Clinical trial NCT03818737
Conditions: Osteoarthritis
Keywords: mesenchymal stem cells corticosteroids bone marrow aspiration adipose-derived stromal vascular fraction
Sponsor: Emory University
Start date: 2019-03-28; Completion date: 2022-05-31
Enrollment: 475 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is a multicenter trial conducted to compare the effectiveness of an injection of a corticosteroid control to mesenchymal stem cell (MSC) preparations from autologous bone marrow concentrate (BMAC), adipose derived stem cells in the form of Stromal Vascular Fraction (SVF), and third-party human mesenchymal stem cells manufactured from umbilical cord tissue (UCT) for the treatment of unilateral Knee Osteoarthritis (OA). The study will be conducted in 4 sites in the United States, and a total of 480 participants will be enrolled in this study.

Detailed description:
Primary osteoarthritis is a debilitating disease characterized by extensive damage to the joints and excruciating pain leading to loss of activity and depression. Despite advances in diagnosis and relatively efficient control of nociception, to date, the quest for the development of a disease modifying osteoarthritis drug has proven unsuccessful. The potential of mesenchymal stem cells (MSCs) to inhibit inflammation while promoting healing makes them amenable for the treatment of various ailments ranging from cancer to genetic diseases. In orthopedic practice, autologous stem cell injections are performed to alleviate the pain associated with osteoarthritis. A serious gap in knowledge remains whether the currently used cellular treatments are beneficial in the long term and if one cell therapy outperforms another.

The most popular form of autologous MSC therapy has been through the use of autologous bone marrow concentrate (BMAC). The rationale is that when a sample of bone marrow aspirate (BMA) is collected and the components that are not beneficial to the joint are filtered out (i.e. red blood cells, neutrophils, etc.) the remaining concentrate (MSCs, platelets, interleukins, etc) can have a "healing" effect on the environment in which it is injected. However it is still unknown as to how effective BMAC is for treating orthopedic conditions compared to other MSC procedures and the most important components of the BMAC mixture that could aid patients suffering from osteoarthritis.

Adipose tissue has been found to have a large amount of MSCs versus that in bone marrow. These cells are currently being used in a variety of clinical research studies within the regenerative medicine field. Through a tissue process which includes washing and centrifuging, the cellular components can be extracted as a cell pellet, which is also known as stromal vascular fraction (SVF). Adipose derived SVF is obtained via liposuction, or the removal of adipose tissue via a suction method.

Although the use of various stem cell preparations for knee osteoarthritis has become increasingly prevalent, well-designed studies with conclusive proof of comparative effectiveness and identification of the optimal cell source and "dose" have not been performed. This study is the first randomized study comparing three types of cellular treatments to corticosteroids. The main objective of the study is to identify a superior source of stem cells for the treatment of osteoarthritis and validate its advantages over corticosteroid injections as the traditional gold standard treatment.

Participants will be randomized study arms with different types of MSCs (bone marrow derived MSC, adipose derived MSC, and umbilical cord tissue MSC) and then will be further randomized to receive an injection of the MSC type they were initially assigned to or corticosteroid. Participants randomized to bone marrow derived MSC or adipose derived MSC will undergo a procedure (bone marrow aspiration or liposuction). Participants will be blinded to whether they receive the MSC or corticosteroid injection.

Arms: arm 1: Participants randomized to this arm will undergo bone marrow aspiration and then will be further randomized to receive a standard orthobiologic injection into the knee joint of autologous bone marrow concentrate (BMAC). arm 2: Participants randomized to this arm will undergo small volume lipoplasty, and then will be further randomized to receive an injection into the knee joint of adipose-derived stromal vascular fraction (SVF). arm 3: Participants randomized to this arm will receive an injection into the knee joint of cryopreserved doses of umbilical cord tissue MSCs. arm 4: Participants randomized to the bone marrow derived MSC, adipose-derived MSC, or umbilical cord tissue MSC study arms will be further randomized within the arm in a 3:1 ratio to receive either MSCs derived from the study arm of the initial randomization or a corticosteroid (CS) injection. Participants randomized to the control group will receive an injection of corticosteroid into the knee joint.
Interventions: intervention 1: Bone Marrow Derived MSCs intervention 2: Adipose-derived MSCs intervention 3: Umbilical Cord Tissue (UCT) MSCs intervention 4: Corticosteroid injection
Intervention descriptions: intervention 1: Autologous bone marrow concentrate (BMAC) is a standard orthobiologic injection for knee osteoarthritis. The procedure involves harvesting of bone marrow aspirate (BMA) from the posterior superior iliac spine (PSIS) and then following centrifugation in an FDA approved device (EmCyte GenesisCS Pure BMAC®-60 ml) will be injected back into the knee joint. All injections will be made via ultrasound guidance using a standard approach. intervention 2: Adipose-derived Stromal Vascular Fraction (SVF) will be obtained from a mini lipoaspirate. The lipoaspirate will then be enzymatically digested to produce a SVF that will be injected into the knee joint. All injections will be made via ultrasound guidance using a standard approach. intervention 3: Cryopreserved doses of umbilical cord tissue MSCs will be used. These MSCs were cryopreserved at P2 culture in plasmalyte A + 5% human serum albumin in 5 finger cryobags containing 20 million cells in 4 mL and stored under liquid nitrogen until shipment. Cells will be transported in a dry shipper and thawed at the study sites. The dose of MSCs will be aspirated from the cryobag into a sterile syringe and directly injected into the knee. All injections will be made via ultrasound guidance using a standard approach. intervention 4: The corticosteroid injection is prepared by mixing 1cc of 40mg/dL depomedrol and 6cc of normal saline in a 10cc syringe will be made into the knee joint. All injections will be made via ultrasound guidance using a standard approach.

Protocol documents:
Prot_SAP_000.pdf: 
Study Protocol 
 
Title: Randomized multicenter phase 3 single-blind trial comparing the 
efficacy of corticosteroid control to mesenchymal stem cell 
preparations from autologous bone marrow concentrate (BMAC), 
adipose derived stem cells in the form of Stromal Vascular Fraction 
(SVF), and third party human mesenchymal stem cells manufactured 
from umbilical cord tissue for the treatment of unilateral Knee 
Osteoarthritis (OA)  
 
NCT Number: NCT03818737 
 
IRB Approval Date: October 22, 2020 
 


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CLINICAL STUDY PROTOCOL
Randomized multicenter phase 3 single-blind trial comparing the efficacy of corticosteroid control 
to mesenchymal stem cell preparations from autologous bone marrow concentrate (BMAC), 
adipose derived stem cells in the form of Stromal Vascular Fraction (SVF), and third party human 
mesenchymal stem cells manufactured from umbilical cord tissue for the treatment of unilateral 
Knee Osteoarthritis (OA).
Protocol Number:  Multicenter trIal of stem ceLl thErapy for oSteoarthritis (MILES)
Protocol Version: 9.0
Protocol Date: 22-Oct-2020
Sponsor-Investigator Name:  Scott Boden, MD
Study Leadership:
Scott Boden, MD: Overall Study PI (Emory)
Hicham Drissi, PhD: Scientific Program Director (Emory)
Lora Black, RN, MPH: CRO Director (Sanford)
Krish Roy, PhD: Cell analytics center Core Director (Georgia Tech)
Joanne Kurtzberg, MD: Cord Blood Bank Director (Duke)
Michael Gottschalk, MD: Clinical Research Director (Emory)
Eric Wagner, MS, MD: Medical Monitor (Emory)
Sites:
Emory University:  
Kenneth Mautner, MD
Sanford Health:
Fargo
Benjamin Noonan, MD, MS
Sioux Falls
Chad Kurtenbach, MD
Duke University:
Blake Boggess, DO
Andrews Institute:
Joshua Hackel, MD


