Clinical trial NCT02886884
Conditions: Diabetes Mellitus, Type 2
Keywords: Diabetes Endothelial dysfunction Stem cells
Sponsor: Joshua M Hare
Start date: 2017-10-20; Completion date: 2020-09-03
Enrollment: 16 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 16 subject trial to demonstrate the safety of allogeneic hMSCs administered via infusion therapy for diabetic subjects with endothelial dysfunction.

Detailed description:

Arms: arm 1: Participants in this group will receive one peripheral intravenous infusion of 20 million allogeneic Mesenchymal Human Stem Cells (hMSCs) arm 2: Participants in this group will receive one peripheral intravenous infusion of 100 million allogeneic Mesenchymal Human Stem Cells (hMSCs) arm 3: Participants in this group will receive one peripheral intravenous infusion of 20 million allogeneic Mesenchymal Human Stem Cells (hMSCs) arm 4: Participants in this group will receive one peripheral intravenous infusion of 100 million allogeneic Mesenchymal Human Stem Cells (hMSCs)
Interventions: intervention 1: 20 million Allogeneic Mesenchymal Human Stem Cells intervention 2: 100 million Allogeneic Mesenchymal Human Stem Cells
Intervention descriptions: intervention 1: 1 single intravenous infusion intervention 2: 1 single intravenous infusion

Protocol documents:
Prot_SAP_000.pdf: 
Interdisciplinary Stem Cell Institute 
University of Miami/ Miller School of Medicine 
Clinical Research Protocol 
Study Title:  
A Phase I/II, Randomized, Double Blind, Pilot trial to 
evaluate the Safety and Efficacy of Allogeneic 
Mesenchymal Human Stem Cells infusion therapy for 
Endothelial DySfunctiOn in diabetic subjects. (ACESO 
Study) 
 
Study Product: 
 
Allogeneic Human Mesenchymal Stem Cells (hMSCs) 
Indication:  
 
Endothelial Dysfunction in Diabetes 
FDA IND No.:  
 
BB-IND #17054 
NCT#  
 
 
NCT02886884 
 
 
Principal Investigator:       Joshua M. Hare, M.D                
   
 
 
 
Telephone: (305) 243 – 5579 
 
 
 
 
 
 
 
Protocol Version:  
5.7, dated October 26, 2020 
Protocol Agreement Signature: 
 
 
_________________________________________ 
 
 
______________________ 
Joshua M. Hare, M.D   
 
 
 
 
Date 
(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  Acceptance of this document constitutes agreement by the recipient that no unpublished 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 .............................................................................................................................................................. 6 
Protocol Synopsis .................................................................................................................................................................... 7 
1. 
INTRODUCTION ............................................................................................................................................ 10 
1.1 
Background ....................................................................................................................................................... 10 
2.  
STUDY OBJECTIVES AND ENDPOINTS ........................................................................................ 12 
2.1 
Study Objectives ............................................................................................................................................. 12 
2.1.1 
Primary Objective ......................................................................................................12 
2.1.2 
Secondary Objectives ...............................................................................................12 
2.2 
Study Endpoints .............................................................................................................................................. 12 
2.2.1 
Primary Endpoints (Safety) .......................................................................................12 
2.2.2. 
Secondary Endpoints (Efficacy) ................................................................................13 
3. 
STUDY DESIGN ............................................................................................................................................. 13 
3.1 
Description of the Study .............................................................................................................................. 13 
4. 
SUBJECT SELECTION............................................................................................................................... 14 
4.1 
Inclusion Criteria ............................................................................................................................................. 14 
4.2 
Exclusion Criteria ............................................................................................................................................ 14 
4.3 
Concomitant Treatments, Procedures, and Nondrug Therapies ............................................ 15 
4.4 
Withdrawal Criteria ........................................................................................................................................ 15 
5. 
DONORS ............................................................................................................................................................ 16 
5.1 
Normal Donor Eligibility ............................................................................................................................... 16 
5.2 
Donor Consent ................................................................................................................................................. 17 
5.3 
Follow-up Schedule for Donors ............................................................................................................... 18 
5.4 
Biomarker Assessment for Donors ........................................................................................................ 18 
6. 
TREATMENT OF SUBJECTS ................................................................................................................. 18 
6.1 
Study Investigational Product ................................................................................................................... 18 
6.2 
Dosing .................................................................................................................................................................. 19 
6.3 
Dosage Rationale ........................................................................................................................................... 19 
6.4 
Administration Rate ....................................................................................................................................... 19 
6.4.1 
Infusion Monitoring ....................................................................................................20 
6.5 
Concomitant Therapy ................................................................................................................................... 20 
6.5.1 
Permitted therapy ......................................................................................................20 
6.5.2 
Excluded therapy ......................................................................................................20 
6.5.3 
Subject monitoring ....................................................................................................20 


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6.6 
Blinding and Unblinding............................................................................................................................... 20 
6.7 
Study Investigational Therapy Management .................................................................................... 21 
6.7.1 
Investigational Product Labeling and Storage ................................................................................. 21 
6.7.2 
Investigational Product Accountability Procedures ....................................................................... 21 
7 
STUDY PROCEDURES ............................................................................................................................. 22 
7.1 
Time and Events Schedule ........................................................................................................................ 22 
8 
Study Phases and Visits ............................................................................................................................. 26 
8.1 
Screening Visit ................................................................................................................................................. 26 
8.2 
Baseline Visit .................................................................................................................................................... 27 
8.3 
Day 0 Visit .......................................................................................................................................................... 28 
8.4 
Day 3, Day 7, Day 14, and Day 28 (Post-Intervention Visit)..................................................... 28 
8.5 
Month 3, Month 6, and Month 12 (Post-Intervention Visit) ........................................................ 28 
8.6 
Genetic Testing ............................................................................................................................................... 28 
8.7 
Immune Monitoring for Graft Rejection ............................................................................................... 29 
9. 
SAFETY .............................................................................................................................................................. 30 
9.1  
Safety Variables .............................................................................................................................................. 30 
9.2  
Laboratory Evaluations ................................................................................................................................ 30 
9.2.1 
Pulse Oximetry ..........................................................................................................30 
9.2.2 
Pregnancy .................................................................................................................31 
9.2.3 
Determination of Infusional Toxicity ...........................................................................31 
9.2.4 
Subject Stopping Guidelines .....................................................................................31 
9.3 
Definition of an Adverse Event ................................................................................................................ 33 
9.4 
Definition of Adverse Reaction ................................................................................................................ 34 
9.5 
Definition of Suspected Adverse Reaction ........................................................................................ 34 
9.6 
Definition of Serious ...................................................................................................................................... 34 
9.7 
Definition of Unexpected ............................................................................................................................. 35 
9.8 
Clinical Laboratory Assessments and Other Abnormal Assessments as Adverse 
Events and Serious Adverse Events .................................................................................................... 35 
9.9 
Recording of Adverse Events and Serious Adverse Events .................................................... 35 
9.10 
Intensity of Adverse Events and Serious Adverse Events ........................................................ 36 
9.11 
Causality of Adverse Events and Serious Adverse Events ....................................................... 36 
9.12 
Follow-Up of Adverse Events and Serious Adverse Events ..................................................... 37 
9.13 
Timeframes for Submitting SAE Reports ........................................................................................... 37 
9.14 
Post-Study Adverse Events and Serious Adverse Events ........................................................ 38 
9.15 
Regulatory Aspects of Adverse Event Reporting ........................................................................... 38 
10. 
STATISTICAL ANALYSIS .......................................................................................................................... 39 


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10.1  
Determination of Sample Size and Analysis Population............................................................. 39 
10.2  
General Statistical Methods ...................................................................................................................... 39 
10.3 
Interim Analyses.............................................................................................................................................. 39 
11 
Data Safety and Monitoring Board (DSMB) ...................................................................................... 40 
11.1  
INTRODUCTION.......................................................................................................40 
11.2  
ROLE OF THE DSMB ...............................................................................................40 
11.3  
Purpose of the DSMB................................................................................................................................... 40 
11.4  
DSMB MEMBERSHIP ................................................................................................................................. 41 
11.4.2 DSMB Responsibilities ...................................................................................................42 
11.4.3 DSMB Chair(s) Responsibilities .....................................................................................42 
11.4.4 DSMB Conflict of Interest ...............................................................................................43 
11.4.5 DSMB Confidentiality .....................................................................................................43 
11.5 Investigator Responsibilities ................................................................................................................................ 43 
11.6 
DSMB MEETINGS ......................................................................................................................................... 43 
11.6.1 Discussion of Confidential Material .................................................................................45 
11.6.2 Reports of DSMB Deliberations ......................................................................................45 
11.7  
COMMUNICATION ....................................................................................................................................... 46 
11.8 Reports to the DSMB ............................................................................................................................................... 47 
11.9 Expedited Adverse Event Review and DSMB Notification Process ...................................48 
11.10 Clinical Holds ............................................................................................................................................................ 48 
11.11 Review of New Protocols .................................................................................................................................... 49 
11.12 Statistical Monitoring Guidelines ..................................................................................................................... 50 
12. 
STUDY ADMINISTRATION ...................................................................................................................... 50 
12.1 
Regulatory Authority Approval ................................................................................................................. 50 
12.2  
Ethics Approval ................................................................................................................................................ 50 
12.3  
Subject Informed Consent ......................................................................................................................... 51 
12.4  
Confidentiality of Information .................................................................................................................... 51 
12.5  
Payments to Subjects................................................................................................................................... 52 
APPENDIX 1:  
Infusion Guidelines ....................................................................................................................... 53 
13. 
References .......................................................................................................................................................... 56 
 
 
 


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Authorship Team (alphabetical order) 
 
The following individuals provided substantial input during protocol development: 
 
