prior expected failure rate.  
This leads to prior Beta parameters where a=0.8 and b=5.2.  The Beta distribution will 
have a prior mean of 0.13 and a prior probability of <0.05 of exceeding 0.40.  The 
guideline is derived such that there is strong evidence (posterior probability >0.95) that 
the probability of the event is greater than 40%, the trial will be stopped. The resulting 
boundaries tabulated in Table A2 were rounded to be conservative with the stopping 
guideline and is considered after 5 subjects are enrolled on the study.
TABLE A2
Bayesian Stopping Guideline for Event Rate of 13% *
# Events
#  Subjects in Study
3
5
4
6-9
5
10-14
6
15
* 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.
A simulation study was conducted to evaluate the operating characteristics of this 
stopping rule.  Data were generated from the binomial distribution with varying 
probabilities of failure () and assuming a sample size of 15 subjects.  Table A3 shows 
the probability of stopping the trial early and the average sample size (N), conditional on 
stopping early, at which the boundary is crossed for each value of .  The unconditional 
average sample size of the trials for each value of  is displayed. 
Table A3
Operating Characteristics for Bayesian Motivated Stopping Guideline
Mean 
of 
Prior 
Distribution

Probability 
of stopping
Conditional 
Average 
Sample Size (N)
Unconditional 
Average Sample 
Size of Trials (N)
0.13
0.13
0.05
8.4
14.7
0.18
0.12
8.8
14.2
0.23
0.25
8.9
13.5
0.28
0.40
8.8
12.5
0.33
0.56
8.5
11.4
0.40
0.75
8.0
9.8
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Although the motivation for the boundary is Bayesian, the operating characteristics can 
be evaluated from a frequentist perspective of Type I error and power.  The stopping rule 
for a 13% event rate has a 5% chance (“Type I error”) of suggesting early termination 
when the true rate is 0.13, and a 75% chance (“power”) when the true rate is 0.40. 
Limitations
A major limitation to the second infusion approach is the small sample size.  While it is 
assumed that all 15 subjects will be eligible for a second infusion, there is a chance that 
subjects will not want to undergo a second infusion and thus would further limit the 
amount of information received.  However, the second infusion strategy is being 
implemented to obtain information on the safety of a second infusion of allogeneic 
MSCs to help guide future studies.  
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Addendum B: Penicillin/streptomycin free cell safety study 
B.1 
Rationale and Description for penicillin/streptomycin free cell safety 
study
This addendum to the protocol is designed to gain additional safety of 
penicillin/streptomycin free intravenous infusion of allo-hMSCs in subjects with aging 
frailty.  Up to twenty subjects will be recruited to participate in a single dose of 
allogeneic MSCs in this follow-on phase.  All study specific processes and procedures 
included in the protocol apply in this addendum unless otherwise noted.  This population 
will not be included in the main phase of the trial, which included 15 pilot and 30 
randomized subjects. Additionally, subjects receiving a dose in the 
penicillin/streptomycin free study are eligible to receive up to three (3) additional 
infusions. 
B.2 
STUDY OBJECTIVES AND ENDPOINTS
B.2.1 
Study Objectives
B.2.1.1
Primary Objective
1.  Demonstrate the safety and tolerability of penicillin/streptomycin 
free intravenous infusion of allo-hMSCs in subjects with aging 
frailty.
B.2.1.2
Secondary Objectives
6. To explore treatment efficacy (decrease in frailty, frequency of 
acute exacerbations, change in symptom related quality of life, 
improved cardiovascular status, decrease in inflammatory 
biomarkers, endothelial function and 1 year survival).
B.2.2
Study Endpoints
B.2.2.1
Primary Endpoints (Safety)
1. Safety (Primary): Incidence (at one month post second infusion) of 
any treatment-emergent serious adverse events (TE-SAEs), 
defined as the composite of: death, non-fatal pulmonary embolism, 
stroke, hospitalization for worsening dyspnea and clinically 
significant laboratory test abnormalities, determined per the 
Investigator’s judgment. 
- Laboratory tests included in the primary endpoint include the 
following:

Serum chemistry: chloride, sodium, Carbon Dioxide, BUN, 
creatinine, glucose, calcium, AST/SGOT, ALT/SGPT, total 
bilirubin (fractionate if total >1.5 times normal), alkaline 
phosphatase, albumin, 
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
Hematology (CBC): hemoglobin, hematocrit, platelets, WBC, 
WBC differential
B.2.2.2
Secondary Endpoints (Efficacy)
The following efficacy endpoints will be evaluated in this trial (During the 
screening, baseline, Month 3 and/or Month 6 visits):
1. Difference in rate of decline of Frailty defined as:

Reduced Activity (assessed via CHAMPS questionnaire)

Slowing of Mobility (assessed via a 4 meter gait speed test 
and SPPB assessment)

Weight Loss

Diminished handgrip strength (assessed via dynamometer)

Exhaustion (assessed via the MFI questionnaire)