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Responsibility Acknowledgement:
I have read this study protocol and agree to adhere to the requirements.  I, or my designee, will 
provide copies of this study protocol and all pertinent information to the study personnel.  I, or 
my designee, will discuss this material with them and ensure they are fully informed regarding 
the study interventions and the conduct of the study according to the Food and Drug 
Administration (FDA) Guidelines for Good Clinical Practices (GCP), the institutional policies 
and procedures, and pertinent individual country laws/regulations.
Investigator
Date


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Sponsor Signature Page:
______________________________________
_____________________________
Scott Boden, MD
Date
Sponsor-Investigator
Emory University


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Contents
1.0
Protocol Summary .....................................................................................................10
1.1
Synopsis.............................................................................................................................10
1.2
Schema ..............................................................................................................................13
1.3
Schedule of Activities (SoA)................................................................................................14
2.0
Introduction...............................................................................................................16
2.1
Study Rationale..................................................................................................................16
2.2      Background ..........................................................................................................................16
2.3      Benefit/Risk Assessment ......................................................................................................18
2.3.1
Procedural-Related Risks.....................................................................................................................18
2.3.2
Mitigation of Risks ...............................................................................................................................21
3.0
Objectives and Endpoints...........................................................................................22
3.1
Primary Objective...............................................................................................................22
3.2
Secondary Objectives .........................................................................................................22
3.3
Exploratory Objectives .......................................................................................................22
4.0
Study Design ..............................................................................................................22
4.1
Overall study design...........................................................................................................22
4.2
Scientific Rationale for Study Design ..................................................................................23
4.3
Enrollment .........................................................................................................................25
4.4
End of Study Definition.......................................................................................................25
4.5
Study Stopping Rules..........................................................................................................25
5.0
Study Population........................................................................................................25
5.1 
Eligibility Criteria:...............................................................................................................25
5.1.1
Inclusion Criteria..................................................................................................................................25
5.1.2
 Exclusion Criteria ................................................................................................................................26
5.2
Screen Failures ...................................................................................................................27
6.0
Study Intervention......................................................................................................27
6.1
Study Intervention(s) Administered:...................................................................................28
6.1.1
Autologous Bone Marrow Concentrate (BMAC) .................................................................................28
6.1.2
Adipose-derived Stromal Vascular Fraction (SVF) ...............................................................................28
6.1.3
Mesenchymal Stem Cells derived from Umbilical Cord Tissue (UCT)..................................................28
6.1.4
Corticosteroid Injection.......................................................................................................................28
6.2
Measures to Minimize Bias: Randomization and Blinding...................................................28
6.2.1
Randomization Methods .....................................................................................................................29
6.2.2
Implementation of Randomization and Blinding.................................................................................29


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6.3
Study Compliance...............................................................................................................29
6.4
Concomitant Therapy.........................................................................................................30
7.0
Subject Discontinuation/Withdrawal..........................................................................30
7.1
Subject Discontinuation .....................................................................................................30
7.2
Subject Withdrawal of Consent ..........................................................................................30
7.3
Lost To Follow Up...............................................................................................................30
7.4
Treatment failure ...............................................................................................................31
7.5
Discontinuation of the Clinical Study ..................................................................................31
8.0
Study Assessments and Procedures ............................................................................31
8.1 
Study Visit Assessments .....................................................................................................31
8.1.1 Screening Visit (Visit 1)..............................................................................................................................31
8.1.2
Treatment Visit (Visit 2, Day 0)............................................................................................................31
8.1.3
Week 1 (Visit 3, Day 7).........................................................................................................................32
8.1.4
Month 1 (Visit 4, Day 30).....................................................................................................................32
8.1.5
Month 3 (Visit 5, Day 90).....................................................................................................................32
8.1.6
Month 6 (Visit 6, Day 180)...................................................................................................................33
8.1.7
Month 9 Phone Call (Visit 7, Day 270) .................................................................................................33
8.1.8
Month 12/ (Visit 8, Day 365) ...............................................................................................................33
8.1.9
Unscheduled Visits...............................................................................................................................33
8.1.10
 End of Study Visit ...........................................................................................................................33
8.2
Clinical Assessments and Procedures..................................................................................33
8.2.1
Informed consent and HIPAA Authorization .......................................................................................33
8.2.2
Assignment of Screening Number .......................................................................................................34
8.2.3
Inclusion/Exclusion Criteria .................................................................................................................34
8.2.4
Demographics......................................................................................................................................34
8.2.5
Medical and Surgical History ...............................................................................................................34
8.2.6
Prior Medications ................................................................................................................................34
8.2.7
Concomitant Medications and Treatments.........................................................................................34
8.2.8
Physical Examination ...........................................................................................................................34
8.2.9
Vital Signs.............................................................................................................................................35
8.2.10
MRI..................................................................................................................................................35
8.2.11
Patient Reported Outcomes ...........................................................................................................35
8.2.11.1  Visual Analog Pain Scale (VAS) .......................................................................................................35
8.2.11.2  Euro-Quality of Life (EQ5D 3L)........................................................................................................35
8.2.11.3  Knee Injury and Osteoarthritis Outcome Score (KOOS).................................................................35
8.2.11.4  Patient-Reported Outcomes Measurement Information System (PROMIS 29).............................35
8.2.12
Adverse Event Monitoring ..............................................................................................................35
8.2.13  Physical Therapy ....................................................................................................................................35
8.2.14
 Cell Characterization......................................................................................................................36
8.2.15
Local Laboratory Assessments........................................................................................................36
8.2.15.1 Hematology.....................................................................................................................................36
8.2.15.2 Clinical Chemistry............................................................................................................................36
8.2.15.3 Coagulation Assays..........................................................................................................................36