 
Moisaniel DaFonseca 
 
University of  Miami 
 
Darcy L. DiFede, RN, BSN  
University of Miami 
 
Joshua M. Hare, MD 
 
University of Miami 
 
Marietsy V. Pujol, MBA 
 
University of Miami 
 
Ivonne H. Schulman, MD*   
University of Miami 
 
 
* Principal investigator 
 
 
 
 
 
 
 
 
 
 
 
 


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List of Abbreviations 
 
ADA 
American Diabetes Association 
ACE 
Angiotensin converting enzyme 
AE 
Adverse event 
CHF 
Chronic heart failure 
CRF 
Case report forms 
CPL 
Cell Processing Laboratory 
CTCAEv4 
Common Terminology Criteria for Adverse Events 
CVD 
Cardiovascular disease 
DM 
Diabetes Mellitus 
EPC 
Endothelial progenitor cells 
FDA 
Food and Drug Administration 
FMD% 
Flow Mediated Diameter percent  
GM-CSF 
Granulocyte Macrophage Colony Stimulating Factor 
BMMNCs 
Bone marrow mononuclear cells 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
hMSCs 
Human mesenchymal stem cells 
HF 
Heart failure 
HLA 
Human Leukocyte Antigen 
IL 
Interleukin 
IRB 
Institutional review board 
IV 
Intravenous Infusion 
LV 
Left ventricular 
MDRD 
Modification of Diet in Renal Disease 
MSC 
Mesenchymal Stem Cells 
NIH 
National Institutes of Health 
NO 
Nitric Oxide 
PHI 
Protected health information 
PRA 
Panel Reactive Antibody 
QOL 
Quality of Life Questionnaires 
ROS 
Reactive oxygen species 
SAE 
Serious adverse event 
SDF-1 
Stromal derived factor 1 
SCF 
Stem cell factor 
SLE 
Systemic Lupus Erythematosus 
TNF 
Tumor Necrosis Factor 
TNFR1 
TNF-α receptor 
UM 
University of Miami 
VEGF 
Vascular endothelial growth factor 
 


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Protocol Synopsis 
 
Sponsor:  ISCI / University of Miami Miller School of Medicine  
Name of Study Therapy: Allogeneic human Mesenchymal Stem Cells (hMSCs) 
Title of Study: A Phase I/II, Randomized, Double Blind, Pilot trial to evaluate the 
Safety and Efficacy of Allogeneic Mesenchymal Human Stem Cells infusion 
therapy for Endothelial DySfunctiOn in diabetic subjects. (ACESO Study) 
 
Study Center: ISCI / University of Miami Miller School 
of Medicine  
Phase 
of 
Development: 
Phase I/II 
Objectives:   
Primary: To demonstrate the safety of allogeneic hMSCs administered via infusion 
therapy for diabetic subjects with endothelial dysfunction. 
 
Secondary:  
-To determine the mechanisms underlying the endothelial effects of MSCs and 
whether targeting endothelial function via MSC therapy ameliorates Cardiovascular 
Disease (CVD) outcomes in subjects with diabetes mellitus.  
-To evaluate the dose and timing of the stimulatory effect of MSCs on circulating 
angiogenic factor levels and EPC function as well as FMD% within 28 days post-
infusion. 
-To evaluate the long term effect of MSCs on circulating angiogenic factor levels and 
EPC function as well as FMD% at 3, 6, and 12 months post-infusion. 
Design and Investigational Plan:  
To evaluate the role of allogeneic mesenchymal stem cells therapy for endothelial 
dysfunction in diabetes. 
Sixteen (16) diabetic subjects with endothelial dysfunction will be scheduled to 
undergo a peripheral intravenous infusion after meeting all inclusion/exclusion criteria 
at baseline. 
PILOT PHASE (Unblinded): 
The dose for subjects in the pilot phase will vary from 20 million cells to 100 million 
cells and will be Unblinded, with subjects and study team members aware of the 
doses administered to the subject. The pilot phase will consist of: 
Three (3) subjects will be treated with 20 million (20 x 106) allogeneic hMSC’s Three 
(3) subjects will be treated with 100 million (100 x 106) allogeneic hMSC’ 
The three (3) subjects in the low dose group will not be treated less than 5 days apart 
and will each undergo full evaluation during those five days to show that there are no 
signs of treatment emergent SAE’s (TE-SAE) before continuing with the treatment of 
further subjects.   


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The three (3) subjects in the high dose will not be treated until the three (3) subjects 
in the low dose have completed their one-month follow-up assessments and safety 
measures have been reviewed to confirm that there have been no treatment 
emergent SAE’s. In addition, the three (3) subjects in the high dose group will not be 
treated less than 5 days apart.  
Randomized Phase (Double-Blind): 
After the pilot phase, subjects will be randomized to one of two treatments in a 1:1 
fashion. This phase of the study will be blinded to both subjects and study team 
members. The randomized phase will consist of ten (10) diabetic subjects with 
endothelial dysfunction will be subsequently randomized to undergo a peripheral 
intravenous infusion after meeting all inclusion/exclusion criteria at baseline: 
Five (5) subjects will be treated with 20 million (20 x 106) allogeneic hMSC’s and Five 
(5) subjects will be treated with 100 million (100 x 106) allogeneic hMSC’s 
The Allo-hMSCs will be supplied from an allogeneic human mesenchymal stem cell 
source or commercial clinical grade bone marrow source manufactured by the 
University of Miami. 
Follow up: Subjects will be followed at 3, 7, 14 and 28 days to evaluate the dose and 
timing of the stimulatory effect of MSCs on circulating angiogenic factor levels, EPC 
function, and FMD%, and at 3, 6, and 12 months post-infusion to complete all long-
term safety and efficacy assessments.  
Route of Administration: Peripheral Intravenous Infusion 
Duration of Study participation: Approximately 12 months 
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): (Assess at Baseline, Day 3, 7, 14, 28, and Month 3, 6, and 12 
following IV allogeneic MSC infusion) 
1. 
Assess EPC-colony forming units (CFUs) 
2. 
Assess circulating inflammatory markers (IL-1, IL-6, TNFα, and CRP) 
3. 
Assess circulating angiogenic factors known to mobilize and recruit EPCs 
(VEGF, SDF-1α, and SCF) 
4. 
Assess FMD% 
Major Inclusion Criteria: 
• Be ≥ 21 and <90 years of age. 
• Provide written informed consent.  


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• Have endothelial dysfunction defined by impaired flow-mediated vasodilation 
(FMD <7%). 
• Have DM type 2 documented by hemoglobin A1C > 7% OR on medical therapy 
for diabetes. 
• Females of childbearing potential must use two forms of birth control for the 
duration of the study. Female subjects must undergo a serum pregnancy test at 
screening and within 36 hours prior to infusion. 
Major Exclusion Criteria: 
• Be younger than 21 years or older than 90 years of age. 
• Have a baseline glomerular filtration rate <35 ml/min 1.73m2 estimated 
using the MDRD formula. 
• Have an ejection fraction <45% by gated blood pool scan, two-dimensional 
echocardiogram, cardiac MRI, cardiac CT or left ventriculogram within the 
past year, as documented by medical history. 
• Have poorly controlled blood glucose levels with hemoglobin A1C > 8.5%. 
• Have a history of proliferative retinopathy or severe neuropathy requiring 
medical treatment. 
• Have a hematologic abnormality as evidenced by hematocrit < 25%, white 
blood cell < 2,500/ul or platelet values < 100,000/ul without another 
explanation. 
• Have liver dysfunction, as evidenced by enzymes (AST and ALT) greater 
than three times the ULN. 
• Have a bleeding diathesis or coagulopathy (INR > 1.3), cannot be 
withdrawn from anticoagulation therapy, or will refuse blood transfusions. 
• Be an organ transplant recipient or have a history of organ or cell transplant 
rejection. 
• Have a clinical history of malignancy within the past 5 years (i.e., subjects 
with prior malignancy must be disease free for 5 years), except curatively 
treated basal cell or squamous cell carcinoma, or cervical carcinoma. 
• Have a condition that limits lifespan to < 1 year. 
• Have a history of drug or alcohol abuse within the past 24 months. 
• Be serum positive for HIV, Syphilis – VDRL (Confirmation with FTA-ABS if 
needed (Syphilis)), hepatitis B surface antigen, or viremic hepatitis C. 
• Be currently participating (or participated within the previous 30 days) in an 
investigational therapy/medication or device trial. 
• Be pregnant, nursing, or of childbearing potential while not practicing 
effective contraceptive methods. 
• Any other condition that in the judgment of the Investigator would be a 
contraindication to enrollment or follow-up. 
 
 
 


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1. 
INTRODUCTION 
 
1.1 
Background 
 
Cardiovascular disease (CVD) is the leading cause of death and disability among people 
with type 2 diabetes mellitus (DM)1. Not only are people with DM more likely to have a 
myocardial infarction (MI), their prognosis is worse, highlighting the need for novel 
targeted therapies1. It has long been appreciated that endothelial dysfunction underlies 
the high rates of CVD associated with long-term DM2-5. The persistent hyperglycemia and 
other metabolic abnormalities directly affect the endothelium, contributing to the 
pathophysiology of disease2;6;7. Numerous cell-based therapy clinical trials in subjects 
with ischemic heart disease illustrate that mesenchymal stem cell (MSC) administration 
improves cardiac structure, function and quality of life8-11. Our recent observation that 
MSCs improve endothelial progenitor cell (EPC) function (measured by colony forming 
assay) and endothelial function (measured by brachial artery flow-mediated vasodilation, 
FMD%) in subjects with ischemic as well as non-ischemic cardiomyopathy12, independent 
of their age or DM, suggests that we now have a means to target a primary cause of the 
CV manifestations of DM. Moreover, the effect on EPCs and FMD% was sustained at 3 
months after MSC administration, and evident in subjects receiving allogeneic but not 
autologous MSCs12. The mechanisms underlying the therapeutic effects of MSCs are due 
to a combination of multilineage differentiation, secretion of anti-inflammatory and 
proangiogenic paracrine factors, as well as stimulation of endogenous progenitor cells 
growth and differentiation12;13. Moreover, comorbidities and aging are potential factors 
underlying the difference in efficacy between autologous (subject-derived) and allogeneic 
(healthy donor) MSCs14-16. 
 