Decrease in subject quality of life assessment(s) (assessed 
via ICECAP, SF-36, EQ-5D Questionnaires)
2. Death from any cause.
3. Change between screening and 6 months in dobutamine stress 
echo induced ejection fraction.
4. Change between screening and 6 months for the following panel of  
inflammatory markers:  CRP, IL-6, D-dimer, fibrinogen,
CBC with differential, and TNFα
5. The incidence of each component of the primary endpoint including 
non-fatal pulmonary embolism, stroke, hospitalization for worsening 
dyspnea and clinically significant laboratory test abnormalities
6. Change in Smell Identification Test (UPSIT)
B.3
Inclusion and Exclusion Criteria
B.3.1
Inclusion Criteria for penicillin/streptomycin free cell safety 
study
In order to participate in this study, a subject MUST:
1.
Provide written informed consent.
2.
Subjects age > 60 and <95 years at the time of signing the Informed 
Consent Form.
3.
Show signs of frailty apart from a concomitant condition as assessed 
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by the Investigator with a frailty score of 4 to 7 using the Canadian Clinical 
Frailty Scale
4.
Female subjects must have an FSH > 25.8 mIU/mL, if not currently on 
hormone replacement therapy.
B.3.2
Exclusion Criteria for penicillin/streptomycin free cell safety 
study
In order to participate in this study, a subject MUST NOT have any of the following:
1.
Score of <24 on the Mini Mental State Examination (MMSE)
2.
Inability to perform any of the assessments required for endpoint analysis 
(report safety or tolerability concerns, perform PFTs, undergo blood 
draws, read and respond to questionnaires.
3.
Active listing (or expected future listing) for transplant of any organ.
4.
Clinically important abnormal screening laboratory values, including but 
not limited to: hemoglobin <8 g/dl, white blood cell count <3000/mm3, 
platelets<80,000/mm3, INR > 1.5 not due to a reversible cause (i.e. 
Coumadin), aspartate transaminase, alanine transaminase, or alkaline 
phosphatase > 3 times upper limit of normal, total bilirubin > 1.5 mg/dl.
5.
Serious comorbid illness that, in the opinion of the investigator, may 
compromise the safety or compliance of the subject or preclude successful 
completion of the study.  Including, but not limited to: HIV, advanced liver or 
renal failure, class III/IV congestive heart failure, myocardial infarction, 
unstable angina, or cardiac revascularization within the last six months, or 
severe obstructive ventilatory defect.
6.
Any other condition that, in the opinion of the investigator, may 
compromise the safety or compliance of the subject or preclude   successful 
completion of the study. 
7.
Be an organ transplant recipient.
8.
Have a clinical history of malignancy within 3 years (i.e., subjects with prior 
malignancy must be disease free for 3 years), except curatively-treated 
basal cell carcinoma, squamous cell carcinoma, melanoma in situ or 
cervical carcinoma if recurrence occurs.
9.
Have a non-pulmonary condition that limits lifespan to < 1 year. 
10.
Have a history of drug or alcohol abuse within the past 24 months. 
11.
Be serum positive for HIV, hepatitis BsAg or Viremic hepatitis C.
12.
Be currently participating (or participated within the previous 30 days) in an 
investigational therapeutic or device trial. 
13.
Be a female who is pregnant, nursing, or of childbearing potential while not 
practicing effective contraceptive methods. Female subjects must undergo 
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a blood or urine pregnancy test at screening and within 36 hours prior to 
infusion.
14.
Have hypersensitivity to dimethyl sulfoxide (DMSO)
B.4
Dosing
After subjects complete have completed their screening and continue to meet 
inclusion/exclusion criteria subjects will receive a single infusion of allogeneic 
penicillin/streptomycin free hMSCs: 1 x 108 (100 million) cells delivered via peripheral 
intravenous infusion.
The penicillin/streptomycin free Allo-hMSCs will be derived from donors meeting criteria 
for allogeneic unrelated human bone marrow stem cell source manufactured by the 
University of Miami or from a commercial clinical grade bone marrow source.
B.5
Dosage Rationale
A safety profile for IV infusion of hMSCs was based on results from previous completed 
toxicology results(Hare et al. 2277-86). The results from previous studies demonstrate that the 
product can be administered intravenously without toxic events at up to 65 x 106 
hMSC/kg dose delivered in one bolus infusion or at 100 x 106 hMSC/kg cumulative dose 
delivered by 5 infusions (20 x 106 hMSC/kg per infusion).
The evidence supports the conclusion that it is feasible to dose subjects in this study 
based on a standard dose of hMSCs rather than per kilogram of body weight. The total 
cell number corresponds to a range of 1.3 - 4.4 x 106 hMSCs per kg per infusion for 
subjects with 45 to 150kg body weight, the weight range for this study.
Therefore, results from previous trials support the rationale on the safety and potential 
efficacy of an infusion of the selected maximum dose of 100 x106 allo-hMSCs.
B.6
Administration Rate
Prior clinical trials have used rates up to 30×106 hMSC/min where no infusion related 
toxicity was observed. 
In the proposed study addendum, the cell dose to be delivered is 1 x 108 (100 million), in 
the following total volume
- 40ml for 100 million dose (5 million hMSC/min)
Cells are placed in an 80ml bag and will be delivered at a rate of 2ml/min, and delivered 
at a maximum rate of 16×106 hMSC/minute and will last approximately:
40 minutes for delivery of 40ml of 100 million dose in an 80ml bag.
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B.7
Data and Safety Monitoring Board (DSMB)
DSMB will continue to provide the same oversight as noted in Section 9.4 of the Main 
protocol.
B.8
Concomitant Treatments, Procedures, and Nondrug Therapies
Refer to section 4.3 of the main study protocol
B.9
Infusion Monitoring Guidelines
Refer to section 6.4.1 and Appendix 1 of the main protocol.
B.10
Adverse Events and Serious Adverse Events
Refer to section 8.9 through 8.15 of the main study protocol.
B.11
Stopping Guidelines
Refer to section 8.2.4 of the main study protocol for further stopping guidelines.
B.12
Payments to Subjects and Donors in the Follow-on Phase
Subjects will be reimbursed $25 at the end of each follow-up visit (Month 1 – Month 6) 
for a total remuneration of $75.  These disbursements are meant to cover the time 
required to complete these study visits and all necessary travel and parking expenses. 
Normal donors for generation of allo-MSC will be reimbursed $500 at the end of BM 
aspiration. This payment will compensate donors for lost time, parking, and travel 
expenses.
B.13
Study Procedures for Penicillin/Streptomycin Free hMSCs Infusion
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Table B1: Time and Events Table for Penicillin/Streptomycin Free Dose Schedule
Visit Schedule 
Screening
- 45 days
From 
baseline
Baseline
(0 to -4 
weeks)
Day 
1
Month 1
(Day 30)
(+/- 2 
weeks)
Month 3 
(Day 90)
(+/- 30 days)
Month 6 
(Day 180)
(+/-30 days)
Month 12 
(Day 365) 
(+/-2 weeks) 
*Phone Call 
Follow-up 12
Informed Consent
x
Full Medical History 
x
Physical Exam
x
x
x
x
x
x
12-lead (ECG)
x
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
x
Mini Mental State Examination (MMSE)
x
x
Infusion Treatment (IP)
x
Dobutamine Stress Echo Test (DSE)11
x
x
Bone Density Scan (DEXA)8
x
x
FEV-1
x
x
6 Minute Walk Test
x
x
4 Meter Gait Speed Test7
x
x
SPPB Assessment
x
x
Dynamometer (handgrip)
x
x
Smell Identification Test (UPSIT)
x
x
IIEF, SQOL-F Questionnaires
x
x
x
x
QOL Questionnaires (ICECAP, EQ-5D, SF-36,CHAMPS, MFI)
x
x
x
x
Urinalysis
x
x
x
x
Hemat., Chem., CBC, LFTs, INR,   and other labs1
x
x
x
x
x
HIV 1, HIV 2, Hep. B & C, and CMV10
x
Serum or Urine Pregnancy Test2
x
x
Review Adverse Events
x
x
x
x
x
Immune Monitoring4
x
x
x
x
Biomarker Assessment3
x
x
Optional: Brachial Ultrasound 5
x
x
Optional: Endothelial blood samples6
x
x

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Time and Events Table Key:
1 – The minimal laboratory requirements for hematological, liver function and renal 
function include:
Hematology Tests: white blood cell count, platelet count, hemoglobin and 
hematocrit, red blood cell count, CBC with Differential: neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils.
Liver Function Tests: Albumin, alkaline phosphatase, alanine transaminase, 
asparate aminotransferase, prothrombin time / activated partial thromboplastin
time, and bilirubin(fractionate if total >1.5 times normal). 
Renal Function Tests: creatinine, creatinine clearance, blood urea nitrogen 
(BUN), glomerular filtration rate, sodium, potassium, chloride, calcium, carbon 
dioxide, total protein, glomerular filtration rate (GFR), and glucose, (HbA1c) will 
be collected at every follow-up visit only for subjects diagnosed with diabetes 
mellitus (DM).  
Serum Uric Acid, Pro-BNP, and high sensitivity C-reactive protein (hs-CRP), 
IL6, fibrinogen, D-Dimer, DNA**, TNFα, testosterone (males only), estrogen 
(females only), and FSH***.
- Laboratory work may be completed at a diagnostic center or home health 
agency should the subject be unable to come to the site.
** Deoxyribonucleic acid (DNA) will only be collected once during the subject’s 
participation. There is no specific point DNA needs to be collected as it can 
occur at any time point.
***FSH will need to be collected at screening to verify that female subjects have 
an FSH > 25.8 mIU/mL, if not currently on hormone replacement therapy for 
inclusion in the trial.
2 – A serum or urine pregnancy test will be completed within 36 hours prior to infusion  
for females of childbearing potential.
3 – The following biomarkers will be analyzed: 

Cell-surface markers: CD19, CD27, IgD, and CD5 (for Switched Memory, 
Naïve, Late/Exhausted, IgM memory B cells and regulatory B cells); CD19 
and intracellular TNF-α (to assess intracellular TNF-α); CD3, CD4, CD8, 
CCR7 and CD45RA (for Central Memory, Naïve, Effector Memory, TEMRA 
T cells and CD4 to CD8 ratio); CD3, CD25 and FOXP3 (to assess regulatory 
T cells)

Transcriptomic/Proteome: 
RNA, 
miRNA, 
protein 
samples, 
and 
telomerase, akt

Growth factors: Sdf-1, notch, 
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
Functional Assays: cell growth rate, VEGF, and CFU assay
4 – Immune monitoring for graft rejection. Calculated panel reactive antibodies (cPRA) 
will be performed from the serum of the subjects on day 1 and 6 months post infusion to 
check for donor specific antibodies. In addition, the following markers will be used for 
analysis to assess for activated T-cells based upon a CD3+CD25+ (late/chronic T cell 
activation) or CD3+CD69+ phenotype (early T cell activation).
5 – Optional brachial ultrasound to assess endothelial function. 
6 – Optional: An additional five (5) lavender top tubes (EDTA) will be drawn of 
approximately 8ml per tube.
7 – 4 meter gait speed test will be performed twice per visit and the average of the 
exams will be taken.
8 – DEXA scan will be performed twice at each visit. The first scan will be of the hip and 
spine for bone density and the second will be to assess the total body composition.
9 – Dynamometer will be performed at least three (3) times during each applicable visit 
for each hand. The three values collected will be averaged for each hand. (Please 
reference the instruction manual on how to administer).
10– Infectious disease tests – HIV, HIV 2, Hep B (HBsAG, Anti-HBs, Anti-HBc), and 
Hep C (Anti-HCV), VDRL, Syphilis, West Nile Virus, and CMV. (Conducted within 30 
days of infusion, if test expire prior infusion, they must be performed again)
11– Guidelines for completing the (DSE) are outlined in Appendix 2 of this protocol.
12–Month 12 follow-up phone call may be waived if the subject has a screening visit for 
an additional infusion prior to this visit.
B.14
Study Visits
B.14.1 
Screening Visit 
See Table B1 for the procedures and assessments to be performed during the 
screening visit. Screening visit test and procedures will occur upon signing the informed 
consent form (ICF). No screening exams will take place until the subject is fully informed 
of the research and signs the consent form. The tests may take place over several days 
and will need to be completed prior to the start of the baseline visit. There will be up to a 
45 day window from the time the subject signs the informed consent form to the 
baseline visit to complete screening procedures. There will be up to a +/-2 week window 
from the subjects Month 12 phone call from the subject’s previous infusion to begin 
screening procedures. Month 12 follow-up phone call may be waived if the subject has 
a screening visit for an additional infusion prior to this visit.
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If a dobutamine stress echo was performed within 6 months, the report may be used in 
place of screening DSE for additional infusions.
B.14.2
Baseline Visit 
See Table B1 for the procedures and assessment to be performed during the baseline 
visit of the study. Once all screening exams are completed and it has been determined 
that the subject remains eligible for the study, subjects will be enrolled into the study. 
The baseline visit will take place within four weeks from treatment. The listed 
procedures should all be performed as soon as practicable. If DEXA was performed 
within 6 months, the report may be used in place of baseline DEXA for additional 
infusions.
Endothelial function (Optional Assessments) will occur upon the subject signing the 
optional section of the informed consent form (ICF). No endothelial function tests will take 
place until the subject is fully informed of the research and signs the optional portion of 
the consent form.