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8.2.15.4 Immunogenicity Testing..................................................................................................................36
8.2.16
Pregnancy Testing...........................................................................................................................36
8.3
Protocol Deviations............................................................................................................37
8.4
Adverse Event Reporting and Safety Monitoring ................................................................37
8.4.1
Adverse Events ....................................................................................................................................37
8.4.2
Serious Adverse Events........................................................................................................................37
8.4.3
AE and SAE Collection..........................................................................................................................37
8.4.4
Follow-up of AEs and SAEs...................................................................................................................38
8.4.5
Adverse Event and Serious Adverse Event Reporting..........................................................................38
8.4.6
Investigational New Drug (IND) Safety Reports...................................................................................38
8.4.7
Unanticipated Problems (Emory IRB Requirement) ............................................................................38
9.0
Statistical Considerations...........................................................................................39
9.1
Statistical Hypothesis .........................................................................................................39
9.2
Sample Size Determination ................................................................................................39
9.3
Efficacy Analyses ................................................................................................................40
9.3.1
Efficacy Variables.................................................................................................................................40
9.3.2    Primary and Secondary Efficacy Analyses ..............................................................................................40
9.3.3
Efficacy Analyses across Subgroups.....................................................................................................41
9.4
Safety Analyses ..................................................................................................................41
9.4.1
Trial Drug Exposure..............................................................................................................................41
9.4.2
Adverse Events ....................................................................................................................................42
9.4.3
Continuous Monitoring of Specific Adverse Events.............................................................................42
9.4.4
Analysis of Adverse Events ..................................................................................................................43
9.5
Interim Analyses and Data Monitoring ...............................................................................44
10.0 Ethical Considerations and Compliance with Good Clinical Practice.............................44
10.1
Statement of Compliance ...................................................................................................44
10.2
Participating Centers..........................................................................................................45
10.3    Informed Consent.................................................................................................................45
10.4    Study Subject Confidentiality................................................................................................45
10.5
Study Documentation and Case Report Forms (CRFs) .........................................................46
10.6
Monitoring of the Study .....................................................................................................46
10.7 
Direct Access to Source Data/Documents...........................................................................47
10.8
Medical Monitor and Data Safety Monitoring Board (DSMB)..............................................47
10.9
Publication Policy...............................................................................................................48
10.10
Maintenance and Retention of Records..........................................................................48
11.0
References .................................................................................................................49
12.0
Appendices.................................................................................................................50


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12.1 Joint Rehab.................................................................................................................................................50
12.2 Lab Value Reference Ranges......................................................................................................................51


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List of Abbreviations
ADP
Adipose Tissue
ADSC
Adipose Derived Stem Cells
AE/SAE/UP
Adverse Event/Serious Adverse Event/Unanticipated Problem
BMAC
Autologous Bone Marrow Concentrate
BMI
Body Mass Index
CDC
Centers for Disease Control
CFR
Code of Federal Regulations
CRF/eCRF
Case Report Form/electronic Case Report Form
CRO
Contract Research Organization
CSI
Corticosteroid Injections
DHHS
Department of Health and Human Services 
DOD
Department of Defense
DSMB
Data Safety Monitoring Board
FDA
Food and Drug Administration
FCBP
Female of Child Bearing Potential
GCP 
Good Clinical Practices
GEE 
Generalized Estimating Equations
GMP
Good Manufacturing Practices
HIPAA
Health Insurance Portability and Accountability Act
ICF
Informed Consent Form
ICH
International Conference on Harmonization
IKDC 
International Knee Documentation Committee 
IND
Investigational New Drug
IRB
Institutional Review Board
KOOS
Knee Injury and Osteoarthritis Outcome Score
MAR
Missing at Random
MC3M 
Marcus Center for Therapeutic Cell Characterization and Manufacturing 
MedDRA
Medical Dictionary of Regulatory Activities
MRI
Magnetic Resonance Imaging
MSCs
Mesenchymal Stem Cells
NCI-CTCAE National Cancer Institute-Common Terminology Criteria for Adverse Events
NIH
National Institutes of Health
NSAIDs
Non-Steroidal Anti-Inflammatory


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OA
Osteoarthritis
OHRP
Office for Human Research Protections
PHI
Personal Health Information
PI
Principal Investigator
PRO
Patient Reported Outcomes 
PRP
Platelet Rich Plasma
PSIS
Posterior Superior Iliac Spine 
RCT
Randomized Controlled Trial
RPM
Revolutions per Minute
SAP
Statistical Analysis Plan
SAS
Statistical Analysis System
SoA
Schedule of Activities 
SVF
Stromal Vascular Fraction
UCT
Umbilical Cord Tissue
UP
Unanticipated Problem 
USA
United States of America
VA
Veteran's Administration
VAS
Visual Analog Scale


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1.0
Protocol Summary
1.1
Synopsis
Title of Study
Randomized multicenter phase 3 single-blind trial comparing the efficacy of 
corticosteroid control to mesenchymal stem cell preparations from autologous bone 
marrow concentrate (BMAC), adipose derived stem cells in the form of Stromal 
Vascular Fraction (SVF), and third party human mesenchymal stem cells 
manufactured from umbilical cord tissue (UCT) for the treatment of unilateral Knee 
Osteoarthritis (OA).
Study 
Objectives
To identify a superior source of stem cells for the treatment of osteoarthritis and 
validate its advantages over corticosteroid injections as traditional gold standard 
treatment.  The primary efficacy co-outcomes are: a change in the visual analog 
score (VAS) pain score and a change in the pain subsection of the knee injury and 
osteoarthritis outcome (KOOS) score. Secondary endpoints include total KOOS 
score, Magnetic Resonance Imaging (MRI) and additional patient reported outcomes 
(PROs).
Study Design
Multicenter prospective single-blinded randomized controlled clinical trial. The 
study will include a parallel design using a blocked central randomization scheme of 
1:1:1:1. Subjects will be allocated to three different arms with a 3:1 assignment.  
Autologous bone marrow concentrate (n=120): corticosteroid (n=40), umbilical cord 
tissue (n=120): corticosteroid (n=40), and adipose derived SVF (n=120): 
corticosteroid (n=40). 
Eligibility 
Criteria
Inclusion Criteria:
1.
Age ≥40 but ≤70 years old 
2.
Males and Females
3.
Recent knee radiograph of the targeted knee (Standing AP lateral and sunrise 
view)
4.
Diagnosis of OA in the targeted knee (radiographic evidence of OA in the 
medial and/or lateral tibiofemoral compartment, which would include one or 
more osteophytes on a standard radiograph taken within 3 months). Subjects 
may have concomitant patellofemoral but must have grade II or higher medial 
or lateral tibiofemoral knee OA and the primary pain must be related to 
tibiofemoral arthritis. 
5.
Continued OA pain in the targeted knee despite conservative measures (per 
treating provider’s discretion)
6.
Average daily VAS ≥ 3
7.
Kellgren-Lawrence system of Grade II, III, or IV
8.
Females of childbearing potential (FCBP) only, must have a negative 
pregnancy test done at screening prior to enrollment. FCBP is defined as any 
premenopausal female unless they have had a surgical sterilization procedure 
such as, but not limited to, hysterectomy, oophorectomy, or tubal ligation
9.
Women and men of child-producing potential must agree to use acceptable 
contraception methods for the duration of the trial such as birth control pills or 
condoms with spermicide