Endothelial Dysfunction in Subjects with Cardiovascular Diseases 
 
Endothelial dysfunction – defined by impaired flow-mediated vasodilation (FMD) and 
endothelial progenitor cell (EPC) dysfunction – is a crucial component of the 
pathophysiology of cardiovascular disease (CVD) and manifests in subjects with 
cardiovascular risk factors such as atherosclerosis, hypertension, chronic kidney disease, 
metabolic syndrome, and diabetes mellitus (DM)17. The endothelium plays an essential 
role in maintaining circulatory homeostasis by the release of factors that relax and 
contract vascular smooth muscle, ensuring appropriate blood flow to tissues. As a major 
regulator of peripheral blood flow, it controls the balance between nitric oxide (NO), 
reactive oxygen species, vasomotor tone, and inflammation18;19. Any change in the 
vasomotor regulatory balance may be characterized as endothelial dysfunction that leads 
to impaired control of vascular tone and participates in the pathogenesis of CVD. By 
stimulating the release of NO from the endothelium, EPCs play a pivotal part in 
maintaining vascular homeostasis as well as in mediating vascular repair in damaged 
endothelium. EPCs regulate the health of the vasculature by incorporating into the 
endothelium, replacing injured endothelial cells, and secreting angiogenic factors that 
activate mature endothelial cells20. Subjects with CVD have decreased circulating EPC 
levels and bioactivity21. Indeed, circulating EPC levels serve as a predictor of CV 
events22;23. Low numbers of EPC-colony forming units (EPC-CFUs) have been linked to 


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high Framingham risk scores for adverse cardiovascular health outcomes23. Similarly, 
brachial reactivity measurements (FMD%) predict long-term cardiovascular events24;25.  
 
Mesenchymal Stem Cells Transplantation for Patients with CVD and Endothelial 
Dysfunction 
The field of cell-based therapy for CVD, particularly ischemic heart disease, has had 
major advances in the past few years2;8-12.  Several studies support the safety and efficacy 
of MSC based therapy for this large group of subjects who are at major risk for MI, heart 
failure (HF), sudden cardiac death, and other major CV complications17-22. The DM 
subject population is at an especially high risk for ischemic heart disease and has a worse 
prognosis. According to the 2014 National Diabetes Statistics Report, 29.1 million 
Americans, or 9.3% of the population, had DM in 2012 (mostly type 2). In 2003-2006, 
CVD death rates were about 1.7 times higher among age-matched adults with DM than 
among those without DM. Similarly, in 2010 hospitalization rates for MI were 1.8 times 
higher among adults with DM than among those without DM. 
 
MSCs, under evaluation as a regenerative therapeutic approach for ischemic and non-
ischemic cardiomyopathy8;9;11;12;26, have significant potential for clinical benefit in CVD by 
virtue of their antifibrotic27, anti-inflammatory, and pro-angiogenic properties26, 27, as well 
as their ability to stimulate endogenous progenitor cells and capacity to differentiate into 
endothelial cells20, 28, 29. Moreover, there is evidence that NO deficient environments 
stimulate MSC involvement in angiogenesis12;28. We demonstrated in porcine models of 
ischemic cardiomyopathy that MSCs reduce infarct size by 35% and significantly improve 
global and regional left ventricular function29;30. These effects are due to cell engraftment, 
differentiation into myocytes and blood vessels, and stimulation of endogenous cardiac 


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stem cell proliferation and differentiation13. Given this capacity of MSCs and the role of 
impaired EPCs in CVD31;32, we tested the hypothesis that MSCs stimulate EPC function 
and augment vascular relaxation in subjects with heart failure due to idiopathic dilated or 
ischemic cardiomyopathy12. We found that allogeneic, but not autologous, MSCs improve 
EPC bioactivity and endothelial function (FMD%) in heart failure subjects, regardless of 
etiology. These findings demonstrated a novel clinical beneficial effect of allogeneic 
MSCs administration in patients with heart failure and have implications for all disorders 
associated with endothelial dysfunction, such as DM. Notably, DM subjects have impaired 
EPC mobilization and trafficking from bone marrow as well as functionally impaired 
MSCs33;34. 
 
Numerous cell-based therapy clinical trials in subjects with ischemic heart disease 
illustrate that MSC administration improves cardiac structure and function and quality of 
life8-11. Our recent observation that MSCs improve EPC function (measured by colony 
forming assay) and endothelial function (measured by brachial artery flow-mediated 
dilation, FMD%) in subjects with ischemic as well as non-ischemic cardiomyopathy12, 
independent of age or DM, suggests that we now have a means to target a primary cause 
of the cardiovascular manifestations of DM. Moreover, the effect on EPCs and FMD% 
was sustained at 3 months after MSC administration, and evident in subjects receiving 
allogeneic but not autologous MSCs12. The mechanisms underlying the therapeutic 
effects of MSCs are due to a combination of multilineage differentiation, secretion of anti-
inflammatory and proangiogenic paracrine factors, and stimulation of endogenous 
progenitor cells growth and differentiation12;13. Moreover, comorbidities and aging are 
potential factors underlying the difference in efficacy between autologous (subject-
derived) and allogeneic (healthy donor) MSCs14-16.   
 
2.  
STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Study Objectives 
2.1.1 Primary Objective 
- 
To demonstrate the safety of allogeneic hMSCs administered via infusion therapy 
for diabetic subjects with endothelial dysfunction. 
 
 
2.1.2 Secondary Objectives 
- 
To determine the mechanisms underlying the endothelial effects of MSCs and 
whether targeting endothelial function via MSC therapy ameliorates CVD 
outcomes in subjects with diabetic mellitus. 
 
- 
To evaluate the dose and timing of the stimulatory effect of MSCs on circulating 
angiogenic and inflammatory factor levels and EPC function, as well as FMD%. 
 
2.2 
Study Endpoints 
 
2.2.1 Primary Endpoints (Safety) 


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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. 
 
2.2.2. Secondary Endpoints (Efficacy) 
(Assess at Baseline, Day 3, 7, 14, and 28, and Month 3, 6 and 12 following IV allogeneic 
MSC infusion) 
1. 
Assess EPC-colony forming units (CFUs) 
2. 
Assess circulating inflammatory markers (IL-1, IL-6, TNFα, and CRP) 
3. 
Assess circulating angiogenic factors known to mobilize and recruit EPCs 
(VEGF, SDF-1α, and SCF) 
4. 
Assess FMD%  
3. 
STUDY DESIGN 
3.1 
Description of the Study 
 
Sixteen (16) diabetic subjects with endothelial dysfunction will be scheduled to undergo 
a peripheral intravenous infusion after meeting all inclusion/exclusion criteria at baseline. 
The study will consist of a Pilot Phase and Randomized Phase. 
 
PILOT PHASE 
 
To test the safety of allogeneic mesenchymal stem cells therapy for endothelial 
dysfunction in diabetes subjects administered via peripheral intravenous infusion, a non-
randomized, unblinded pilot phase of six subjects will be performed.  
 
Three (3) subjects will be treated with 20 million (20 x 106) allogeneic hMSCs  
Three (3) subjects will be treated with 100 million (100 x 106) allogeneic hMSCs. 
 
The three (3) subjects in the low dose group will not be treated less than 5 days apart and 
will each undergo full evaluation during those five days to show that there are no signs of 
treatment emergent SAE’s before continuing with the treatment of further subjects.   
 
The three (3) subjects in the high dose will not be treated until the three (3) subjects in 
the low dose have completed their one-month follow-up assessments and safety 
measures have been reviewed to confirm that there have been no treatment emergent 
SAE’s. In addition, the first three (3) subjects in the high dose group will not be treated 
less than 5 days apart. 


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RANDOMIZED PHASE 
After the Pilot Phase, the Randomized Phase will begin. Ten (10) diabetic subjects with 
endothelial dysfunction will be randomized to undergo a peripheral intravenous infusion 
in a 1:1 ratio after meeting all inclusion/exclusion criteria at baseline. 
Five (5) subjects will be treated with 20 million (20 x 106) allogeneic hMSCs Five (5) 
subjects will be treated with 100 million (100 x 106) allogeneic hMSCs 
 
The Allo-hMSCs will be supplied from an allogeneic human mesenchymal stem cell 
source manufactured by the University of Miami. 
 
Electronic randomization will be performed by the University of Miami Biostatistics 
Collaboration and Consulting Core (BCCC) and communicated to cellular laboratory 
personnel who have no contact with the investigators or subjects.  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 (EPC’s, FMD%, and inflammatory markers) will be 
assessed at baseline, Day 3, 7, 14, and 28, Month 3, Month 6 and Month 12 following the 
IV infusion of the allocated investigational product.  Clinical laboratory tests to assess 
safety will be performed at every clinic visit, excluding the screening visit.   
 
4. 
SUBJECT SELECTION 
 
4.1 
Inclusion Criteria 
 
In order to participate in this study, a subject MUST: 
• 
Be ≥ 21 and <90 years of age. 
• 
Provide written informed consent. 
• 
Have endothelial dysfunction defined by impaired flow-mediated vasodilation 
(FMD <7%). 
• 
Have DM type 2 documented by hemoglobin A1C > 7% or on medical therapy 
for diabetes.  
• 
Females of childbearing potential must use two forms of birth control for the 
duration of the study. Female subjects must undergo a serum pregnancy test 
at screening and within 36 hours prior to infusion. 
 