Brachial ultrasound testing and blood collection will be performed to assess 
endothelial function in the aging frailty population at baseline and 3 months 
post stem cell infusion. This will help provide cumulative data in assessing 
whether or not stem cell infusion improves endothelial function.  

Flow Mediated Diameter percent change (FMD%):  All measurements of the 
brachial artery diameter and FMD will be performed in the morning, in a quiet 
and dark room and at controlled ambient temperatures between 20°C and 
26°C. Studies will be conducted after an overnight fast of at least 10 hours 
(water is permitted), with the subjects supine and after 10 minutes of rest. The 
subject's right arm will be comfortably immobilized in an extending position, 
allowing for ultrasound scanning of the brachial artery 5–10 cm above the 
antecubital fossa. In each examination, recording of vessel images will be 
followed by inflation of a cuff to supra-systolic pressure (40 to 50 mmHg 
above systolic pressure) for 5 minutes. Then the cuff will be deflated and the 
brachial artery diameter will be imaged and recorded for 3 minutes. FMD% 
more than 10% is considered a normal response. Lower than 10% FMD% 
reflects endothelial dysfunction, which means a high likelihood to develop 
cardiovascular event in the future. Subjects with negative FMD% results (the 
artery is constricted after stress and not dilated as was expected) have the 
worst prognosis.
Blood drawn from fasting subjects will be separated and the serum will be 
frozen until processed as one batch towards the end of the study. Blood will 
be processed twice – in the beginning of the study and after 3 months.

Biochemical analysis: soluble pro inflammatory cytokines (interleukin-1, 
interleukin-6, interleukin-10, VEGFR2, TNF-a).
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
Assay of colony forming units: Fresh blood will be processed for cell culture 
assays for endothelial progenitor stem cells colonies counting (a 5 days’ 
protocol). Fifty milliliter of blood will be processed; peripheral-blood 
mononuclear cells will be isolated by Ficoll density-gradient centrifugation, will 
be washed twice in phosphate buffered saline with 5% fetal bovine serum and 
re-suspended in media (EndoCult basal media with supplements; StemCell 
Technologies, Vancouver, British Columbia, Canada) for EPC colony-forming 
assay. Cells will be  planted on human fibronectin-coated plates (BIOCOAT; 
Becton Dickenson Labware, Bedford, Massachusetts) at a density of 5X106 
cells/well and incubated at 370C in humidified 5% CO2. After 48 hours, the 
non-adherent cells will be re-plated onto fibronectin-coated 24 well plates at a 
density of 1X106 cells/well. After 5 days, colony forming units (defined as a 
central core of rounded cells surrounded by elongated and spindle-shaped 
cells) will be counted manually in 8 wells out of a 24-well plate. 
B.14.3
Day 1 Visit 
See Table B1 for the procedures and assessment to be performed during the Day 1 visit 
of the study. The Day 1 visit will occur after all baseline tests are completed and it has 
been determined that the subject remains eligible. Once the subject is deemed eligible 
to continue in the study the subject will be administered the investigational product. The 
subject will be monitored for 2 – 3 hours, following administration of the investigational 
product, and will be sent home the same day.
B.14.4
Month 1 Visit 
See Table B1 for the procedures and assessment to be performed for the Month 1 visit 
of the study. Subject visits should be completed as close to the scheduled visit dates as 
possible. There will be a +/- window of 2 weeks for the month 1 study visit.
B.14.5
Month 3 and Month 6 Visit 
See Table B1 for the procedures and assessment to be performed for month 3 and 6 
visit of the study. Subject visit should be completed as close to the scheduled visit dates 
as possible. There will be a +/- window of 30 days for the month 3 and 6 study visit.
B.14.6
Month 12 Visit
See Table B1 for the procedures and assessments to be performed for Month 12 visit. 
This visit will be conducted via a phone interview with the subject. A phone script will be 
provided to the study personnel to use when interviewing the subject. There will be a +/- 
window of 2 weeks for this visit.
The Month 12 visit will be waived if screening visits for subsequent infusions take place 
prior to this visit.
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B.15
Statistical Considerations
All subjects will be offered the penicillin/streptomycin free hMSCs and formal statistical 
considerations regarding sample size and power are not provided.  Based on prior 
studies, stem cells are safe but strict safety monitoring will be employed to continue the 
safety assessment of penicillin/streptomycin free allogeneic infusion of MSCs.  No 
detailed analyses will be described in the statistical analysis plan.  
B.16
Safety Monitoring of 30-Day Rate of TE-SAEs
Monitoring of the rate of TE-SAEs by 30-days post infusion among subjects who received 
the infusion of penicillin/streptomycin free allogeneic MSCs will be employed to assist the 
DSMB in prospective monitoring of this study.  The guideline is to be used to indicate 
boundaries requiring discussion by the DSMB and is designed to assist the independent 
DSMB in overseeing the study. The DSMB may also request additional interim analyses 
and develop other criteria including provision for monitoring of potential late effects to 
determine when to intervene in the enrollment or treatment of subjects in the study. 
Monitoring of key safety endpoints will be conducted. If rates significantly exceed the pre-
set threshold, then the DSMB will be notified.  
A Bayesian motivated safety stopping guideline for monitoring the 30-day TE-SAE rate 
will be used for this trial.  The expected underlying rate of TE-SAE at 30 days post- 
infusion is assumed to be 10% based on the assumption that 2 out of 20 subjects 
experience a TE-SAE.  It would then be assumed that a rate of greater than 40.0% is 
unacceptable. 
A Beta distribution can be used as the prior distribution of ; where  is the proportion of 
subjects who experience an TE-SAE by 30-days post infusion.  The stopping rule is based 
on the beta-binomial methodology and assumes a prior expected failure rate.  This leads 
to prior Beta parameters where a=0.8 and b=5.2.  The Beta distribution will have a prior 
mean of 0.13 and a prior probability of <0.05 of exceeding 0.40.  The guideline is derived 
such that there is strong evidence (posterior probability >0.95) that the probability of the 
event is greater than 40%, the trial will be stopped. The resulting boundaries tabulated in 
table B2 were rounded to be conservative with the stopping guideline and is considered 
after 5 subjects are enrolled on the study.
TABLE B2
Bayesian Stopping Guideline for Event Rate of 10% *
# Events
#  Subjects in Study
3
5
4
6-9
5
10-14
6
15
* 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.
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A simulation study was conducted to evaluate the operating characteristics of this 
stopping rule.  Data were generated from the binomial distribution with varying 
probabilities of failure () and assuming a sample size of 15 subjects.  Table B3 shows 
the probability of stopping the trial early and the average sample size (N), conditional on 
stopping early, at which the boundary is crossed for each value of .  The unconditional 
average sample size of the trials for each value of  is displayed. 
Table B3
Operating Characteristics for Bayesian Motivated Stopping Guideline
Mean 
of 
Prior 
Distribution