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Exclusion Criteria:
1.
Clinically apparent tense effusion of the targeted knee
2.
Significant valgus/varus deformities (+/- 10 degrees) 
3.
Viscosupplementation within 6 months in the targeted knee
4.
Other Biologic Injection (PRP or stem cell) within 1 year in the targeted knee
5.
Surgery in the targeted knee within the past 6 months (either open or scope)
6.
Systemic or intra-articular injection of corticosteroids in any joint within 3 
months before screening
7.
Daily opioid use for the past three months
8.
History of malignancy in the previous 5 years prior to study entry, with the 
exception of in-situ cancers treated only by local excision with curative intent.
9.
History of, or ongoing, autoimmune disorder that requires treatment with an 
immunosuppressive medication
10.
Active, suspected, or prior infection to the joint in the targeted knee
11.
Part of a vulnerable population per Office for Human Research Protections 
(OHRP) definition (pregnant women and breast-feeding women, cognitively 
impaired, prisoners, etc.)
12.
Unwilling to discontinue the use of Non-Steroidal Anti-Inflammatory 
(NSAID)s for 7 calendar days prior to the procedure
13.
Unwilling to discontinue use of NSAIDS for 5 calendar days after procedure
14.
History of bleeding disorders or inflammatory joint disease
15.
Inability to hold anti-platelet therapy according to treating provider prior to 
procedure
16.
Subject is, in the opinion of the investigator, unable to comply with the 
requirements of the study protocol or is unsuitable for the study for any reason.
17.
Uncontrolled diabetes (determined by the treating investigator)
18.
Subject has an active workers’ compensation case in progress with targeted 
knee
19.
Subject with insufficient amount of subcutaneous tissue, at the discretion of the 
treating investigator upon examination. 
20.
Hemoglobin less than 10g/dL at the time of screening
21.
Leukocytes <3,000/µL; neutrophils <1,500/µL; lymphocytes <800/µL; 
platelets <100,000/µL at the time of screening
22.
Diagnosis of liver disease as defined by alanine aminotransferase (ALT) >3x 
the upper limit of age-determined normal (ULN) or total bilirubin > 1.5x ULN
23.
Subjects who have had greater than 3 corticosteroid injections in the targeted 
knee in the 12 months prior to screening or at the physician’s discretion.
24.
Subjects with a known diagnosis of osteoporosis
25.
Subjects with anticipated use of systemic corticosteroids during the study 
period for treatment of a chronic medical condition
Sample Size
Total of 480 subjects.  120 subjects at each of the 4 institutions.
Statistical 
Analysis
The sample size calculations for the proposed intention-to treat, parallel-group, 
multicenter, randomized, controlled trial is based on improvements (from baseline to 
1-year) in the visual analog scale (VAS) pain score and the knee injury and 
osteoarthritis outcome (KOOS) score. As the pain subsection of the KOOS is more 
sensitive and specific, using the full KOOS score as a proxy should provide ample 
power for the study. 
Study 
Treatment
Subjects will be divided among three parallel arms for ease of blinding.
Arm 1 includes randomization to bone marrow derived MSCs versus 
corticosteroid injection.
Arm 2 includes randomization to adipose derived MSCs versus 
corticosteroid injection.
Arm 3 includes randomization to umbilical cord tissue MSCs versus 


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corticosteroid injection.
Study 
Evaluations
Follow-up exams will occur at intervals of 7 days, 1 month, 3 months, 6 months, and 
9 months (telephone only), and 1 year.
Subjects will undergo a pre-injection MRI and a follow-up MRI at 6 and 12 months. 
Total of 3 MRIs per subject.
Subject will complete PROs at each time point.
Study Period
All randomized subjects will be followed in the study for approximately 1 year 
after treatment. If subjects continue to show improvement at the 1-year time frame, 
additional funding may be sought to provide ongoing treatment. 


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1.2
Schema
Adipose derived SVF 
vs. Corticosteroid 
injection
Autologous Bone 
Marrow Concentrate vs. 
Corticosteroid Injection
 Potential Subject presents to the Clinic 
with Continued OA knee pain despite 
conservative measures
Umbilical Cord Tissue 
MSCs vs. Corticosteroid 
Injection
Randomization
Screening Visit
Injection
Follow-up Evaluations
Informed Consent
Enrolled


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1.3
Schedule of Activities (SoA)
This study consists of the following phases:  
Screening 
Visit
Treatment
Follow-Up
Unscheduled 
Visit/EOSjm
Days
-30 days
0
7
30
90
180
270
365
UNS
Scheduling Window (+/- days)
+/- 1 day
+/-15 days
+/-15 days
+/-30 day
+/-30 days
+/-30 days
As needed
Administrative Procedures
Informed Consent & HIPAA 
X
Randomization
X
Inclusion/Exclusion Criteria
X
Demographics & Medical/Surgical 
History
X
Prior and Concomitant Medications 
and Treatments
X
X
X
X
X
X
X
X
X
Knee Osteoarthritis History
X
Clinical Procedures and Assessments
Focused Knee Assessment (knee & 
harvest sitek)
X
Xn
X
X
X
X
X
X
Vital Signs
X
X
X
X
X
X
X
X
Phone Call
X
MRI
Xe
X
X
PROs
X
X
X
X
X
X
Adverse Events Monitoring
X
X
X
X
X
X
X
X
X
Study Procedure/Treatment
Pre-Treatment Confirmation of 
Eligibilityp 
X
Lipoaspirate procedure, Bone Marrow 
Aspiration, or UCT-MSCs Dispensing
Xd
Cell Processingq
X
Product Release Criteria Testingo
X
CSI Preparationr
X
Arthrocentesisf & Knee injection
X
Cell Characterization (MC3M samples)
Sample Processing and Storage 
X


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Local Laboratory Assessments
CBCah
X
X
X
Basic Metabolic Panelai
X
X
X
PT/INRag
X
X
X
Liver Function Testsai
X
X
X
Immunogenicity Testing (UCT arm 
only)cl
X
X
Pregnancy Test
Xb
Xb
a   Subject will be referred to their primary care provider if any abnormalities (not already known to the subject or in the medical history) are discovered from the safety labs and deemed 
clinically significant by the treating investigator. 
b   FCBP: Obtain urine or serum pregnancy test.
c    Immunogenicity testing which consists of a panel reactive antibodies (PRA), will be performed on the  recipients of the umbilical cord tissue. All subjects in the UCT arm will have a 
blood draw to maintain subject blinding.        
d  Subjects randomized to Arm 1 will undergo the bone marrow aspiration. Subjects randomized to Arm 2 will undergo the lipoaspirate procedure. UCT-MSCs dispensing will only occur for 
subjects randomized to Arm 3 / UCT treatment group. 
e  Only subjects that meet all eligibility criteria will undergo the Screening MRI
f   Investigator will aspirate synovial fluid prior to knee injection when possible (physician’s discretion). Collected synovial fluid will be sent to MC3M for testing (details in study manuals).
g  PTT may be ordered if deemed appropriate by the treating investigator
h  CBC should include a platelet count
i  Basic metabolic panel and Liver function panel may be substituted for a Comprehensive metabolic panel (physician’s discretion) as long as the test includes an ALT and Total Bilirubin
j  Assessments completed during an Unscheduled Visit will be at the discretion of the treating investigator based on the reason for visit and examination of the subject. Laboratory 
assessments may be ordered at the discretion of the treating investigator.
k Observation of the harvest site will be completed at the 7-day follow-up and 30-day follow-up visits. This will only be done for subjects on Arm 1 and Arm 2.
l  Please refer to the Operations Manual for specific results required for this testing
m End of study visit: Assessments required will be at the discretion of the treating investigator in order to ensure subject safety. The EOS visit would only occur in the event the study is 
discontinued early (see Section 7.5) 
n  Optional, at the discretion of the treating investigator
o   Refer to the Operations Manual for Arm-specific product release criteria requirements. 
p  Treating Investigator must complete the Pre-Treatment Confirmation of Subject Eligibility form PRIOR to procedure or UCT dispensing. 
q  Only subjects randomized to Arm 1 or Arm 2. 
r   Only subject randomized to receive the CSI treatment in any of the 3 arms.