4.2 
Exclusion Criteria 
 
In order to participate in this study, a subject MUST NOT: 
• 
Be younger than 21 years or older than 90 years of age. 
• 
Have a baseline glomerular filtration rate <35 ml/min 1.73m2 estimated using 
the MDRD formula. 


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• 
Have an ejection fraction < 45% by gated blood pool scan, two-dimensional 
echocardiogram, cardiac MRI, cardiac CT or left ventriculogram within the past 
year, as documented by medical history if history of heart failure. 
• 
Have poorly controlled blood glucose levels with hemoglobin A1C > 8.5%. 
• 
Have a history of proliferative retinopathy or severe neuropathy requiring 
medical treatment. 
• 
Have a hematologic abnormality as evidenced by hematocrit < 25%, white 
blood cell < 2,500/ul or platelet values < 100,000/ul without another 
explanation. 
• 
Have liver dysfunction, as evidenced by enzymes (AST and ALT) greater than 
three times the ULN. 
• 
Have a bleeding diathesis or coagulopathy (INR > 1.3), cannot be withdrawn 
from anticoagulation therapy, or will refuse blood transfusions.  
• 
Be an organ transplant recipient or have a history of organ or cell transplant 
rejection.  
• 
Have a clinical history of malignancy within the past 5 years (i.e., subjects with 
prior malignancy must be disease free for 5 years), except curatively-treated 
basal cell or squamous cell carcinoma, or cervical carcinoma.  
• 
Have a condition that limits lifespan to < 1 year.  
• 
Have a history of drug or alcohol abuse within the past 24 months.  
• 
Be on chronic therapy with immunosuppressant medication, such as 
corticosteroids or TNFα antagonists. 
• 
Be serum positive for HIV, Syphilis – VDRL (Confirmation with FTA-ABS if 
needed (Syphilis)), hepatitis BsAg, or viremic hepatitis C. 
• 
Be currently participating (or participated within the previous 30 days) in an 
investigational therapeutic or device trial. 
• 
Be pregnant, nursing, or of childbearing potential while not practicing effective 
contraceptive methods. 
• 
Any other condition that in the judgment of the Investigator would be a 
contraindication to enrollment or follow-up. 
 
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 
in endothelial dysfunction, 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: 
 


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- 
Subject’s request. 
- 
Subject is unable or unwilling to comply with the protocol. 
- 
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. 
DONORS 
5.1 
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 
- 
Human T-lymphotropic Virus I/II (HTLV I/II) 
- 
T. cruzi ELISA test (Chagas disease) 


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- 
Zika Virus (RNA qualitative Real Time RT-PCR and/or Virus Antibody (IgM), 
MAC-ELISA) 
- 
Rapid Plasma Reagin (RPR) or VDRL (confirmation with FTA-ABS if needed 
(Syphilis)) 
 
Prospective donors will also have the following blood and urine tests: 
- 
Complete blood count with differential 
- 
Comprehensive metabolic panel, magnesium, calcium, and uric acid 
- 
Urinalysis 
- 
Serum 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 Surface Antigen, Hepatitis C antibody, RPR or 
VDRL, Chagas, HIV 1 and 2 antibody screen, HTLV I and II antibody screen, 
Zika Virus, and West Nile Virus.   
- 
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 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. 
 
5.2 
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. 


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Donors will need to have virology’s redrawn if BMA procedure not completed 7 days from 
the initial virology results. 
 
5.3 
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. This call will take place approximately 
24 hours after leaving the hospital to determine the well-being and health status of 
the donor.  The donor will be provided with contact telephone numbers in the 
consent form for any questions or comments. 
5.4 
Biomarker Assessment for Donors 
A separate blood sample of about 10mL 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. A separate genetic consent 
form will need to be completed for the donors’ participation.  
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 donor of bone 
marrow or from a commercial clinical grade bone marrow source. 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 and as specified in the 
POSEIDON-DCM trial (IND #: 14419; NCT01087996). BM will be obtained from normal 
volunteers and 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 
with or without antibiotics. Subjects with a penicillin allergy will not receive antibiotic 
treated cells. 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 14 days of culture, passage zero (P0) cells will be harvested by trypsin 
treatment and expanded into 60 flasks (P1 cells). After 7 to 10 days P1 cells are harvested 
by trypsin treatment (P1 cells).  Cells from P1 will be cultured for 7 to 10 days and 
harvested by trypsin treatment and expanded into 180 flasks (P2 cells) with the option of 


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expanding them once again, to P3.  After 7-10 days P3 cells would be harvested by trypsin 
treatment and cryopreserved.  
 
Before dispensing the investigational product, Cell Therapy Lab staff will confirm the CMV 
status of eligible recipients. This information will be used to select the Allo-hMSC product. 
CMV status of the recipient and donor of the Allo-hMSC product will be matched. CMV 
positive or negative Allo-hMSC products may be infused to a CMV positive recipient. All 
CMV negative recipients will receive CMV negative Allo-hMSC product91. 
 
6.2 
Dosing 
 
The Allo-hMSCs are manufactured by the University of Miami Interdisciplinary Stem Cell 
Institute, as specified in the POSEIDON-DCM trial (IND #: 14419; NCT01087996). 
6.3 
Dosage Rationale 
 
A safety profile for IV infusion of hMSCs was based on outcomes from previous completed 
toxicology results8. The results from these 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 45kg to 150kg body weight. 
 
In addition, the data from the administration of allogeneic MSCs in the DCM (IND #: 
14419; NCT01087996) trial supports the clinical safety of the proposed MSC doses to be 
administered. Therefore, results from previous trials support the rationale on the safety 
and potential efficacy of the selected maximum dose of 100 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.  
 
In the proposed study, the cell dose to be delivered is 20 million (20 x 106) and 100 million 
(100×106) hMSC/infusion, reconstituted as 0.25 to 1.25 million hMSC/ml, in the following 
total volume: 
 
80 ml for the 20 million dose (0.5 million hMSC/min) 
 
80 ml for the 100 million dose (2.5 million hMSC/min) 
 


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Cells are placed in an 80ml bag and will be delivered at a rate of 2ml/min, and 
delivered at a maximum rate of 2.5×106 hMSC/minute and will last approximately 40 
minutes for both doses 
 
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. 
 
6.4.1 Infusion Monitoring 
 
Subjects will be monitored in the Clinical Translational Research Site (CTRS) at the 
University of Miami Hospital (UMH) for two hours prior to infusion to establish baseline 
vital signs (oxygen saturation, heart 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 and therapies. 
 
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) 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 
 


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To ensure the primary objective of safety with infusing Allogeneic MSCs in diabetic 
subjects with endothelial dysfunction, the pilot phase of this trial will not be blinded.  
 
In the Randomized Phase, subjects will be randomized into active groups and study 
personnel will be blinded to treatment assignments. The designated cell-processing 
technicians will prepare the allogeneic hMSCs for infusion. The investigational agent 
infusions will be prepared in identical infusion bags and labeled with the identical 
investigational drug labels as to preserve the blind. The designated technicians in the 
ISCI Cell Processing Laboratory (CPL) or designee will be responsible for maintaining the 
investigational product records including randomized treatment assignments by subject 
identification. Although the subjects and investigator will remain blinded to treatment 
allocation throughout the study, the blinding is necessary only for the first 28 days of the 
study, as these timepoints are what are necessary for the short-term  efficacy and safety 
outcomes of the study. The follow up time points at 3 months, 6 months, and 12 months, 
are for long-term safety and long-term efficacy but do not require blinding. The 28 day 
data will be used to determine the dose and time point at which MSCs exert the greatest 
effect on FMD and EPC-CFUs, as designed in the study, in order to design the next study 
protocol. The 28 day data will be analyzed by the UM Biostatistics group to determine 
which dose and at which time point within the 28 day follow up period shows the greatest 
efficacy. These results will be submitted to the NIH DSMB and the FDA. 
 
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 Experimental and Clinical Cell Based Therapies 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 CMP will directly store and deliver the 
designated cell processing technologist in the CPL, 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 personnel prior to 
preparation for infusion. After preparation for infusion, the Investigator and his or her 
designees are permitted to administer the Investigational Product only to subjects 
participating in this protocol. 
 
6.7.2 Investigational Product Accountability Procedures 
 
In accordance with all applicable regulatory requirements, the Cell Processing Laboratory 
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.  