Probability 
of stopping
Conditional 
Average 
Sample Size (N)
Unconditional 
Average Sample 
Size of Trials (N)
0.13
0.13
0.05
8.4
14.7
0.18
0.12
8.8
14.2
0.23
0.25
8.9
13.5
0.28
0.40
8.8
12.5
0.33
0.56
8.5
11.4
0.40
0.75
8.0
9.8
Although the motivation for the boundary is Bayesian, the operating characteristics can 
be evaluated from a frequentist perspective of Type I error and power.  The stopping rule 
for a 13% event rate has a 5% chance (“Type I error”) of suggesting early termination 
when the true rate is 0.13, and a 75% chance (“power”) when the true rate is 0.40. 
Limitations
A major limitation to this approach is the small sample size.  However, the penicillin 
streptomycin free infusion strategy is being implemented to obtain information on the 
safety of a penicillin/streptomycin free allogeneic MSCs to help guide future studies.  
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Addendum C: Pilot and Penicillin/Streptomycin Free Subjects Optional 
Follow-on Phase
C.1 
Rationale and Description of additional infusions for subjects who have 
received one or two infusions in the phase I open-label phases of this protocol.
This addendum protocol is designed to test the safety of sequential infusions of 
allogeneic mesenchymal stem cells 6 to 18 months following previous infusion.   
Subjects in this protocol have previously participated in protocols receiving open label 
infusions (phase I subjects).  There is an important need to assess the safety and 
immunologic tolerability of additional doses of intravenous allogeneic MSCs in the target 
population.  Previously a group of 12 subjects received two doses delivered 12-18 
month apart with excellent safety and no adverse effects attributed to the study agent.  
A second group of 20 subjects received a single dose of MSCs, in the 
penicillin/streptomycin free cohort.  Subjects receiving either one or two sequential 
doses have not mounted significant immunologic reactions to the study agent. 
Subjects in the pilot phase would have received two (2) of the possible four (4) infusions 
of allogeneic MSCs and are eligible to participate in this optional follow-on phase.  
Additionally, subjects receiving one dose (100 Million cells) in the penicillin/streptomycin 
free protocol are eligible to receive up to three (3) additional infusions. Because several 
studies, reviewed below, have now shown safety of repeat doses of MSCs in a variety 
of medical conditions, additional safety testing in the subject population of aging frailty 
enrolled in the CRATUS trial is required92. All study specific processes and procedures 
included in the pilot phase and penicillin free follow-on phase of the protocol apply in 
this addendum unless otherwise noted.
Pilot subjects participating in this addendum are eligible to receive up to two (2) 
additional infusions and subjects participating from Penicillin Free cohort are eligible to 
receive up to three additional infusions of MSCs (100 Million cells) administered 6 -18 
months apart.  The MSCs provided to study subjects in this addendum may be 
penicillin/streptomycin free. Subjects from the Pilot phase returning for their additional 
infusions may receive cells with penicillin/streptomycin. Altogether, subjects will have 
received four (4) infusions over a time span ranging approximately 3 to 6 years.  
Subjects will have ongoing safety monitoring that will include detailed immunologic 
assessments.
Subjects that do not want an additional infusion will not be eligible to continue in the 
study and/or receive additional infusions under this addendum. 
C.2 
Demonstrated Safety and Increased Efficacy of Multiple Infusions of 
Allogeneic Mesenchymal Stem Cells
Active clinical trials and ongoing preclinical work provide an accumulating data set 
supporting the safety and, in some cases, therapeutic efficacy of allogeneic 
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mesenchymal stem cells (MSCs).  Allogeneic mesenchymal stem cells are both 
immunoprivileged and immunosuppressive, thereby enabling their use as an allograft93.  
Cellular therapy with allogeneic MSCs has abundant support from both animal studies 
and human clinical trials for a wide range of disorders (Table 1).  For example, the 
POSEIDON study addressed the major issue of the use of allogeneic MSCs as a cell-
based therapeutic18.  In this study, subjects with cardiac failure were randomized to 
receive either autologous MSCs or identically prepared allogeneic MSCs from healthy 
donors.
Accumulating evidence also supports the concept that repeated doses and/or co-
administration of allogeneic MSCs could further enhance therapeutic outcomes. This is 
an extremely important area for medical investigation, since repeat dosing could 
potentially have an additive effect and/or reverse disease pathology, depending on the 
disorder.
Recently, several clinical studies have demonstrated that multiple infusions of 
allogeneic MSCs are well tolerated with minimal side-effects.  Importantly, repeat dosing 
has no increased level of side effects compared with single doses.  For example, results 
from Franco Locatelli’s group92 clearly demonstrate the safety and efficacy of multiple 
allogeneic MSC infusions in children with steroid-refractory acute graft versus host 
disease (aGvHD).  Doses in these studies were 1-2x106 MSCs/kg recipient body mass, 
and each child received on average 2 doses (range was 1-13 doses) separated on 
average by 15 days (range 3-43 days).  The results of this study indicated increased 
effectiveness when the therapy was commenced early in the disease.  Furthermore, the 
study indicated the therapeutic benefits of repeat doses to subjects who did not achieve 
complete remission after a single dose. 
Koc et al94; further investigated Hurler syndrome (mucopolysaccharidosis type-IH) and 
metachromatic leukodystrophy (MLD) and studied allogeneic MSCs based on their 
potential to differentiate into cells of bone, cartilage, tendon, muscle and other 
adventitial tissues and offer potential for corrective cellular therapy95. Their results 
demonstrated no infusion-related toxicity, improvement in nerve conduction, and bone 
mineral density was either maintained or improved in all subjects.
A Phase II study on the 3-year efficacy of allogeneic MSCs in the treatment of system 
lupus erythrematosus (SLE) was reported by Lingyun Sun’s group96.  The results of this 
study demonstrated the therapeutic efficacy of allogeneic MSCs in treating SLE.  
However, no advantage was found by administering a second or higher dose of 
allogeneic MSCs.  Despite this lack of additional efficacy over a single dose, the results 
of this study confirmed the safety of multiple infusions of allogeneic MSCs.  The doses 
(1x106 MSCs/kg body mass) were administered 1 week apart.   Another study reported 
on the use of repeated dosing of allogeneic MSCs in subjects with chronic obstructive 
pulmonary disease.  The study showed minimal therapeutic efficacy after 2 years19.  
Importantly, in this subject population repeated allogeneic MSC infusions, which were 
given 4 times at 30 day intervals (1x108 MSCs/infusion) were safe.
In the pilot phase of this trial, subjects (N=12) have been administered two doses of 
MSCs 12 to 18 months apart with no adverse effects.  
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Taken together, these various clinical studies provide a solid rationale for repeat 
allogeneic MSC infusions.  In no case did the administration of multiple doses lead to a 
significant increase in the frequency of adverse effects, or to a decrease in therapeutic 
efficacy over a single dose.  In many cases, repeated infusions indeed improved clinical 
outcomes, demonstrating an additive effect of allogeneic MSC therapy.  Given these 
promising results, investigations are now warranted to determine optimal dosing 
frequency and total doses of allogeneic MSCs to administer.  
It is particularly important to establish safety of repeat doses of allogeneic MSCs in the 
subject population enrolled in the CRATUS study.  These individuals are of older age 
and are not represented in the previous studies described.   In this follow-on study 
subject s in earlier open label pilot study and penicillin/streptomycin free phase will be 
asked to participate in this repeat infusion protocol.  Subjects in the pilot-phase or 
penicillin/streptomycin free phase, which received either one or two infusions previously 
will be eligible, and all subjects will get a total of four infusions.  Each infusion will be 6 
to 18 months apart.
C.3 
STUDY OBJECTIVES AND ENDPOINTS
C.3.1 
Study Objectives
C.3.1.1
Primary Objective
1. Demonstrate the safety and tolerability of up to four intravenous 
infusions of allo-hMSCs in subjects with aging frailty who had 
previously received an infusion of allogeneic MSCs as part of an 
open label phase (phase I) of the protocol or the 
Penicillin/streptomycin free addendum (Addendum B).
2. To determine immunologic safety of sequential infusions of allo-
hMSCs in subjects with aging frailty.
C.3.1.2
Secondary Objectives
1. To explore treatment efficacy (decrease in frailty, frequency of 
acute exacerbations, change in symptom related quality of life, 
improved cardiovascular status, decrease in inflammatory 
biomarkers, endothelial function and 1 year survival).
C.3.2
Study Endpoints
C.3.2.1
Primary Endpoints (Safety)
1. Safety (Primary): Incidence (at one month post each additional 
infusion) of any treatment-emergent serious adverse events (TE-
SAEs), defined as the composite of: death, non-fatal pulmonary 
embolism, stroke, hospitalization for worsening dyspnea and 
clinically significant laboratory test abnormalities, determined per 
the Investigator’s judgment.
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Laboratory tests included in the primary endpoint include the 
following:

Serum chemistry: chloride, sodium, Carbon Dioxide, BUN, 
creatinine, glucose, calcium, AST/SGOT, ALT/SGPT, total 
bilirubin (fractionate if total >1.5 times normal), alkaline 
phosphatase, albumin, 

Hematology (CBC): hemoglobin, hematocrit, platelets, WBC, 
WBC differential
C.3.2.2
Secondary Endpoints (Efficacy)
The following efficacy endpoints will be evaluated in this trial (During the 
screening, baseline, Month 3 and/or Month 6 visits):
1. Difference in rate of decline of Frailty defined as:

Reduced Activity (assessed via CHAMPS questionnaire)

Slowing of Mobility (assessed via a 4 meter gait speed test 
and SPPB assessment)

Weight Loss

Diminished handgrip strength (assessed via dynamometer)

Exhaustion (assessed via the MFI questionnaire)