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2.0
Introduction 
2.1
Study Rationale
Primary osteoarthritis is a debilitating disease characterized by (i) extensive damage to 
the joints, (ii) excruciating pain leading to loss of activity and depression. Osteoarthritis 
is a significant clinical dilemma in the USA and around the world. Despite advances in 
diagnosis and relatively efficient control of nociception, to date, the quest for the 
development of a disease modifying osteoarthritis drug has proven unsuccessful. The 
consequence of this has been to employ ineffective non-surgical procedures until 
extensive wearing of the cartilage has forced surgeons to perform expensive and risky 
joint replacement therapies.
The economic burden [4] for treatment and lost productivity caused by osteoarthritis 
amounts to 60 billion annually in the US alone. According to the Centers for Disease 
Control (CDC), arthritis currently affects more than 20 million Americans.
With an ever-growing aging population, debilitating pain, loss of muscle function and 
decreased physical activity further enhance associated costs of care to treat diabetes, 
depression and other secondary consequences of osteoarthritis. A lesser-recognized 
consequence of such chronic ailment is the emotional burden of family members who 
care for osteoarthritic patients.
2.2      Background
The potential of mesenchymal stem cells to inhibit inflammation while promoting healing 
makes them amenable for the treatment of various ailments ranging from cancer to 
genetic diseases. In orthopedic practice, autologous stem cell injections are performed to 
alleviate the pain associated with osteoarthritis. Thus, at all recruiting sites, physicians 
have led multiple studies geared towards understanding the advantages and disadvantages 
of using autologous stem cells for the treatment of osteoarthritic joints. A thorough search 
of the orthopedic literature yielded limited injectable cell data, most of which describe 
case series. A serious gap in knowledge remains whether the currently used cellular 
treatments are beneficial in the long term and if one cell therapy outperforms another. 
Finally, our survey of the clinical trials in the continental U.S. failed to show any head to 
head comparisons of the three-proposed mesenchymal derived cell lines. 
Although the use of various stem cell preparations for knee OA has become increasingly 
prevalent, well-designed studies with conclusive proof of comparative effectiveness and 
identification of the optimal cell source and "dose" have not been performed. Thus, we 
propose the first Randomized Clinical Trial (RCT) comparing three types of cellular 
treatments in one study. Our exhaustive outcomes, which include Patient Reported 
Outcomes (PROs), radiographic data analyses (cartilage and joint health), and high level 
cell characterization has never before been described and will fill in a significant gap in 


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knowledge. Finally, we will integrate our clinical studies with state of the art evaluations 
of the cells that will be injected. This blend of clinical and translational research will be 
highly impactful and will help transform the current clinical practice of cellular therapy 
for orthopedic applications and beyond. This information will substantially advance the 
science behind stem cell usage in orthopedics and hopefully provide support to justify 
broader usage and approval as an alternative to surgical "salvage" intervention.
Autologous Mesenchymal Stem Cells (MSCs) have been used for more than two decades 
to treat orthopedic conditions.  The most popular form of MSC therapy has been through 
the use of Autologous Bone Marrow Concentrate (BMAC).  The rationale is that when a 
sample of Bone Marrow Aspirate (BMA) is collected and the components that are not 
beneficial to the joint are filtered out (i.e. red blood cells, neutrophils, etc.) the remaining 
concentrate (MSCs, platelets, Interleukins, etc.) can have a “healing” effect on the 
environment in which it is injected.  This healing affect is mediated mostly through 
paracrine functions of the MSCs as well as potential differentiation into healthy tissue.  
Over the last 10 years since the FDA has stopped allowing culture and expansion of cells 
in the laboratory, the use of same day MSC treatments through BMAC has become more 
popular. What is still unknown is how effective is BMAC for treating orthopedic 
conditions compared to other MSC procedures. Also, it is unknown what are the most 
important components of the BMAC mixture that could aid patients suffering from 
orthopedic conditions, particularly osteoarthritis.
Bone Marrow Aspiration (BMA) procedures have been done for many years now with 
few reported complications. A large case series of complications following BMA 
procedures was published by Centeno et al in 2015 and reveals that of 3012 procedures, 
there were a total of 325 Adverse Events (AE) reported. 183 of these AE’s were related 
to pain at the harvest site or the injection site due to the patients’ underlying degenerative 
joint disease.  The other reported complications were mostly due to procedural risk that 
would be present with any percutaneous procedure, namely infection either locally or 
deeper in the bone marrow.  There were seven reported neoplasms during the study 
follow up which is actually lower than the incidence of neoplasms in the general 
population so is largely thought to not be at all related to the BMA procedure.  The MSCs 
themselves, because of their known immuno-privileged status, are not thought to confer 
any additional risk to the subject other than potential increased pain at the site of injection 
from the pro-inflammatory cytokines that are known to be in the concoction.
Umbilical cord tissue (UCT) is less well defined.  However, as reported in 
NCT02176317, the safety and tolerability profile of autologous CB infusion in ASD was 
excellent. No serious adverse events were reported, and adverse events, in general, were 
sparse. Three children had mild allergic reactions associated temporally with the 
infusions, consisting of cough and hives during infusion for 1 child and cough post-
infusion for 2 children. Also, one child was noted to be more irritable for 2 days post-
infusion. No subjects discontinued prematurely from the study due to adverse events.


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Lipoaspirate is obtained via liposuction, or the removal of adipose tissue via a suction 
method, is a common cosmetic procedure performed by plastic surgeons. Depending on 
the liposuction location and indication, 100cc to 2,000cc of lipoaspirate can be safety 
removed from a subject during a single liposuction procedure. Through a tissue process 
which includes washing and centrifuging, the cellular components can be extracted as a 
cell pellet, which is also known as Stromal Vascular Fraction (SVF). This cellular 
product is thought to contain adipose tissue-derived stem cells as well as leukocytes, 
erythrocytes and other cell types. However, numerous pre-clinical studies that have 
analyzed SVF have shown that it contains a heterogeneous cell population, thus, making 
its precise cellular components unclear. Furthermore, the fate of these cellular 
components can vary significantly; the age of the adipose tissue donor, the type and 
localization of the adipose tissue, and cellular isolation process may affect the cellular 
analysis outcome.
Adipose tissue has been found to have a large amount of mesenchymal stem cells versus 
that in bone marrow. These cells are currently being used in a variety of clinical research 
studies within the regenerative medicine field. The cellular pellet, SVF, can be easily 
maintained and expanded in culture, showing stable growth and proliferation rates [8].
2.3      Benefit/Risk Assessment
2.3.1
Procedural-Related Risks
Subjects may experience pain and/or discomfort during and after the bone 
marrow and liposuction procedures despite the local anesthesia. 
Bone Marrow Aspiration (Arm/Group 1)
Less Common (10-20%)

Blood pressure may get low and cause symptoms such as 
dizziness, lightheadedness, confusion, or blurred vision [5]
Rare (1-10%)

Bleeding

Hematoma (bleeding under skin)

Risk of infection at the needle insertion sites
Liposuction Procedure (Arm/Group 2)
Less Common (10-20%)

Bruising

Hematoma (bleeding under skin)

Change in skin sensation that may persist

Swelling

Fluid accumulation


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Rare (1-10%)

Local anesthesia risks

Damage to deeper structures such as nerves, blood vessels, 
muscles, lungs and abdominal organs (<1%)

Deep vein thrombosis

Cardiac and pulmonary complications

Infection

Irregular contours or asymmetries

Irregular pigmentation

Need for revision surgery

Persistent swelling

Rippling or loose skin, worsening cellulite

Poor wound healing
SVF and BMAC Cell Mixture Injection
The exact risks from the cell application are not entirely known. However, 
literature shows that using your own cells for a clinical therapy does not 
cause inflammation, rejection or tumor growth. 
UCT Mesenchymal Stem Cell Injection
Below are risks associated with UCT MSCs given intravenously for other 
conditions. To date, there are no reported risks with knee injections of 
UCT MSCs.