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7.1 
STUDY PROCEDURES                                                                                        
Time and Events Schedule 
The Time and Events Schedule for the conduct of this study is shown in Table 1:


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ISCI / University of Miami Miller School of Medicine      ***CONFIDENTIAL AND PROPRIETARY*** 
 
 
 Schedule of Assessments  
Table 1: Time and Events Table 
 
VISIT 
Screening 
Baseline 
Day 0 
Day 3 
Post-
Infusion 
Day 7 
Post-
Infusion 
Day 14 
Post-
Infusion 
Day 28 
Post-
Infusion 
Month 3 
Post-
Infusion 
Month 6 
Post-
Infusion 
Month 12 
Post-
Infusion 
1-6 weeks 
prior to 
Baseline 
0-14 Days 
Prior to 
Day 0 
 
+ 2 days 
± 2 days 
± 2 days 
± 2 days 
± 2 weeks 
± 2 weeks 
± 62 
weeks 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
Full Medical History  
X 
 
 
 
 
 
 
 
 
 
Physical Exam and Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-lead (ECG) 
X 
 
X 
 
 
 
X 
X 
X 
X 
Concomitant Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Infusion Treatment (IP) 
 
 
X 
 
 
 
 
 
 
 
QOL Questionnaires (IIEF, SQOL-F, EQ-5D, SF-36)1 
 
X 
 
 
 
 
X 
X 
X 
X 
Review Adverse Events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Brachial Artery Ultrasound2 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
Laboratory Testing 
Urinalysis 
X 
 
 
 
 
 
X 
X 
X 
X 
Hematology & Chemistry 3 
X 
 
X 
 
 
 
X 
X 
X 
X 
Coagulation 4 
X 
 
 
 
 
 
 
 
 
 
HbA1c 
X 
 
 
 
 
 
 
X 
X 
X 
Viral Serology5 
X 
 
 
 
 
 
 
 
 
 
Serum Pregnancy Test6 
X 
 
X 
 
 
 
 
 
 
 
MNCs8 
 
 
X 
 
 
X 
X 
 
X 
X 
Serum9  
 
X  
 
X 
X 
X 
X 
X 
X 
X 
Endothelial Progenitor Cells10 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Genetic RNA 
 
X 
 
 
 
 
 
X 
 
 
Genetic DNA 
 
X 
 
 
 
 
 
 
 
 


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Time and Events Table Key: 
1 – Questionnaires: IIEF will only be given to male subjects, and SQOL-F will only be 
given to female subjects. 
2 – Brachial Artery Ultrasound to assess endothelial function should be performed in the 
morning, prior to 12 p.m.  
3 – The minimal laboratory requirements for hematology and chemistry include: 
Hematology Tests: Complete Blood Count with Differential (white blood cell 
count, platelet count, hemoglobin, hematocrit), and Glycated Hemoglobin 
(HbA1c)*. 
HbA1C will not be collected for Day 0 and Day 28 
Liver Function Tests: Albumin, alkaline phosphatase, alanine transaminase 
(ALT), asparate aminotransferase (AST), and bilirubin (fractionate if total >1.5 
times normal).  
Renal Function Tests: creatinine, blood urea nitrogen (BUN), glomerular filtration 
rate, sodium, potassium, chloride, calcium, total protein, carbon dioxide and 
glucose. 
 
4 - Coagulation Tests: prothrombin time (PT/INR), activated partial thromboplastin time 
(aPTT) at screening.  
5 – Viral Serology testing at screening will include the following: HIV 1 and HIV 2 antibody 
screen, Hepatitis B (Hep B surface antigen, surface antibody, and core antibody), 
Hepatitis C antibody, Syphilis (VDRL or RPR, with reflex FTA-antibody if positive), 
and CMV antibody. 
6 – For females of childbearing potential: serum pregnancy test (βHCG) will be completed 
at screening and within 36 hours before infusion. 
7 – During immune monitoring for graft rejection, Panel reactive antibodies (PRA) will 
be performed from the serum of the subjects to check for donor specific antibodies 
at Baseline and Month 3 only. 
8--IThe following markers may 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). 
9 – The following biomarkers may be analyzed at any or all of the time points in Table 1:  
Circulating pro-inflammatory markers: serum high sensitivity C-reactive protein 
(hs-CRP), IL-6, IL-1, and TNFα 
Circulating angiogenic factors known to mobilize and recruit EPCs: VEGF, 
SDF-1α, and SCF 
Transcriptomic/Proteome: DNA (at baseline only), RNA (at Baseline and Month 
3 only) 


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10 – Endothelial Progenitor Cell-Colony Forming Units (EPC-CFUs): Blood will be 
collected in Lavender top tubes (EDTA) for EPC-CFU analysis. 
11 - Postdoctoral (experimental laboratory) studies:   
The separate blood samples for the immune markers, biomarkers, and EPC-CFUs 
described above in 7-9 will be obtained 1) to provide storage of critical biomaterials 
derived from subjects enrolled in ACESO 2) to provide long-term integrity of these 
biospecimens and samples, and 3) to provide management of samples for postdoctoral 
studies of immunologic, immunohistochemical, cellular, and molecular analyses of 
collected samples; including cell-surface markers (CXCR4, C-Kit, & Connexin 43), 
transcriptomic/proteonomic (DNA, RNA, miRNA, protein samples, and telomerase), 
growth factors (noted in 8, above), functional Assays (cell growth rate, CFU assay noted 
in 9 above),  CD3, CD25, CD69 (noted in 7 above),  and inflammatory (noted in 8 above), 
but not limited to these. These biospecimens will be used for research purposes only, will 
be stored without personal identifying information, and will be shared with approved 
researchers who will conduct studies to improve the understanding of the effects of cell 
therapies and/or of diabetes disease on cardiovascular function and outcomes. 
 
12- Since trial participants may not be able to come to the investigational site for 
protocol specified visits during the “Coronavirus Disease 2019” (COVID-19) pandemic,  
alternative methods for assessments (e.g., phone contact, virtual visit, alternative 
location for assessment, including local labs or imaging centers) could be implemented 
when necessary and feasible, and would be sufficient to assure the safety of trial 
participants. Assessments could be completed as follows: 
- Physical Examination could be done via telemedicine using a virtual platform. 
- Vital Signs and 12-Lead EKG: If subject has completed an EKG or vital signs within the 
window specified per protocol with their PCP or any othe treating physciain a copy could 
be requested. Alternatively, subjects may record and report their own vital signs or EKG 
using home testing equipment (such as thermometer, automated blood pressure monitor, 
pulse oximeter, wearable health devices, or other method for recording vital signs. 
 
- Questionnaires, concomitant medications, and review of adverse events may be 
completed by study team via email, phone contact, virtual visit or alternative methods.  
 
- Laboratory assessments: A copy of SOC labs (urinalysis, hematology, chemistry, and 
HbA1c) may be obtained from PCP or treating physician if done within the protocol 
specified time window. If participant has not completed any laboratory assessments, they 
may complete this in any local laboratory facility.  
 
- Brachial Artery Ultrasound, Immune Monitoring, EPC-CFUs and Biomarkers 
Assessment: If participant is willing to come to site to complete this assessment all 
necessary safety precautions must be taken. Study team will provide the subject with a 
mask and gloves upon arrival to the site. If subject prefers to complete this assessment 
at another time, the study team must document that the assessment will be completed 
out of the protocol specified window and report to the regulatory authorities accordingly. 


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8 Study Phases and Visits 
8.1 
Screening Visit 
 
See Table 1 for the procedures and assessment to be performed during the screening 
visit of the study, which can take place over several days. 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.  
All subjects will be enrolled at the University of Miami (UM) hospital and clinics. At the 
time of enrollment, we will review the medical records to ensure that the ADA guidelines 
for diabetic care are being followed. We will inform the subjects’ primary care physician 
that the subject is enrolled in our study and must continue to follow the ADA guidelines 
throughout the trial. All the investigators follow these guidelines, and monitoring of the 
subjects’ care by the clinical investigator or principal investigator will be ongoing through 
the trial at each follow 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. 
 
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 height (screening only), weight, 
respiratory rate, heart rate, blood pressure, oxygen saturation, and temperature. 
Respiratory rate, heart rate, and blood pressure should be measured in a seated position.  
 
Endothelial function 
- 
Brachial ultrasound testing and blood collection will be performed to assess 
endothelial function in the diabetic population at screening, baseline and 3 
days, 7, 14, 28 days, 3 months, 6 months, and 12 months post stem cell 
infusion. This will help provide cumulative data in assessing whether or not 
stem cell infusion improves endothelial function. This test will be done in the 
morning prior to 12p.m.   
 
- 
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 subject’s 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 


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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 7% 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. 
 
8.2 
Baseline Visit 
 
See Table 1 for the procedures and assessment to be performed during the baseline visit 
of the study. This visit will occur after all screening tests are completed and it has been 
determined that the subject meets eligibility criteria. This visit should occur within 2 weeks 
prior to Day 0 (the infusion visit). 
The following endothelial function tests will be performed: 
- 
Brachial ultrasound testing and blood collection will be performed to assess 
endothelial function in the diabetic population at screening, baseline and 3 
days, 7, 14, 28 days, 3 months, 6 months, and 12 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 subject’s 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 7% 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 for biomarker and PRA analysis will be 
separated and the serum will be frozen until processed as one batch towards 
the end of the study.  
 


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- 
Biomarker analysis: Soluble pro inflammatory cytokines (interleukin 1, 
interleukin-6, tumor necrosis factor alpha, high-sensitivity C Reactive Protein, 
and circulating angiogenic factors) (VEGF, SDF-1α, and SCF) using 
immunological and ELISA methods. 
 
- 
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.  
8.3 
Day 0 Visit 
See Table 1 for the procedures and assessment to be performed during the Day 0 visit 
of the study. The Day 0 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. 
8.4 
Day 3, Day 7, Day 14, and Day 28 (Post-Intervention Visit) 
See Table 1 for the procedures and assessment to be performed for Day 3 through Day 
28 visit. Outpatient visits should be completed as close to the scheduled visit dates as 
possible. There will be a window of + 2 days for Day 3 visit, and ± 2 days for Day 7, Day 
14, and Day 28 study visits. 
8.5 
Month 3, Month 6, and Month 12 (Post-Intervention Visit) 
See Table 1 for the procedures and assessment to be performed for the Month 3, Month 
6, and Month 12 study visits. 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 3 
and Manth 6 visits. Month 12 will have a window of ± 6 weeks. 
8.6 
Genetic Testing 
A separate blood sample of about 10mL for gene expression (DNA) profiling of WBC (at 
baseline visit) and for RNA expression analysis (at baseline and month 3 visits) will be 
obtained from the study participants, as detailed on Table 1.  A separate genetic consent 
form is completed by the study participants. 
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 


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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.   
8.7 
Immune Monitoring for Graft Rejection 
The studies planned in this protocol will utilize allogeneic mesenchymal stem cells (MSC) 
in subjects with endothelial dysfunction. 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 and prolonging 
skin allograft survival. 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 this protocol we will obtain peripheral blood samples from all subjects to 
evaluate the presence and/or development of Panel Reactive Antibodies (PRA) and the 
presence of activated T cells. Heparinized (green top) and Serum Separator Tube (SST) 
(which are either gold top or red tiger vacutainer tubes), approx. 15 cc total blood, will be 
collected at different time points during the study (please reference Table 1). Peripheral 
blood mononuclear cells (PBMC) will be isolated from heparinized blood by Eicoll 
sedimentation and will be viably cryopreserved for planned assessments of T cell 
activation. 
 