Decrease in subject quality of life assessment(s) (assessed 
via ICECAP, SF-36, EQ-5D Questionnaires)
2. Death from any cause.
3. Change between screening and 6 months in dobutamine stress 
echo induced ejection fraction.
4. Change between screening and 6 months for the following panel of  
inflammatory markers:  CRP, IL-6, D-dimer, fibrinogen,
CBC with differential, and TNFα
5. The incidence of each component of the primary endpoint including 
non-fatal pulmonary embolism, stroke, hospitalization for worsening 
dyspnea and clinically significant laboratory test abnormalities
6. Change in Smell Identification Test (UPSIT)
C.4
Inclusion and Exclusion Criteria
C.4.1
Inclusion Criteria for Follow-on Phase
In order to participate in this study, a subject MUST:
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1.
Provide written informed consent.
2.
Subjects age >60 and <95 years at the time of signing the Informed 
Consent Form for this follow-on phase.
3.
Have previously participated in the pilot phase of the trial, or have 
previously participated in the penicillin free (open label) phase of the trial.
4.
Female subjects must have an FSH > 25.8 mIU/mL, if not currently on 
hormone replacement therapy.
C.4.2
Exclusion Criteria for Follow-on Phase
In order to participate in this study, a subject MUST NOT have any of the following:
1.
Score of <24 on the Mini Mental State Examination (MMSE)
2.
Inability to perform any of the assessments required for endpoint analysis 
(report safety or tolerability concerns, perform PFTs, undergo blood 
draws, read and respond to questionnaires.
3.
Active listing (or expected future listing) for transplant of any organ.
4.
Clinically important abnormal screening laboratory values, including but 
not limited to: hemoglobin <8 g/dl, white blood cell count <3000/mm3, 
platelets<80,000/mm3, INR > 1.5 not due to a reversible cause (i.e. 
Coumadin), aspartate transaminase, alanine transaminase, or alkaline 
phosphatase > 3 times upper limit of normal, total bilirubin > 1.5 mg/dl.
5.
Serious comorbid illness that, in the opinion of the investigator, may 
compromise the safety or compliance of the subject or preclude  
successful completion of the study.  Including, but not limited to: HIV, 
advanced liver or renal failure, class III/IV congestive heart failure, 
myocardial infarction, unstable angina, or cardiac revascularization within 
the last six months, or severe obstructive ventilatory defect.
6.
Any other condition that, in the opinion of the investigator, may 
compromise the safety or compliance of the subject or preclude successful 
completion of the study. 
7.
Be an organ transplant recipient.
8.
Have a clinical history of malignancy within 3 years (i.e., subjects with prior 
malignancy must be disease free for 3 years), except curatively-treated 
basal cell carcinoma, squamous cell carcinoma, melanoma in situ or 
cervical carcinoma if recurrence occurs.
9.
Have a non-pulmonary condition that limits lifespan to < 1 year. 
10.
Have a history of drug or alcohol abuse within the past 24 months. 
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11.
Be serum positive for HIV, hepatitis BsAg or Viremic hepatitis C.
12.
Be currently participating (or participated within the previous 30 days) in 
an investigational therapeutic or device trial. This does not exclude 
subjects that participated in addendum A or B.  
13.
Be a female who is pregnant, nursing, or of childbearing potential while 
not practicing effective contraceptive methods. Female subjects must 
undergo a blood or urine pregnancy test at screening and within 36 hours 
prior to infusion.
14.
Have hypersensitivity to dimethyl sulfoxide (DMSO)
C.5
Dosing
Subjects participating in this protocol will have received either one or two infusions of 
study agent. All subjects who have received their first two infusions, will then have the 
option of receiving an additional infusion of allogeneic hMSCs: 1 x 108 (100 million) cells 
delivered via peripheral intravenous infusion. Subjects will be eligible to receive a total 
of four (n=4) infusions, 6 to 18 months apart. 
The Allo-hMSCs will be derived from donors meeting criteria for allogeneic unrelated 
human bone marrow stem cell source manufactured by the University of Miami or from 
a commercial clinical grade bone marrow source. Subjects from the Pilot phase 
returning for their additional infusions may receive cells with penicillin/streptomycin.
C.6
Dosage Rationale
A safety profile for IV infusion of hMSCs was based on results from previous completed 
toxicology results(Hare et al. 2277-86). The results from previous studies demonstrate that the 
product can be administered intravenously without toxic events at up to 65 x 
106hMSC/kg dose delivered in one bolus infusion or at 100 x 106hMSC/kg cumulative 
dose delivered by 5 infusions (20 x 106hMSC/kg per infusion).
The evidence supports the conclusion that it is feasible to dose subjects in this study 
based on a standard dose of hMSCs rather than per kilogram of body weight. The total 
cell number corresponds to a range of 1.3 - 4.4 x 106 hMSCs per kg per infusion for 
subjects with 45 to 150kg body weight, the weight range for this study.
Therefore, results from previous trials support the rationale on the safety and potential 
efficacy of a second infusion of the selected maximum dose of 100 x106 allo-hMSCs.
C.7
Administration Rate
Prior clinical trials have used rates up to 30×106 hMSC/min where no infusion related 
toxicity was observed. 
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In the proposed study addendum, the cell dose to be delivered is 1 x 108 (100 million), in 
the following total volume
-   40ml for 100 million dose (5 million hMSC/min)
Cell s are placed in an 80ml bag and will be delivered at a rate of 2ml/min, and delivered 
at a maximum rate of 16×106 hMSC/minute and will last approximately:

40 minutes for delivery of 40ml of 100 million dose in an 80 ml bag
C.8
Data and Safety Monitoring Board (DSMB)
DSMB will continue to provide the same oversight as noted in Section 9.4 of the Main 
protocol.
C.9
Concomitant Treatments, Procedures, and Nondrug Therapies
Refer to section 4.3 of the main study protocol
C.10
Infusion Monitoring Guidelines
Refer to section 6.4.1 and Appendix 1 of the main protocol.
C.11
Adverse Events and Serious Adverse Events
Refer to section 8.9 through 8.15 of the main study protocol.
C.12
Stopping Guidelines
Refer to section 8.2.4 of the main study protocol for further stopping guidelines.
C.13
Payments to Subjects and Donors
Subjects will be reimbursed $25 at the end of each follow-up visit (Month 1 – Month 6 
for a total remuneration of $75.  These disbursements are meant to cover the time 
required to complete these study visits and all necessary travel and parking expenses. 
Normal donors for generation of allo-MSC will be reimbursed $500 at the end of BM 
aspiration. This payment will compensate donors for lost time, parking, and travel 
expenses.
C.14
Study Procedures for Optional Additional Infusions for Pilot and 
Penicillin/Streptomycin Free Subjects (See Table C1)
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Table C1: Time and Events Table for Optional Pilot Phase and PCN/Streptomycin Free Additional Infusion(s) Schedule
Visit Schedule for Additional Infusions (repeating for up 
to 4 doses every 6 -18 months)
Screening
- 45 days 
from 
baseline
Baseline
(-4 weeks)
Day 
1
Month 1
(Day 30)
(+/- 2 
weeks)
Month 3 
(Day 90)
(+/- 30 days)
Month 6 
(Day 180)
(+/-30 days)
Month 12 
(Day 365) 
(+/- 2 
weeks) 
*Phone Call 
Follow-up11
Informed Consent
x
Full Medical History 
x
Physical Exam
x
x
x
x
x
x
12-lead (ECG)
x
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
x
Mini Mental State Examination (MMSE)
x
x
Infusion Treatment (IP)
x
Dobutamine Stress Echo Test (DSE)12
x
x
Bone Density Scan (DEXA)8
x
x
FEV-1
x
x
6 Minute Walk Test
x
x
4 Meter Gait Speed Test7
x
x
SPPB Assessment
x
x
Dynamometer (handgrip)9
x
x
Smell Identification Test (UPSIT)
x
x
IIEF, SQOL-F Questionnaires
x
x
x
x
QOL Questionnaires (ICECAP, EQ-5D, SF-36,CHAMPS, MFI)
x
x
x
x
Urinalysis
x
x
x
x
Hemat., Chem., CBC, LFTs, INR,   and other labs1
x
x
x
x
x
HIV 1, HIV 2, Hep. B & C, and CMV
x
Serum or Urine Pregnancy Test2
x
x
Review Adverse Events
x
x
x
x
x
Immune Monitoring4
x
x
x
x
Biomarker Assessment3
x
x
Optional: Brachial Ultrasound 5
x
x
Optional: Endothelial blood samples6
x
x