Transient headache

Transient fever

Allergic reaction
Knee Injection (All Arms/Groups)
Rare (1-10%)

Pain at the site of injection

Bleeding

Infection

Swelling at the site of injection

Granulomatous inflammation of the synovium

Saphenous Neuropathy

Aseptic acute arthritis

Septic Arthritis

Pigment changes

Mild pain or swelling at the site of injection may occur in up to 
20% of subjects

Severe local inflammation, warmth, and joint effusion are rare [6]


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
Allergic reaction (UCT)
Steroid Injection (All Arms/Groups)
Less common (10-20%)

Bruising at the injection site
Rare (1-10%)

Death of nearby bone

Joint infection

Nerve damage

Thinning of skin and soft tissue around the injection site

Temporary flare of pain and inflammation in the joint

Tendon weakening

Lightening of skin surrounding the injection site

Redness at the injection site

Swelling at the injection site

Bleeding at the injection site

Infection

Calcium deposits on the tendon site

Allergic reaction
Epinephrine (Arm/Group 2)
Rare (1-10%)

The feeling of a “racing heart”

Temporary skin discoloration at the site of injection

Sweating 

Nausea and vomiting

Pale skin

Feeling short of breath

Dizziness

Weakness or tremors

Headache

Feeling nervous or anxious
Lidocaine (All Arms/Groups)
Rare (1-10%)

Tingling

Prolonged numbness

Temporary skin discoloration

Mild bruising, redness, itching or swelling where the medication 
was injected

The feeling of “pins” and needles

Feeling anxious, shaky, dizzy, restless, or depressed

Drowsiness, vomiting, ringing in your ears

Feeling like you may pass out


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Oral Percocet (optional as needed)
Less common (10-20%)

Dizziness

Drowsiness

Feel like throwing up

Feeling faint

Head Pain

Stomach cramps
Rare (1-10%)

Itching

Not feeling well

Dry mouth

Excessive sweating

Incomplete or infrequent bowel movements
Oral Valium (optional as needed)
Rare (1-10%)

Memory problems

Drowsiness, tired feeling

Dizziness, spinning sensation

Feeling restless or irritable

Muscle weakness

Nausea, constipation

Drooling or dry mouth, slurred speech

Blurred vision, double vision

Mild skin rash, itching

Confusion

Depression
Blood draw
Rare (1-10%)

Bleeding

Pain

Bruising

Redness, swelling of the vein

Infection 

Fainting
MRI 
May cause a metal object in your body to move out of place and 
cause serious injury or stop working properly [7]
 


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2.3.2
Mitigation of Risks
Standard subject safety precautions will be employed for the procedures 
listed above, per institutional guidelines and best practice.
3.0
Objectives and Endpoints
3.1
Primary Objective
The primary efficacy co-outcomes are: a change in the visual analog scale (VAS) pain 
score and a change in the pain subsection of the knee injury and osteoarthritis outcome 
(KOOS) score.  
3.2
Secondary Objectives
Secondary outcomes include change in total KOOS score, EuroQuality of Life (EQ5D 
3L) and Patient-Reported Outcomes Measurement Information System (PROMIS 29).
Changes in MRI biomarkers of cartilage and joint health between the four treatment 
groups will be compared. 
3.3
Exploratory Objectives
To provide deep and broad characterization of all cells used in this trial, harmonize and 
standardize analytical and processing parameters across the different clinical sites and 
eventually, as patient outcome data become available, to apply quantitative advanced 
modeling tools to identify predictive signatures of cell properties that correlate with 
efficacy and safety. When feasible, synovial fluid will be aspirated for cell 
characterization.   
4.0
Study Design
4.1
Overall study design
We propose a multicenter prospective single-blinded randomized controlled clinical trial 
to test the safety and efficacy of autologous bone marrow (BMAC), adipose tissue 
(ADP), and third party human mesenchymal stem cells manufactured from umbilical cord 
tissue (UCT) to a current standard, corticosteroid injections (CSI), for the treatment of 
Knee Osteoarthritis.  The study will include a parallel design using a blocked central 
randomization scheme of 1:1:1:1 (BMAC:ADP:UCT:CSI).  
Subjects, who have provided written informed consent and are determined to be eligible, 
will be randomized to one of the following arms and treatments.
Arm 1 includes randomization to bone marrow derived MSCs versus corticosteroid 
injection.
Arm 2 includes randomization to adipose derived MSCs versus corticosteroid injection.


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Arm 3 includes randomization to umbilical cord tissue MSCs versus corticosteroid 
injection.
Subjects randomized to Arm 1 or Arm 2 will undergo a procedure (bone marrow 
aspiration or liposuction) but will only receive one of the possible injections. For 
instance, subjects randomized to the control portion of Arm 1 will undergo a bone 
marrow aspiration but will receive a blinded corticosteroid injection. The bone marrow 
aspirate will be processed and utilized for cell characterization.
The corticosteroid cohort will serve as the control group for the trial. An injection of 
normal saline and Depomedrol will be used in a standard agreed upon preparation as 
described in the Operations Manual.
Two of the MSC preparations, adipose tissue and bone marrow, will be derived from 
autologous tissues and the third will be derived from a third party, unrelated allogeneic 
donor human umbilical cord tissue. The autologous products will be processed at the 
point of care and delivered without cryopreservation.
The allogeneic cord tissue MSC product will be manufactured and cryopreserved at the 
GMP cell manufacturing laboratory at Duke University Medical Center. This product will 
be shipped to the study sites in the cryopreserved state and thawed immediately prior to 
administration at the site. In all cases, the product administered to the subject will be 
characterized with cell counts, viability, sterility cultures, flow cytometry or mass 
cytometry and functional assays.
In order to accurately assess the efficacy of these treatments, routine follow-up 
examinations will be necessary. Follow-up exams will occur at intervals of 1 week, 1 
month, 3 months, 6 months, 9 months (telephone only) and 1 year. After completing the 
screening and consent portion of the trial, the subjects will undergo a pre-injection MRI 
and then an additional MRI at 6 and 12 months. Additionally, subjects will fill out PROs 
at each time point. 
The Marcus Center for Therapeutic Cell Characterization and Manufacturing (MC3M) at 
Georgia Institute of Technology will serve as a core cell analytics center for this clinical 
trial.  MC3M’s goal is to provide deep and broad characterization of all cells used in the 
trial, including synovial fluid, harmonize and standardize analytical and processing 
parameters across the different clinical sites and eventually, as patient outcome data 
become available, the MC3M will apply quantitative advanced modeling tools to identify 
predictive signatures of cell properties that correlate with efficacy and safety.  
4.2
Scientific Rationale for Study Design
The current treatment of osteoarthritis relies on joint stability and non-operative control 
of inflammation. Oral non-steroidal anti-inflammatory (NSAID) options remain the 
initial line of treatment. When oral NSAIDs have failed, treatments with intra-articular 