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 


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both activation phenotypes (CD3+CD69+ and CD3+CD25+) will maximize the sensitivity 
of detection of T cell activation following allogeneic hMSC infusion. 
Additionally, in female subjects who receive allogeneic hMSCs, the stored baseline serum 
will be analyzed to evaluate the antibody responses to HLA and H-Y antigens. 
9. 
SAFETY 
9.1  
Safety Variables 
 
- 
Vital signs 
- 
Physical examination 
- 
Clinical laboratory tests 
- 
Urinalysis 
- 
Adverse events 
9.2  
Laboratory Evaluations 
 
At screening, the HIV-1 and HIV-2 tests, Syphilis – VDRL (Confirmation with FTA-ABS if 
needed (Syphilis)), 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, bicarbonate, BUN, creatinine, 
glucose, calcium, AST/SGOT, ALT/SGPT, total bilirubin (fractionate if total >1.5 
times normal), alkaline phosphatase, albumin, 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. 
 
 
 
9.2.1 Pulse Oximetry 
 
Pulse oximetry will be used to observe oxygen saturation when measuring vital signs at 
the infusion visit (Reference Appendix 1). Pulse oximetry will also be used throughout 
infusions and 2 hours following infusions. Subjects should have a resting oxygen 
saturation of ≥ 93% prior to infusion. Subjects requiring oxygen, need the peripheral artery 
oxygen saturation (SaO2) to be ≥ 93% when given a maximum of 2L/minute supplemental 


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O2 via nasal 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. 
 
9.2.2 Pregnancy 
 
There is no information regarding 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. Any two of the enumerated contraceptive items will 
be acceptable for meeting the studies contraceptive requirements as listed in paragraph 
2 of 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 IU/L). Non-sterilized males who are 
sexually active with a female partner of childbearing potential must use any two of the 
acceptable forms of contraceptive items as listed below: 
 
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. 
 
9.2.3 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. 
 
 
9.2.4 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 


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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.  
 
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 cardiorespiratory distress 
during infusion, subject death, myocardial infarction, hemodynamically unstable 
ventricular tachycardia, stroke, or more than two related, ≥ Grade 3 AEs (based on the 
NIH CTCAEv4).  Study accrual and further treatment of subjects will be put on hold 
(temporary suspension of study drug administration, pending a safety investigation) 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: 
 
- 
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. 
 
- 
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. 
 
- 
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. 
 
- 
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. 
 
- 
The proportion of subjects experiencing TE-SAE as defined in Section 2.2.1 will 
be monitored within 30 days of injection. 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.  
 
- 
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 


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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.    
 
 
9.2.5 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. 
9.3 
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: 
- 
Exacerbation of a chronic or intermittent pre-existing condition including either 
an increase in frequency or intensity of the condition. 
 
- 
Significant or unexpected worsening or exacerbation of the condition/indication 
under study. 
 
- 
A new condition detected or diagnosed after study therapy administration even 
though it may have been present prior to the start of the study. 
 
- 
Pre- or post-treatment events that occur as a result of protocol-mandated 
procedures (e.g., invasive protocol-defined procedures, modification of a 
subject’s previous treatment regimen). 
 
An AE does not include: 
- 
Medical or surgical procedures (e.g., colonoscopy, biopsy).  The medical 
condition that leads to the procedure is an AE. 
 
- 
Social or convenience hospital admissions where an untoward medical 
occurrence did not occur. 
 
- 
Day to day fluctuations of pre-existing disease or conditions present or detected 
at the start of the study that do not worsen. 


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- 
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. 
 
9.4 
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. 
 
9.5 
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. 
 
9.6 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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9.7 
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. 
 
9.8 
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”) and will assess intensity based on the criteria defined in Section 
8.10.  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 use the normal laboratory ranges (or a change in baseline in subject’s 
whose laboratory tests were outside of the normal range when enrolled), as well as the 
NIH CTCAEv4 when exercising medical judgment in assessing whether abnormal 
laboratory values are clinically significant. 
 
9.9 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. 
 


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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 
promptly withdrawn from the study.  Follow-up information regarding the outcome of the 
pregnancy and any postnatal sequelae in the infant will be required.  
9.10 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.” 
 
9.11 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.  
 


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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 makes an assessment of causality. 
 
The relationship between AEs and the study exposure will be classified by the 
investigator as: 
 
- 
None:  
No relationship.  Related to other known etiologies, conditions, or  
 
 
exposures. 
- 
Unlikely:  
Current knowledge suggests that a relationship is unlikely. 
- 
Possible:  
A plausible temporal sequence or response pattern exists but the  
AE may be related to other known etiologies, conditions, or 
exposures. 
- 
Probable:  
A plausible temporal sequence or response pattern exists and the  
AE cannot be related other known etiologies, conditions, or 
exposures. 
 
- 
Definite:  
A plausible temporal sequence or response pattern exists and the  
AE can be confirmed by re-challenge or with other supporting data. 
 
9.12 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 
 
9.13 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 


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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 2. 
 
TABLE 2 
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 
 
 
9.14 Post-Study Adverse Events and Serious Adverse Events 
 
The Investigator should report any death or SAE occurring at any time after a subject has 
completed or terminated a clinical trial, when such death or SAE may reasonably be 
related to the study therapy used in an investigational trial. Investigators are not obligated 
to actively seek AEs from former study participants. 
 
9.15 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.   
 


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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. 
 
10. 
 
STATISTICAL ANALYSIS 
 
10.1  Determination of Sample Size and Analysis Population 
 
No formal statistical justification was performed to determine sample size in this Phase 
I/II study.  The allocation ratio will be 1:1. All randomized subjects will be included in 
summaries of baseline characteristics, safety, and efficacy.  Reasons for study 
discontinuation will be tabulated. 
 
10.2  General Statistical Methods 
 
All statistical tests will be performed at an ∝=0.05 level of significance, using two-sided 
tests.  Because this is a Phase I/II 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.    
10.3 Interim Analyses 
 
Interim analyses will be conducted at times coincident with regularly scheduled meetings 
of the Data and Safety Monitoring Board (DSMB) at approximately six-month intervals.  
The DSMB Chair will be notified each time an SAE occurs. After all subjects in the low 
dose have 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 or to recommend a dose modification.   
 
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.” 


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11 Data Safety and Monitoring Board (DSMB) 
 
NHLBI Gene and Cell Therapy Data and Safety Monitoring Board 
 11.1  INTRODUCTION 
 
This Charter describes the roles and responsibilities for the NHLBI Gene and Cell 
Therapy Data and Safety Monitoring Board (DSMB).     
The DSMB may wish to review this Charter at regular intervals to determine whether any 
changes are needed.   
11.2  ROLE OF THE DSMB 
This study is designed to test the safety of hMSCs in diabetic subjects with endothelial 
dysfunction.  
The purpose of the data safety monitoring board (DSMB), which is the NHLBI Gene and 
Cell Therapy 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.  
The University of Miami Clinical Research Operations and Regulatory Support (CRORS) 
will be monitoring this trial. The Biostatistics Collaboration and Consulting Core will be the 
DCC for this trial. 
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.  
The UM Biostatistics Collaboration and Consulting Core will prepare semi-annual 
summary reports of all AEs/SAEs for the NHLBI Project Officer and DSMB Chairman.  
Semi-annual reports will be made available as part of the semi-annual DSMB meeting 
materials. 
11.3  Purpose of the DSMB 
The primary function of the NHLBI Gene and Cell Therapy 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 


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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 diabetic subjects with endothelial dysfunction. Given the 
importance of mortality, 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.  
11.4  DSMB MEMBERSHIP 
In the NHLBI Gene and Cell Therapy DSMB, rather than corresponding directly with the 
DSMB chair, AE reports will be sent to Dr. Denis Buxton as the NHLBI project officer with 
Charlene Schramm copied as the Executive Secretary of the DSMB. The NHLBI will then 
forward the reports to the DSMB. Charlene Schramm will be responsible for the minutes 
for DSMB meetings. 
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.  
11.4.1 Roles of NHLBI Staff in DSMB meetings   
• 
NHLBI program staff members involved in the day-to-day conduct of the study 
may attend the open sessions of DSMB meetings.  These Program staff may 
attend portions of a closed session as needed, but not when post-randomization 
outcome data by treatment group will be discussed.    
 
• 
NHLBI’s Office of Biostatistics Research has assigned one or more statisticians 
to this DSMB.  The statistician(s) will not be involved in the day-to-day operations 
of the study, but will be involved in statistical aspects of protocol development, 
monitoring safety and efficacy data in an unmasked fashion, as well as working 
with the DCC on analytic plans and publications.  The NHLBI study statistician(s) 
will also serve as a resource to the DSMB as needed.    
 
• 
The NHLBI ES will be a federal employee or contractor with appropriate expertise 
and training who has no other involvement in the conduct of the trial and does not 
report directly to the lead program official.  
 
• 
The ES is the only NHLBI staff member who can routinely be in the executive 
session.  The DSMB can opt to have an executive session without the ES, but 
then will be responsible for minutes for that portion of the meeting.  The DSMB 
can request to have other staff members attend the executive session to provide 
additional information as needed.  
 