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Time and Events Table Key:
1 - The minimal laboratory requirements for hematological, liver function and renal 
function include:
Hematology Tests: white blood cell count, platelet count, hemoglobin and 
Hematocrit, red blood cell count, CBC with Differential: neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils.
Liver Function Tests: Albumin, alkaline phosphatase, alanine transaminase, 
asparate aminotransferase, prothrombin time / activated partial thromboplastin 
time, and bilirubin (fractionate if total >1.5 times normal). 
Renal Function Tests: creatinine, creatinine clearance, blood urea nitrogen 
(BUN), glomerular filtration rate, sodium, potassium, chloride, calcium, carbon 
dioxide, total protein, glomerular filtration rate (GFR) and glucose, (HbA1c) will 
be collected at every follow-up visit only for subjects diagnosed with diabetes 
mellitus (DM).
Serum Uric Acid, Pro-BNP, and high sensitivity C-reactive protein (hs-CRP), 
IL6, fibrinogen, D-Dimer, TNFα, DNA**, testosterone (males only), estrogen 
(females only) and FSH***.
- Laboratory work may be completed at a diagnostic center or home health 
agency should the subject be unable to come to the site.
** Deoxyribonucleic acid (DNA) will only be collected once during the subject’s 
participation. There is no specific point DNA needs to be collected as it can 
occur at any time point.
***FSH will need to be collected at screening to verify that female subjects have 
an FSH > 25.8 mIU/mL, if not currently on hormone replacement therapy for 
inclusion in the trial.
2 - A serum or urine pregnancy test will be completed within 36 hours prior to infusion  
for females of childbearing potential.
3 - The following biomarkers will be analyzed (Approximately 10mL blood samples will be 
collected): 

Cell-surface markers: CD19, CD27, IgD, and CD5 (for Switched Memory, 
Naïve, Late/Exhausted, IgM memory B cells and regulatory B cells); CD19 and 
intracellular TNF-α (to assess intracellular TNF-α); CD3, CD4, CD8, CCR7 and 
CD45RA (for Central Memory, Naïve, Effector Memory, TEMRA T cells and CD4 
to CD8 ratio); CD3, CD25 and FOXP3 (to assess regulatory T cells)

Transcriptomic/Proteome: RNA, miRNA, protein samples, and telomerase, 
akt
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
Growth factors: Sdf-1, notch, 

Functional Assays: cell growth rate, VEGF, and CFU assay
4 -    Immune monitoring for graft rejection.  Calculated panel reactive antibodies 
(cPRA) will be performed at day 1, Month 1, 3 and 6 months post infusion to check for 
donor specific antibodies. In addition, the following markers will be used to assess for 
activated T-cells based upon a CD3+CD25+ (late/chronic T cell activation) or 
CD3+CD69+ phenotype(early T cell activation).
5 - Optional brachial ultrasound to assess endothelial function. 
6 - Optional: An additional five (5) lavender top tubes (EDTA) will be drawn of 
approximately 8ml per tube.
7 – 4 meter gait speed test will be performed twice per visit and the average of the 
exams will be taken.
8 – DEXA scan will be performed at baseline and Month 6. The scans of the hip and 
spine for bone density, and total body composition will be assessed at both visits.
9 – Dynamometer will be performed at least three (3) times during each applicable visit 
for each hand. The three values collected will be averaged for each hand. (Please 
reference the instruction manual on how to administer.)
10– Infectious disease tests – HIV, HIV 2, Hep B (HBsAG, Anti-HBs, Anti-HBc), and 
Hep C (Anti-HCV), VDRL, Syphilis, West Nile Virus, and CMV. (Conducted within 30 
days of infusion, if test expire prior infusion, they must be performed again)
11–Month 12 follow-up phone call may be waived if the subject has a screening visit for 
an additional infusion prior to this visit. 
12 - Guidelines for completing the (DSE) are outlined in Appendix 2 of this protocol. 
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C.15
Study Visits
C.15.1 
Screening Visit for additional infusion 
See Table C1 for the procedures and assessments to be performed during the 
screening visit of the study for the subjects that consent to participate in the additional 
infusions. Once the subject signs the informed consent form (ICF), the subject will then 
have a 45-day window from the time the subject signs the ICF to the start of the 
baseline visit to complete all screening procedures. The tests may take place over 
several days to complete. No screening exams will take place until the subject is fully 
informed of the research and signs the consent form. 
There will be up to a +/-2 week window from the subjects Month 12 phone call from the 
subject’s previous infusion to begin screening procedures, at which point the month 12 
phone call visit from the original infusion will be waived, if screening visits for 
subsequent infusions take placed prior to this visit.
If a dobutamine stress echo was performed within 6 months, that report can be used in 
place of screening DSE for additional infusions
C.15.2
Baseline Visit for additional infusion 
See Table C1 for the procedures and assessment to be performed during the baseline 
visit of the study. Once all screening exams are completed and it has been determined 
that the subject remains eligible for the study, subjects will be enrolled into the study. 
The baseline visit will take place within four weeks of the infusion. The listed procedures 
should all be performed as soon as practicable. If DEXA was performed within 6 
months, that report can be used in place of baseline DEXA for additional infusions.
Endothelial function (Optional Assessments) will occur upon the subject signing the 
optional section of the informed consent form (ICF). No endothelial function tests will take 
place until the subject is fully informed of the research and signs the optional portion of 
the consent form.

Brachial ultrasound testing and blood collection will be performed to assess 
endothelial function in the aging frailty population at baseline and 3 months 
post stem cell infusion. This will help provide cumulative data in assessing 
whether or not stem cell infusion improves endothelial function.  

Flow Mediated Diameter percent change (FMD%):  All measurements of the 
brachial artery diameter and FMD will be performed in the morning, in a quiet 
and dark room and at controlled ambient temperatures between 20°C and 
26°C. Studies will be conducted after an overnight fast of at least 10 hours 
(water is permitted), with the subjects supine and after 10 minutes of rest. The 
subject's right arm will be comfortably immobilized in an extending position, 
allowing for ultrasound scanning of the brachial artery 5–10 cm above the 
antecubital fossa. In each examination, recording of vessel images will be 
followed by inflation of a cuff to supra-systolic pressure (40 to 50 mmHg 
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above systolic pressure) for 5 minutes. Then the cuff will be deflated and the 
brachial artery diameter will be imaged and recorded for 3 minutes. FMD% 
more than 10% is considered a normal response. Lower than 10% FMD% 
reflects endothelial dysfunction, which means a high likelihood to develop 
cardiovascular event in the future. Subjects with negative FMD% results (the 
artery is constricted after stress and not dilated as was expected) have the 
worst prognosis.

Blood drawn from fasting subjects will be separated and the serum will be 
frozen until processed as one batch towards the end of the study. Blood will 
be processed twice – in the beginning of the study and after 3 months.

Biochemical analysis: soluble pro inflammatory cytokines (interleukin-1, 
interleukin-6, interleukin-10, VEGFR2, TNF-a).