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injectable corticosteroids for local pain management have proven successful for a short 
period of time, though evidence exists that their long-term use can be detrimental.
Other non-surgical treatment options include the injection of hyaluronic acid or other gels 
and biologics such as platelet rich plasma. While these treatments do provide pain relief, 
their precise mechanism of action is not known. 
Joint arthroplasty is a definitive and successful surgical intervention typically offered to 
age appropriate patients after other less invasive measures have failed. However, this is 
substantial surgical intervention and possesses the inherent risks of any such procedure. 
Concern also exists regarding the longevity of knee arthroplasty, particularly in the 
younger, more active population. 
Cell therapies have been increasingly employed to treat osteoarthritis, which include 
various forms of autologous (harvested from the same patient’s body) mesenchymal stem 
cell injections. However, while this procedure has shown better outcomes than other non-
surgical treatments, questionable reproducibility and the limited supply of stem cells 
limits the potential improvements to this valuable technique.
A large case series (41 subjects, 75 knees) with different biologics injections, most of 
which were autologous bone marrow concentrate (BMAC) + adipose derived stromal 
vascular fraction (SVF) were injected into the knee joint. Visual analog score (VAS), 
knee injury and osteoarthritis score (KOOS), international knee documentation 
committee (IKDC) and Lysholm knee Scores (patient reported outcome measures, 
PRO’s) were all improved in the treated group [1]. Better outcomes were noted in those 
with lower degrees of osteoarthritis.
Recently, a well-designed small clinical (proof of concept) trial was done with 2-year 
follow-up, evaluating different dosages of adipose derived SVF which were cultured and 
injected for the treatment of knee osteoarthritis. What made this study interesting was that 
it examined small, medium, and high doses of MSCs and evaluated their effects using 
MRI, arthroscopy, and clinical outcomes [2].  However, there was no control group and 
the study did not have a large number of subjects.
Another study investigated a control group (saline) compared to same day BMAC 
preparation (non-expanded). The cells were characterized and the injections were done on 
bilateral knees with one knee getting the control and one getting the BMAC. The results 
showed marked improvement in symptoms but it was not statistically different between 
the two groups secondary to under powering of the study [3]. The fact that saline control 
also showed a good outcome indicates that such study was not well controlled and 
more rigorous studies with an unbiased approach throughout several recruiting sites is 
needed.
There is an urgent need to establish which cell based therapy will yield sustained and 
reproducible treatment for osteoarthritis.  We believe that the cell source is a key 


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determinant of the success of the MSC injections into the knee joint to alleviate pain and 
immediately enhance function and even halt the natural progression of the diseases.
4.3
Enrollment
Subjects will be enrolled after the investigator has completed the following: confirm the 
subject has signed the informed consent and Health Insurance Portability and 
Accountability Act (HIPAA) Authorization, all screening assessments have been 
completed, and confirm that the subject has met all the inclusion criteria and none of the 
exclusion criteria. 
Randomization can occur at any time after confirmation that the subject meets eligibility, 
but should occur within 30 days of the date of informed consent form signing. If the 
period is more than 30 days, an updated informed consent process must take place. 
Enrollment of subjects is expected to last approximately 13 months in order to obtain the 
numbers needed. An additional three months has been incorporated into the study to 
allow for unanticipated delays and potential protocol changes. 
4.4
End of Study Definition
A subject is considered to have completed the study if he/she has completed all phases of 
the study including the one-year follow-up visit. The end of the study is defined as the 
date of the last visit of the last subject in the study shown in the Schedule of Activities for 
the last subject in the trial. 
Final data analysis will occur following completion of study activities.
4.5
Study Stopping Rules
If one of the following safety issues occurs, further enrollment will be halted until the 
Medical Monitor, Dr. Eric Wagner, reviews all available data and makes 
recommendations as to the next steps:

Any potential related serious adverse event (SAE).

Other findings that, at the discretion of the study team, DSMB, investigator and/or 
Medical Monitor, indicate that the study should be halted.
5.0
Study Population
5.1 
Eligibility Criteria:
The following is a list of stringent inclusion and exclusion criteria that is designed to 
reduce confounding and conflicting variables while studying the effect of biologic 
injections for knee osteoarthritis.
5.1.1
Inclusion Criteria
1. Age ≥40 but ≤70 years old 
2. Males and Females


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3. Recent knee radiograph of the targeted knee (standing AP lateral and 
sunrise view)
4. Diagnosis of OA in the targeted knee (radiographic evidence of OA in 
the medial and/or lateral tibiofemoral compartment, which would 
include one or more osteophytes on a standard radiograph taken within 
3 months). Subjects may have concomitant patellofemoral but they 
must have grade II or higher medial or lateral tiobiofemoral knee OA 
and the primary pain must be related to the tibiofemoral arthritis. 
5. Continued OA pain in the targeted knee despite conservative measures 
(per treating provider’s discretion)
6. Average daily VAS ≥3
7. Kellgren-Lawrence system of Grade II, III, or IV
8. Females of childbearing potential (FCBP) only, must have a negative 
pregnancy test done at screening prior to enrollment. FCBP is defined 
as any premenopausal female unless they have had a surgical 
sterilization procedure including, but not limited to, hysterectomy, 
tubal ligation or oophorectomy.
9. Women and men of child-producing potential must agree to use 
acceptable contraception methods for the duration of the trial such as 
birth control pills or condoms with spermicide.
5.1.2
 Exclusion Criteria 
1. Clinically apparent tense effusion of the targeted knee
2. Significant valgus/varus deformities (+/- 10 degrees)
3. Viscosupplementation within 6 months in the targeted knee
4. Other Biologic Injection (PRP or stem cell) within 1 year in the 
targeted knee
5. Surgery in the targeted knee within the past 6 months (either open or 
scope)
6. Systemic or intra-articular injection of corticosteroids in any joint 
within 3 months before screening
7. Daily opioid use for the past three months
8. History of malignancy in the previous 5 years prior to study entry, 
with the exception of in-situ cancers treated only by local excision 
with curative intent.
9. History of, or ongoing, autoimmune disorder that requires treatment 
with an immunosuppressive medication
10. Active, suspected, or prior infection to the joint in the targeted knee
11. Part of a vulnerable population per Office for Human Research 
Protections (OHRP) definition (pregnant women and breast-feeding 
women, cognitively impaired, prisoners, etc.)
12. Unwilling to discontinue the use of Non-Steroidal Anti-Inflammatory 
(NSAID)s for 7 calendar days prior to the procedure