• 
The NHLBI ES and statistician(s) are expected to report issues of substantive 
concern to the NHLBI Division Director responsible for the trial.  The NHLBI 
Division Director will communicate with the Office of the Director, NHLBI. Under 
special circumstances, and with the concurrence of the DSMB Chair, the Division 


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leadership and Director and Deputy Director of the NHLBI may see unmasked 
data presented at DSMB meetings.   
 
• 
There may be occasions when it is appropriate for new staff not involved in the 
study to attend a DSMB meeting as a training opportunity.  This will be discussed 
with the DSMB Chair before the meeting; the new staff member(s) would attend 
only the portions of the meeting outlined in the first bullet above. 
11.4.2 DSMB Responsibilities 
 
The DSMB is responsible for safeguarding the interests of study participants, assessing 
the safety and efficacy of study procedures, ensuring data quality, and for monitoring the 
overall conduct of the studies.  For each of the clinical trials in its portfolio the DSMB is 
expected to evaluate candidate protocols for safety and equipoise, and monitor ongoing 
studies to ensure compliance with protocols, accurate and timely reporting of adverse 
events, and acceptable subject recruitment rates.  In performance of these duties the 
DSMB may elect to review unblinded study data and/or request detailed information from 
the study Sponsor or Principal Investigator(s).  
  
The DSMB is an independent body that provides recommendations to the Office of the 
Director, NHLBI, and is required to provide recommendations about starting, continuing, 
and stopping the studies.    
  
In addition, the DSMB is asked to make recommendations or provide comments to the 
NHLBI regarding:  
  
• 
Equipoise of the study   
• 
Benefit/risk ratio of procedures and participant burden  
• 
Potential issues related to selection, recruitment, and retention of participants  
• 
Compliance with the protocol and informed consent procedures  
• 
Completeness, quality, and feasibility of study endpoints   
• 
Adequacy of the data and statistical analysis plan  
• 
Amendments to the study protocol and consent forms, including whether any 
modifications may impact  the equipoise of the study  
• 
Performance of regional clinical centers or core labs  
• 
Participant safety, including review of consent form  
• 
Notification of and referral for unanticipated incidents or findings   
• 
Participant safety and parent study burden of proposed ancillary studies, 
including whether the total burden of ancillary studies might compromise the 
parent study  
 
11.4.3 DSMB Chair(s) Responsibilities 
 
The Chair(s) is/are responsible for the conduct of meetings and ensuring that planned 
business, according to the agenda, is addressed. They should ensure that the 
atmosphere of board discussions fosters an open exchange of views and opinions, is 


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focused on salient issues, and is directed toward the formulation of recommendations. 
They should solicit the views of the member(s) with expertise appropriate for the issue at 
hand, and may request additional expertise or consultants if needed.  
Members are expected to review reports of AE/SAE/Ups, new protocols, and/or protocol 
amendments that arise between meetings at the request of the NHLBI program staff and 
DSMB Chair. 
11.4.4 DSMB Conflict of Interest 
Members must submit an annual conflict of interest assessment, and promptly disclose 
any new conflicts of interest that may arise during their tenure. This DSMB will follow NIH 
and NHLBI conflict of interest rules. At the beginning of each meeting, all DSMB members 
will be asked to state whether they have developed any new conflicts of interest since the 
last formal annual report to NHLBI. If a new conflict is reported, the Chair and NHLBI 
program staff will determine if the conflict limits the ability of the DSMB member to 
participate in the discussion.  
11.4.5 DSMB Confidentiality   
Members are expected to maintain the security and confidentiality of study data and 
DSMB discussions.  
Members are expected to review all materials prior to meetings and calls, and participate 
in discussions at all meetings and calls.  
11.5 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.  
11.6 DSMB MEETINGS  
DSMB meetings are usually held twice a year in the Washington, DC area.  In addition to 
regular meetings, it may be necessary to convene the DSMB on an ad hoc basis to 
discuss new studies or new information related to monitored studies that raises questions 


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about equipoise, safety, or anything else in the trial.  Conference calls are appropriate for 
conducting meetings, if the agenda permits.  
The agenda for DSMB meetings and calls will be drafted by the ES in consultation with 
NHLBI staff.  The ES will finalize the agenda after consultation with the DSMB Chair.  The 
agenda and meeting materials should be distributed by the ES at least two weeks before 
each meeting or call.  Documents will be distributed via a SharePoint site where all 
standing DSMB members will have reading and downloading privileges.  Ad hoc (ex 
officio) members will receive from the ES only those documents relevant to the study(ies) 
monitored by each ad hoc member.  
At the time that the agenda is sent out, and again at the beginning of the meeting, the ES 
will ask all DSMB members to state whether they have developed any new conflicts of 
interest since the last formal annual report to NHLBI.  If a new conflict is reported, the 
Chair and staff will determine if the conflict limits the ability of the DSMB member to 
participate in the discussion.    
During the meetings, and depending on the phase of each study, the DSMB will review 
adverse event data, other safety data, quality and completeness of study data, and 
enrollment data at each meeting to ensure proper trial conduct.  Study personnel should 
provide any new literature particularly pertinent to the trial, along with their 
recommendation as to whether it affects the trial conduct or design.  The DSMB will review 
the informed consent form when it reviews the protocol. The DSMB will review the consent 
periodically and/or as needed and consider whether the consent form requires revision in 
light of any new findings or amendments.  At intervals, as noted above, the DSMB will 
also review formal interim analyses of the primary end point.  
Each meeting culminates in a vote regarding a recommendation to the NHLBI whether 
the clinical studies should proceed as planned or with modifications, or be terminated 
according to the review and stopping guidelines outlined in this document.  
It is expected that all DSMB members will attend every meeting and conference call.  
However, it is recognized that this may not always be possible. A quorum for voting is half 
of the standing members plus one. The Board may wish to decide if particular expertise 
is needed within the quorum for a particular meeting. All standing Monitoring Board 
members are voting members.    
To ensure adequate expertise, the Board may elect to appoint ad hoc members for 
studies in its portfolio, and to confer voting rights for studies within their purview.  
Outside entities may request inclusion of additional independent experts during 
discussions of their studies.  The Board may elect to appoint such members in an ex 
officio capacity.  Ex officio members may only be present during open sessions, and are 
not entitled to vote.  


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11.6.1 Discussion of Confidential Material 
DSMB meetings and calls will be organized into open, closed, and executive sessions.  
• 
During the open sessions, information will be presented to the DSMB by the DCC, 
study investigators, and NHLBI staff as appropriate, with time for discussion.  
 
• 
During the closed sessions, the DSMB, DCC unmasked statistician, and 
unmasked NHLBI statistician(s) may discuss confidential data from the studies, 
including information on efficacy and safety by treatment arm.  The NHLBI’s 
expectation is that the DSMB will review unmasked data, but the Board has the 
discretion to remain blinded to study information.  If the closed session occurs on 
a conference call, steps will be taken to ensure that only the appropriate 
participants are on the call, and to invite others to re-join the call only at the 
conclusion of the closed session.  
 
• 
The DSMB may hold an executive session in which only the DSMB members are 
present. The NHLBI ES may attend the executive session at the invitation of the 
DSMB Chair.  If the ES does not attend the executive session, the DSMB Chair 
will be responsible for summarizing the DSMB’s discussion and recommendations 
to the ES.  Based on an overall assessment of risk, the monitoring board will make 
one of three general recommendations: o Continue the study as planned, without 
modification;  
 
 Continue the study with recommendations – specifying the additions 
or modifications;   
 Stop enrollment in the study, either as a whole or for a particular arm.  
Voting on recommendations will follow Robert’s Rules of Order.   
At the conclusion of the closed and executive sessions, the DSMB chair may provide a 
summary of the preliminary recommendations to the lead investigators and masked 
NHLBI staff to provide an opportunity for study investigators, the DCC, and NHLBI to ask 
questions to clarify the recommendations.  Recommendations that would unmask results, 
such as a recommendation to close a study prematurely, should not be disclosed until 
approved by NHLBI leadership.    
11.6.2 Reports of DSMB Deliberations 
• 
Formal minutes:  The NHLBI ES is responsible for preparation and transmission 
of the formal DSMB minutes to the Director of the applicable Division within 14 
calendar days of each meeting or call.  Minutes will document whether there is 
conflict of interest on the part of Board members and will summarize the key points 
of the discussion and debate, requests for additional information, response of the 
investigators to previous recommendations, and the recommendations from the 
current meeting.    


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• 
Following division and, when applicable, DCC review, the minutes are sent to: 
 
 DSMB Chair, who approves them on behalf of the DSMB.  
 Division Director, Division of Cardiovascular Sciences, NHLBI, for 
final Institute Approval.  
 
• 
Once the Division Director, NHLBI has approved the minutes, they are considered 
final.  
 
• 
The NHLBI Program Office will prepare a Summary Report of Board 
Recommendations and submit it to primary study investigators(s) or DCC within 
30 calendar days of each meeting.  Primary study investigators(s) or DCC will 
forward the Summary Report to each participating research site and are 
responsible for forwarding the DSMB reports to their respective IRBs.  
 
• 
If the DSMB does not identify any safety or other protocol-related concerns, the 
Summary Report will state that:  
 A review of outcome data, adverse events, and information relating 
to study performance (e.g., data timeliness, completeness, and 
quality) across all centers took place on a given date  
  The observed frequency of adverse events did not exceed what was 
expected and indicated in the informed consent;  
 A review of recent literature relevant to the research took place, and;  
 The DSMB recommended that the study continue without 
modification of the protocol or informed consent  
 
• 
If the DSMB does identify concerns, the NHLBI staff will distribute, as soon as 
feasible, preferably within 7 calendar days of the DSMB meeting, the Summary 
Report as outlined above, outlining the concerns and the basis for any 
recommendations that the DSMB has made in response to the concerns. Adverse 
event reporting will be consistent with NHLBI policy.    
 