Assay of colony forming units: Fresh blood will be processed for cell culture 
assays for endothelial progenitor stem cells colonies counting (a 5 days’ 
protocol). Fifty milliliter of blood will be processed; peripheral-blood 
mononuclear cells will be isolated by Ficoll density-gradient centrifugation, will 
be washed twice in phosphate buffered saline with 5% fetal bovine serum and 
re-suspended in media (EndoCult basal media with supplements; StemCell 
Technologies, Vancouver, British Columbia, Canada) for EPC colony-forming 
assay. Cells will be planted on human fibronectin-coated plates (BIOCOAT; 
Becton Dickenson Labware, Bedford, Massachusetts) at a density of 5X106 
cells/well and incubated at 370C in humidified 5% CO2. After 48 hours, the 
non-adherent cells will be re-plated onto fibronectin-coated 24 well plates at a 
density of 1X106 cells/well. After 5 days, colony forming units (defined as a 
central core of rounded cells surrounded by elongated and spindle-shaped 
cells) will be counted manually in 8 wells out of a 24-well plate. 
C.15.3
Day 1 Visit for additional infusion
See Table C1 for the procedures and assessment to be performed during the Day 1 
visit of the study. The Day 1 visit will occur after all baseline tests are completed and it 
has been determined that the subject remains eligible. Once the subject is deemed 
eligible to continue in the study the subject will be administered the investigational 
product. The subject will be monitored for 2-3 hours, following administration of the 
investigational product, and will be sent home the same day.
C.15.4
Month 1 Visit for additional infusion 
See Table C1 for the procedures and assessment to be performed for the Month 1 visit 
of the study. Subject visits should be completed as close to the scheduled visit dates as 
possible. There will be a +/- window of 2 weeks for the month 1 study visit.
C.15.5
Month 3 and Month 6 Visit for additional infusion 
See Table C1 for the procedures and assessment to be performed for month 3 and 6 
visit of the study. Subject visit should be completed as close to the scheduled visit dates 
as possible. There will be a +/- window of 30 days for the month 3 and 6 study visit.
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C.15.6
Month 12 Visit
See Table C1 for the procedures and assessments to be performed for Month 12 visit. 
This visit will be conducted via a phone interview with the subject. A phone script will be 
provided to the study personnel to use when interviewing the subject. There will be a +/- 
window of 2 weeks for this visit. The Month 12 visit will be waived, if screening visits for 
subsequent infusions take place prior to this visit.
C.16
Statistical Considerations
All subjects will be offered the re-infusion and formal statistical considerations regarding 
sample size and power are not provided.  Based on prior studies, additional infusions of 
stem cells are safe but strict safety monitoring will be employed to continue the safety 
assessment of allogeneic infusion of MSCs.  Detailed analyses will be described in the 
separate statistical analysis plan.  
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Addendum D: Placebo Group Optional Follow-on Phase
D.1 Rationale and Description of infusion for 10 subjects randomized to placebo 
group 
This addendum protocol is for subjects that have previously participated in the 
randomized portion of the study and received placebo.  Ten (10) subjects are eligible for 
a single infusion of 100 million allogeneic human mesenchymal stem cells (Reference 
section 3.2).
Subjects from the randomized phase who previously received placebo infusions and are 
participating in this addendum will receive one (1) infusion of 100 Million allogeneic 
hMSCs. The hMSCs provided to study subjects in this addendum may have 
penicillin/streptomycin.  Altogether, subjects in this addendum will have the option to 
receive one infusion of MSCs for a total of two (2) infusions (1 placebo infusion from the 
main phase and one infusion of 100 Million hMSCs) once all eligibility criteria have been 
met. 
Subjects will have ongoing safety monitoring that will include detailed immunologic 
assessments. 
D.2 STUDY OBJECTIVES AND ENDPOINTS:
D 2.1 - Study Objectives
D.2.1.1 Primary Objective: 
-
To demonstrate the safety of intravenous allogeneic hMSCs administered in 
subjects with Frailty and to explore treatment efficacy (decrease in frailty, 
frequency of acute exacerbations, change in symptom related quality of life, 
improved cardiovascular status, decrease in inflammatory biomarkers, 
endothelial function and 1 year survival).
D.2.1.2 Secondary Objective:
- To explore effects of allo-hMSCs on symptom related quality of life, 
cardiovascular performance, endothelial function and inflammation.
D.2.2 Study Endpoints
D.2.2.1 Primary Endpoints (Safety)
•
Safety (Primary): Incidence (at one month post infusion) of any treatment-
emergent serious adverse events (TE-SAEs), defined as the composite of: death, non-
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fatal pulmonary embolism, stroke, hospitalization for worsening dyspnea and clinically 
significant laboratory test abnormalities, determined per the Investigator’s judgment.
-
Serum chemistry: chloride, sodium, Carbon Dioxide, BUN, creatinine, 
glucose, calcium, AST/SGOT, ALT/SGPT, total bilirubin (fractionate if total >1.5 
times normal), alkaline phosphatase, albumin, 
-
Hematology (CBC): hemoglobin, hematocrit, platelets, WBC, WBC 
differential
D.2.2.2 Secondary Endpoints (Efficacy)
The following efficacy endpoints will be evaluated in this trial (During the screening, 
baseline, Month 3 and/or Month 6 visits):
1. Difference in rate of decline of Frailty defined as:

Reduced Activity (assessed via CHAMPS questionnaire)

Slowing of Mobility (assessed via a 4 meter gait speed test 
and SPPB assessment)

Weight Loss

Diminished handgrip strength (assessed via dynamometer)

Exhaustion (assessed via the MFI questionnaire)

Decrease in subject quality of life assessment(s) (assessed 
via ICECAP, SF-36, EQ-5D Questionnaires)
2. Death from any cause.
3. Change between screening and 6 months in dobutamine stress echo induced 
ejection fraction.
4. Change between screening and 6 months for the following panel of  inflammatory 
markers:  CRP, IL-6, D-dimer, fibrinogen,CBC with differential, and TNFα
5. The incidence of each component of the primary endpoint including non-fatal 
pulmonary embolism, stroke, hospitalization for worsening dyspnea and clinically 
significant laboratory test abnormalities
6. Change in Smell Identification Test (UPSIT)
D.3
Study Design
Subjects who received placebo in the randomized phase of the trial will have the option 
to receive 1 x 108 (100 million) allogeneic hMSCs, if all study endpoints are met from 
the randomized phase. Up to  ten (10) subjects may be enrolled in this addendum and 
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subjects will follow the study schedule listed in Section D14 (Table D1) of this 
addendum.
D.4 Inclusion and Exclusion Criteria
D.4.1
Inclusion Criteria 
In order to participate in this study, a subject MUST:
1.
Provide written informed consent.
2.
Subjects age >60 and <95 years at the time of signing the Informed 
Consent Form for this follow on phase.
3.
Have previously participated in the randomized phase of the trial and 
received placebo.
4.
Female subjects must have an FSH > 25.8 mIU/mL, if not currently on 
hormone replacement therapy.
D.4.2
Exclusion Criteria 
In order to participate in this study, a subject MUST NOT have any of the following:
1.
Score of <24 on the Mini Mental State Examination (MMSE)
2.
Inability to perform any of the assessments required for endpoint analysis 
(report safety or tolerability concerns, perform PFTs, undergo blood 
draws, read and respond to questionnaires.
3.
Active listing (or expected future listing) for transplant of any organ.
4.
Clinically important abnormal screening laboratory values, including but 
not limited to: hemoglobin <8 g/dl, white blood cell count <3000/mm3, 
platelets<80,000/mm3, INR > 1.5 not due to a reversible cause (i.e. 
Coumadin), aspartate transaminase, alanine transaminase, or alkaline 
phosphatase > 3 times upper limit of normal, total bilirubin > 1.5 mg/dl.
5.
Serious comorbid illness that, in the opinion of the investigator, may 
compromise the safety or compliance of the subject or preclude  
successful completion of the study.  Including, but not limited to: HIV, 
advanced liver or renal failure, class III/IV congestive heart failure, 
myocardial infarction, unstable angina, or cardiac revascularization within 
the last six months, or severe obstructive ventilatory defect.
6.
Any other condition that, in the opinion of the investigator, may 
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compromise the safety or compliance of the subject or preclude successful 
completion of the study. 
7.
Be an organ transplant recipient.
8.
Have a clinical history of malignancy within 3 years (i.e., subjects with prior 
malignancy must be disease free for 3 years), except curatively-treated 
basal cell carcinoma, squamous cell carcinoma, melanoma in situ or 
cervical carcinoma if recurrence occurs.
9.
Have a non-pulmonary condition that limits lifespan to < 1 year. 
10.
Have a history of drug or alcohol abuse within the past 24 months. 
11.
Be serum positive for HIV, hepatitis BsAg or Viremic hepatitis C.
12.
Be currently participating (or participated within the previous 30 days) in 
an investigational therapeutic or device trial. This does not exclude 
subjects that participated in the randomized phase of this trial.  
 
13.
Be a female who is pregnant, nursing, or of childbearing potential while 
not practicing effective contraceptive methods. Female subjects must 
undergo a blood or urine pregnancy test at screening and within 36 hours 
prior to infusion.
14.
Have hypersensitivity to dimethyl sulfoxide (DMSO)
D.5
Dosing
Subjects participating in this protocol will receive one infusion of 1 x 108 (100 million) 
cells delivered via peripheral intravenous infusion. 
The Allo-hMSCs cells may have penicillin/streptomycin and will be derived from donors 
meeting criteria for allogeneic unrelated human bone marrow stem cell source 
manufactured by the University of Miami or from a commercial clinical grade bone 
marrow source.
D.6
Dosage Rationale
A safety profile for IV infusion of hMSCs was based on results from previous completed 
toxicology results(Hare et al. 2277-86). The results from previous studies demonstrate that the 
product can be administered intravenously without toxic events at up to 65 x 
106hMSC/kg dose delivered in one bolus infusion or at 100 x 106hMSC/kg cumulative 
dose delivered by 5 infusions (20 x 106hMSC/kg per infusion).
The evidence supports the conclusion that it is feasible to dose subjects in this study 
based on a standard dose of hMSCs rather than per kilogram of body weight. The total 
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cell number corresponds to a range of 1.3 - 4.4 x 106 hMSCs per kg per infusion for 
subjects with 45 to 150kg body weight, the weight range for this study.
Therefore, results from previous trials support the rationale on the safety and potential 
efficacy of a second infusion of the selected maximum dose of 100 x106 allo-hMSCs.
D.7
Administration Rate
Prior clinical trials have used rates up to 30×106 hMSC/min where no infusion related 
toxicity was observed. 
In the proposed study addendum, the cell dose to be delivered is 1 x 108 (100 million), in 
the following total volume
-   40ml for 100 million dose (5 million hMSC/min)
Cell s are placed in an 80ml bag and will be delivered at a rate of 2ml/min, and delivered 
at a maximum rate of 16×106 hMSC/minute and will last approximately:

40 minutes for delivery of 40ml of 100 million dose in an 80 ml bag
D.8
Data and Safety Monitoring Board (DSMB)
DSMB will continue to provide the same oversight as noted in Section 9.4 of the Main 
protocol.
D.9
Concomitant Treatments, Procedures, and Nondrug 
Therapies
Refer to section 4.3 of the main study protocol
D.10
Infusion Monitoring Guidelines
Refer to section 6.4.1 and Appendix 1 of the main protocol.
D.11
Adverse Events and Serious Adverse Events
Refer to section 8.9 through 8.15 of the main study protocol.
D.12
Stopping Guidelines
Refer to section 8.2.4 of the main study protocol for further stopping guidelines.
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D.13
Payments to Subjects and Donors
Subjects will be reimbursed $25 at the end of each follow-up visit (Month 1 – Month 6 
for a total remuneration of $75.  These disbursements are meant to cover the time 
required to complete these study visits and all necessary travel and parking expenses. 
Normal donors for generation of allo-MSC will be reimbursed $500 at the end of BM 
aspiration. This payment will compensate donors for lost time, parking, and travel 
expenses.
D.14
Study Procedures for Optional Infusion for Placebo Subjects from 
the Randomized phase.
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Table D1: Time and Events Table for Optional Infusion for Placebo Subjects from the Randomized Phase
VISIT Schedule (Table D1)
Screening
- 45 days
Baseline
(-4 weeks)
Day 
1
Month 1 
(Day 30)
(+/-2 weeks)
Month 3    
(Day 90)
 (+/-30 
days)
Month 6     
(Day 180)
(+/-30 days)
Month 12 
(Day 365)
(+/-2 weeks)
*Phone Call Follow-up
Informed Consent
x
Full Medical History 
x
Physical Exam
x
x
x
x
x
x
12-lead (ECG)
x
x
x
x
x
x
Concomitant Medications
x
x
x
x
x
x
x
Mini Mental State Examination (MMSE)
x
x
Randomization
x
Infusion Treatment (IP)
x
Dobutamine Stress Echo Test (DSE)11
x
x
Bone Density Scan (DEXA)8
x
x
FEV-1
x
x
6 Minute Walk Test
x
x
4 Meter Gait Speed Test7
x
x
SPPB Assessment
x
x
Dynamometer (handgrip)9
x
x
Smell Identification Test (UPSIT)
x
x
IIEF, SQOL-F Questionnaires
x
x
x
x
QOL Questionnaires (ICECAP, EQ-5D, SF-36,CHAMPS, MFI)
x
x
x
x
Urinalysis
x
x
x
x
Hemat., Chem., CBC, LFTs, INR,   and other labs1
x
x
x
x
x
HIV 1, HIV 2, Hep. B & C, and CMV
x
Serum or Urine Pregnancy Test2
x
x
Review Adverse Events
x
x
x
x
x
Immune Monitoring4
x
x
x
x
Biomarker Assessment3
x
x
Optional: Brachial Ultrasound 5
x
x
Optional: Endothelial blood samples6
x
x

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Time and Events Table Key:
1 – The minimal laboratory requirements for hematological, liver function and renal 
function include:
Hematology Tests: white blood cell count, platelet count, hemoglobin and 
hematocrit, red blood cell count, CBC with Differential: neutrophils, lymphocytes, 
monocytes, eosinophils, and basophils.
Liver Function Tests: Albumin, alkaline phosphatase, alanine transaminase, 
asparate aminotransferase, prothrombin time / activated partial thromboplastin
time, and bilirubin(fractionate if total >1.5 times normal). 
Renal Function Tests: creatinine, creatinine clearance, blood urea nitrogen 
(BUN), glomerular filtration rate, sodium, potassium, chloride, calcium, carbon 
dioxide, total protein, glomerular filtration rate (GFR), and glucose, (HbA1c) will 
be collected at every follow-up visit only for subjects diagnosed with diabetes 
mellitus (DM).
Serum Uric Acid, Brain Natriuetic Peptide Pro-BNP, and high sensitivity C-
reactive protein (hs-CRP), IL6, fibrinogen, D-Dimer, DNA**, Serum TNFα, 
testosterone (males only), estrogen (females only) and FSH***.
- Laboratory work may be completed at a diagnostic center or home health 
agency should the subject be unable to come to the site.
** Deoxyribonucleic acid (DNA) will only be collected once during the subject’s 
participation. There is no specific point DNA needs to be collected as it can 
occur at any time point. 
***FSH will need to be collected at screening to verify that female subjects have 
an FSH  > 25.8 mIU/mL, if not currently on hormone replacement therapy for 
inclusion in the trial.
2 – A serum or urine pregnancy test will be completed within 36 hours prior to infusion  
for females of childbearing potential.
3 – The following biomarkers will be analyzed (Approximately 10mL blood samples will 
be collected): 

Cell-surface markers: CD19, CD27, IgD, and CD5 (for Switched Memory, 
Naïve, Late/Exhausted, IgM memory B cells and regulatory B cells); CD19 
and intracellular TNF-α (to assess intracellular TNF-α); CD3, CD4, CD8, 
CCR7 and CD45RA (for Central Memory, Naïve, Effector Memory, TEMRA 
T cells and CD4 to CD8 ratio); CD3, CD25 and FOXP3 (to assess regulatory 
T cells)

Transcriptomic/Proteome: 
RNA, 
miRNA, 
protein 
samples, 
and 
telomerase, akt

Growth factors: Sdf-1, notch, 
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
Functional Assays: cell growth rate, VEGF, and CFU assay
4
–  Immune monitoring for graft rejection.  Calculated panel reactive antibodies will be 
performed from the serum of the subjects on day 1 and 6 months post treatment. In 
addition, the following markers will be used to assess for activated T-cells based 
upon a CD3+CD25+ (late/chronic T cell activation) or CD3+CD69+ phenotype (early T 
cell activation).
5 – Optional brachial ultrasound to assess endothelial function. 
6 – Optional: An additional five (5) lavender top tubes (EDTA) will be drawn of 
approximately 8ml per tube.
7 – 4 meter gait speed test will be performed twice per visit and the average of the 
exams will be taken.
8 – DEXA scan will be performed twice at baseline and Month 6. The scans of the hip 
and spine for bone density, and total body composition will be assessed at both 
visits.
9 – Dynamometer will be performed at least three (3) times during each applicable visit. 
for each hand. The three values collected will be averaged for each hand. (Please 
reference the instruction manual on how to administer.) 
10 – Infectious disease tests – HIV, HIV 2, Hep B (HBsAG, Anti-HBs, Anti-HBc), and 
Hep C (Anti-HCV), VDRL, Syphilis, West Nile Virus, and CMV.(Conducted within 30 
days of infusion, if test expire prior infusion, they must be performed again)
11 – Guidelines for completing the (DSE) are outlined in Appendix 2 of this protocol.
D.15
Study Visits
D.15.1 
Screening Visit 
See Table D1 for the procedures and assessments to be performed during the 
screening visit of the study for the subjects that consent to participate in the additional 
infusion. Once the subject signs the consent form the subject will then have a 45-day 
window from the time the subject signs prior to the start of any baseline visit procedures 
to complete all screening procedures. The tests may take place over several days to 
complete. No screening exams will take place until the subject is fully informed of the 
research and signs the consent form. 
There will be up to a + 1 year window for the subject to consent to begin screening 
procedures, from the subject’s receipt of the un-blinding letter for the randomized 
phase.
D.15.2
Baseline Visit  
See Table D1 for the procedures and assessment to be performed during the baseline 
visit of the study. Once all screening exams are completed and it has been determined 
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that the subject remains eligible for the study, subjects will be enrolled into the study. 
The baseline visit will take place within four weeks of the infusion. The listed procedures 
should all be performed as soon as practicable.
D.15.3
Day 1 Visit
See Table D1 for the procedures and assessment to be performed during the Day 1 
visit of the study. The Day 1 visit will occur after all baseline tests are completed and it 
has been determined that the subject remains eligible. Once the subject is deemed 
eligible to continue in the study the subject will be administered the investigational 
product. The subject will be monitored for 2-3 hours, following administration of the 
investigational product, and will be sent home the same day.
D.15.4
Month 1 Visit 
See Table D1 for the procedures and assessment to be performed for the Month 1 visit 
of the study. Subject visits should be completed as close to the scheduled visit dates as 
possible. There will be a +/- window of 2 weeks for the month 1 study visit.
D.15.5
Month 3 and Month 6 Visit 
See Table D1 for the procedures and assessment to be performed for month 3 and 6 
visit of the study. Subject visit should be completed as close to the scheduled visit dates 
as possible. There will be a +/- window of 30 days for the month 3 and 6 study visit.
D.15.6
Month 12 Visit
See Table D1 for the procedures and assessments to be performed for Month 12 visit. 
This visit will be conducted via a phone interview with the subject. A phone script will be 
provided to the study personnel to use when interviewing the subject. There will be a +/- 
window of 2 weeks for this visit. 
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11.
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systole 
(right 
column) 
in 
a 
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