• 
The NHLBI Program Office will distribute the Summary Report to study 
investigators, or when applicable, the DCC.  It is the responsibility of each clinical 
center to forward this information to the local IRB.   
11.7  COMMUNICATION 
 
The following description illustrates the relationship between the DSMB, NHLBI and other 
entities in the studies.    
Communication of study investigators with DSMB members will be primarily through the 
NHLBI Program Office and, if applicable, the Data Coordinating Center (DCC).  It is 
expected that study investigators will not communicate with DSMB members about the 


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study directly, except when making presentations or responding to questions at DSMB 
meetings or during conference calls.   
If requested, this charter and accompanying list of Board members may be sent to an 
IRB.  In the case, this charter will be marked as “not for dissemination” and be sent with 
a cover letter from the Principal Investigator (PI) to the IRB Chair.   
Consistent with NHLBI policy, each DSMB is assigned an Executive Secretary (ES) to 
provide an unbiased staff interface between the DSMB members and other meeting 
participants, especially during closed and executive sessions.  The ES is responsible for 
assuring the accuracy of the final recommendations and DSMB minutes and timely 
transmission to the NHLBI.  
The NHLBI does not release Board members’ names in response to media inquiries until 
after publication of the main results of the study.  
11.8 Reports to the DSMB 
For each meeting, the study investigators, or when applicable, the DCC, with input from 
NHLBI staff, will prepare summary reports and tables to facilitate the oversight role of the 
DSMB.    
The DSMB should discuss at the first or subsequent meetings what data they wish to 
review and how the data should be presented.  
Reports will include at minimum:  
1. Current protocol version  
2.  Name(s) of Principal investigator(s)  
3.  Organization/institution  
4. Date of submission  
5. Study title(s)  
6. Brief description of study(s)  
7. Recruitment status  
8. Interim or final results (if available)  
9. Description of next steps or plans  
10. Summary of protocol amendments during the reporting period  
11. Summary of serious adverse events  
12. Summary of adverse events  
13. List of relevant investigator publications during the reporting period                        
Adverse events will be presented in table format whenever possible and include all 
adverse events over the entire period of the study. For each event, the report will specify, 
at minimum:  
1. Subject ID  
2. Site  
3. Date of Treatment  
4. Date of AE  
5. Description  


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6. Expectedness (Expected/Unexpected)  
7. Severity or Grade (Mild/Moderate/Severe/Life-Threatening/Death; or Grade 1-5)  
8. Relationship to Procedure (Unrelated/Unlikely/Possibly/Probably/Definitely)  
9. Relationship to Study Product (Unrelated/Unlikely/Possibly/Probably/Definitely)  
10. Current Status or Resolution (Ongoing/Resolved/Progressed/Unknown)  
11.9 Expedited Adverse Event Review and DSMB Notification Process  
 
The role of the DSMB is to is to provide an independent assessment of the severity of the 
event experienced by the individual subject and the significance of the event to the trial 
as a whole, that is, to weigh the potential risk of a similar event to other enrolled or future 
subjects, and to make recommendations regarding protocol and study operations to 
ensure subject safety, in an urgent manner when warranted.  
The notification process is as follows:  
• 
The PI, sponsor, or DCC reviews the occurrence in accordance with the DSM plan 
and federal regulatory requirements. The DCC medical monitor, PI, or designee, 
prepares a study AE report form, and sends the form to the NHLBI Program Officer 
in the timeframe established by NHLBI policy and FDA reporting requirements, 
according to whether the event requires expedited reporting. The AE report is often 
accompanied by a summary memorandum for the DSMB, and supporting clinical 
narratives, lab or exam reports.  
 
• 
The NHLBI Program Officer notifies the ES to forward the report and any other 
documents to the appropriate members of the DSMB.  
 
• 
The ES forwards the notification and documents to the board Chair and 
appropriate members of the DSMB.   
• 
Each reviewer is requested to review and provide a statement of her/his 
assessment, in particular whether the event is expected or related, and if her/his 
assessment is in agreement, or in conflict, with that of the study medical monitor 
in any important respect.  
 
• 
The Chair also determines whether the event is sufficiently serious as to require 
notification of the full board, and if the event requires a call for discussion. If so, 
the ES will notify the board with the information by e-mail, and handle 
arrangements for a conference call, as warranted.  
 
• 
If the Chair and/or board require additional information on the event, the ES will 
contact the NHLBI Program Officer, who will communicate the request to the study 
personnel or DCC.  
11.10 Clinical Holds  
If at any time a study is placed on Clinical Hold by the FDA, IRB, or study investigators, 
the DSMB will be notified immediately, as follows:   


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• 
The PI, sponsor, or DCC notifies the NHLBI Program Officer that the study has 
been placed on Clinical Hold.  For external Holds, correspondence from the FDA 
or IRB containing the justification for the Hold will be provided at the time of 
notification.  Notification of internal holds will include a detailed justification 
provided by study investigators, sponsor, or DCC.  
 
• 
The NHLBI Program Officer notifies the ES to forward the notification, 
justification(s), and any other documents to the appropriate members of the DSMB.  
 
• 
The ES forwards the notification and documents to the board Chair and 
appropriate members of the DSMB.   
If/when a Hold is lifted, the PI, sponsor or DCC will notify the NHLBI Program Officer and 
provide, as appropriate, documentation of FDA and IRB approvals, all data or other 
information provided in support of lifting the Hold, and revised protocol.  The Program 
Officer will provide the materials to the ES to forward to the board Chair and appropriate 
members of the DSMB.  
The study investigators will not resume accrual unless/until the DSMB reviews the 
materials and recommends to the NHLBI to allow the study to proceed.  DSMB 
recommendations will be submitted to the Division and Institute by the ES and a summary 
returned to the study investigators as described above in Section 9: Reports of DSMB 
Deliberations.  
11.11 Review of New Protocols  
 
The DSMB will conduct a review of new protocols according to the following process:  
• 
The NHLBI Program Officer notifies the ES when an NHLBI-supported study falls 
under the NHLBI policy for DSMB monitoring of high-risk gene and cell therapy 
clinical trials.  
 
• 
The ES arranges a conference call to take place within approximately four weeks 
and sends the protocol, consent, and other documents to the board members. The 
members will be given at least two weeks for their review, if possible. At the 
discretion of the Chair, review and voting may be conducted by correspondence.  
 
• 
While reviewing the documents, the board members will record their comments 
and questions and forward them to the ES.  
 
• 
The ES will collate the comments and questions into one document.  The ES sends 
the document to the NHLBI Program Officer.  
 
• 
The Program Officer forwards the comments and questions to the study 
investigators and/or DCC for their response, which is then sent to the ES to share 
with the DSMB prior to the meeting.  


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If notification is received within four weeks of a regular meeting of the DSMB, the review 
of the new protocol may occur as part of the regular meeting.  
If a study team wishes to provide an informational introduction to an anticipated protocol, 
a presentation may be included in the agenda of a regular meeting.  However, the DSMB 
will not make recommendations to the NHLBI until provided with the FDA- and IRB-
approved protocol and informed consent forms; investigator brochure, if applicable; 
documentation of FDA review of the protocol; and for gene therapy studies, 
documentation of RAC review.  
11.12 Statistical Monitoring Guidelines  
Review of new protocols will include review of the adequacy of the statistical monitoring 
plan.  The final plan, whether part of a research protocol or separate document, will be 
maintained as an appendix to the DSMB Charter. The DSMB should discuss the statistical 
monitoring procedures that will be followed to guide recommendations about termination 
or continuation of the trial.  These procedures could include guidelines for early 
termination for benefit, termination for futility, and termination for safety reasons. 
12. 
STUDY ADMINISTRATION 
12.1 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. 
 
12.2  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. 


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12.3  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.  
 
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. 
If a subject is unable to come to site due to COVID-19, the following methods will be 
used to obtain informed consent that meets the requirements of local regulations, ICH 
guidelines, and the IRB/EC or study center, where applicable:  
• Obtain the informed consent electronically; OR  
• Obtain the informed consent by teleconference/video conference in alignment 
with local regulatory guidance.  
How the consent was obtained and reason why it was obtained using that particular 
method should be documented in the eCRF. The signature may be obtained via a 
secure email or digital signature. If it is not possible to obtain a digital image of the 
signed page, a statement of consent can be obtained via cellphone text message or via 
secure email. This does not preclude a site from obtaining consent via paper, if such 
arrangements can be made, e.g. fax, mail. During the remote informed consent process 
the subject, a witness, and someone from the study team will be present. 
 
12.4  
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 


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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. 
Participants 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 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.   
12.5  
Payments to Subjects 
 
Subjects will be reimbursed $25 at the end of each follow-up visit (Day 3 – Month 12) for 
a total remuneration of $175. These disbursements are meant to cover the time required 
to complete these study visits and all necessary travel and parking 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 < 93% over a continual period of 3 – 5 
minutes then supplemental oxygen may be added or increased during the 
two hours post-infusion observation period.  
4. 
If at the end of the 2 hour observation period, if a subject’s O2 saturation 
stays below 93% then the subject will be provided additional oxygen to 
maintain a saturation of >93% at room air up to 4 hours post infusion.  
5. 
After the minimum two-hour observation period, the subject will be 
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: 
- 
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. 
 
- 
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. 
 
- 
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 


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infusions but will continue with all scheduled follow-up if such follow-up is 
considered safe in the opinion of the Investigator. 
 
- 
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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