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13. Unwilling to discontinue use of NSAIDS for 5 calendar days after 
procedure
14. History of bleeding disorders or inflammatory joint disease
15. Inability to hold anti-platelet therapy according to treating provider 
prior to procedure 
16. Subject is, in the opinion of the investigator, unable to comply with the 
requirements of the study protocol or is unsuitable for the study for 
any reason.
17. Uncontrolled diabetes (determined by the treating investigator)
18. Subject has an active workers’ compensation case in progress with 
targeted knee
19. Subject with insufficient amount of subcutaneous tissue, at the 
discretion of the treating investigator, upon examination
20. Hemoglobin less than 10g/dL at the time of screening
21. Leukocytes <3,000/µL; neutrophils <1,500/µL; lymphocytes <800/µL; 
platelets <100,000/µL at the time of screening
22. Diagnosis of liver disease as defined by alanine aminotransferase 
(ALT) >3x the upper limit of age-determined normal (ULN) or total 
bilirubin > 1.5x ULN
23. Subjects who have had greater than 3 corticosteroid injections in the 
targeted knee in the 12 months prior to screening or at the physician’s 
discretion.
24. Subjects with a known diagnosis of osteoporosis.
25. Subjects with anticipated use of systemic corticosteroids during the 
study period for treatment of a chronic medical condition.
5.2
Screen Failures
Screen failures are defined as subjects who consent to participate in the clinical study but 
are not subsequently enrolled. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure subjects.  Minimal information should 
include demography, screen failure details, eligibility criteria, and any serious adverse 
event (SAE).
6.0
Study Intervention
Bone marrow aspiration will be completed on all subjects randomized to Arm 1. Small volume 
lipoplasty will be completed on all subjects randomized to Arm 2. 
Prior to the knee injection, all samples will undergo point of care testing. If the BMAC, SVF 
final products or the UCT MSCs do not meet the final product acceptance criteria, as outlined in 
the Operations Manual, the subject will be discontinued from the study. The study team will 
maintain contact with the subject during the subsequent 30 days including in-person visit to 
assess any potential AEs and SAEs that the subject may have experienced after the study 


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treatment procedure. Subject will be withdrawn after 30 days if all study-related AEs are 
resolved.  
All injections will be done into the knee joint via ultrasound guidance using a standard approach 
as described in the Operations Manual. Prior to the study injection, the treating investigator may 
aspirate excess synovial fluid for future cell characterization testing at MC3M (see Section 
8.2.14). 
6.1
Study Intervention(s) Administered: 
6.1.1
Autologous Bone Marrow Concentrate (BMAC)
Bone Marrow Aspiration Concentrate (BMAC) is a standard Orthobiologic 
injection done for patients with knee osteoarthritis. This is a one step, same day 
procedure that involves harvesting of bone marrow aspirate (BMA) from the 
posterior superior iliac spine (PSIS) and then following centrifugation in an FDA 
approved device (EmCyte GenesisCS Pure BMAC®-60 ml), will be injected back 
into the knee joint for therapeutic effect.  Details of the procedure are described in 
the Operations Manual.
6.1.2
Adipose-derived Stromal Vascular Fraction (SVF)
Lipoaspirate is obtained from a mini-lipoaspirate procedure. The
lipoaspirate will then be enzymatically digested to produce a stromal vascular 
fraction (SVF) that will be injected into the knee joint. Details of the procedure 
are described in the Operations Manual.
6.1.3
Mesenchymal Stem Cells derived from Umbilical Cord Tissue (UCT)
Umbilical Cord Tissue has not been extensively studied for injections in knee
Osteoarthritis. For this study, each study site will be provided with cryopreserved 
doses of cord tissue MSCs.  These MSCs were cyopreserved at P2 culture in 
plasmalyte A + 5% human serum albumin in 5 finger cryobags containing 20 
million cells in 4 mL and stored under liquid nitrogen until shipment to the study 
sites.  Cells will be transported in a dry shipper and thawed at the point of care.  
The dose of MSCs will be thawed, aspirated from the cryobag into a sterile 
syringe and directly injected into the study subject’s knee.  Details of the 
procedure are described in the Operations Manual.
6.1.4
Corticosteroid Injection
A standard and routine procedure in the care of subjects with Osteoarthritis is an 
injection of corticosteroids into the knee joint. Corticosteroids have been shown to 
be effective for short-term relief of knee pain associated with Osteoarthritis and 
will serve as our standard of care procedure to compare to our cellular treatments. 
Details of the procedure are described in the Operations Manual.


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6.2
Measures to Minimize Bias: Randomization and Blinding 
The proposed clinical trial will allow for the unbiased evaluation of the efficacy of adult 
autologous versus third party stem cells and compare that efficacy to a gold standard 
treatment (e.g. corticosteroids). 
6.2.1
Randomization Methods
Treatment assignments will be generated using a pseudo-random-number 
generator with randomly permuted blocks.  This method serves to balance the 
treatment group assignments over the course of the study to ensure that the 
desired number of subjects will be allocated to each of the treatment groups at any 
time point during the randomization period.  The statistical method for 
implementation of the randomization plan will be detailed in the Statistical 
Analysis Plan (SAP). Briefly, after obtaining informed consent, all eligibility 
confirmation data will be entered into the RAVE EDC database by the delegated 
study staff. If the subject meets all eligibility criteria, computer randomization 
will be performed and the coordinator will be provided with an audit trail of the 
process including a verifiable link between the unique study ID and treatment 
assignment. The application will be password protected with access restricted to 
designated MILES personnel. 
6.2.2
Implementation of Randomization and Blinding
Subjects randomized to Arm 1 or Arm 2 will undergo a procedure (bone marrow 
aspiration or liposuction) but will only receive one of the possible injections. For 
instance, subjects randomized to the control portion of Arm 1 will undergo a bone 
marrow aspiration but will receive a blinded corticosteroid injection. The bone 
marrow aspirate will still be processed and used to help quantify cell 
characteristics. Subjects randomized to Arm 3 will not undergo the procedures 
mentioned above. They will be blinded and receive either the stem cell injection 
or the corticosteroid injection. 
Four hundred eighty subjects will be randomly assigned to treatment in this 
multicenter trial. Subjects at each clinical site will be randomized to ensure the 
trial is single-blind with a 1:1 allocation ratio across the four treatment groups.
One hundred twenty subjects will be randomized at each of 4 clinical sites.  Arm 
1: Forty subjects will be randomized with a 3:1 allocation ratio (bone marrow 
derived MSCs versus corticosteroid injection; 30:10). This same implementation 
plan will be used to randomize 40 subjects to Arm 2 (adipose derived MSCs 
versus corticosteroid injection) with a 3:1 allocation ratio and to randomize 40 
subjects to Arm 3 (umbilical cord tissue MSCs versus corticosteroid injection) 
with a 3:1 allocation ratio.


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6.3
Study Compliance
Subjects will be contacted regularly by study team members with appointment reminders 
to aid in compliance with the protocol. Subjects will be encouraged to contact the 
investigator or study staff in between follow-up visits to report AEs and SAEs in a timely 
manner. 
6.4
Concomitant Therapy
Concomitant therapy will not be utilized during the study as described in sections 5.1 and 
5.2. Any interventions the subject may require after the study injection, will be monitored 
and recorded during follow-up visits. Concomitant therapies such as anti-inflammatories, 
pain medication, injections and surgery will be recorded on the Concomitant Medications 
and Treatments log.  
7.0
Subject Discontinuation/Withdrawal
7.1
Subject Discontinuation
A subject must be discontinued from the trial for any of the following reasons:

Unacceptable adverse experience 

Investigator’s decision to withdraw the subject for safety, behavioral, compliance, 
or administrative reasons

If the BMAC, SVF final products or UCT MSCs do not meet final product 
acceptance criteria outlined in the Operations Manual
For those subjects who discontinue participation early, each subject will be followed for 
serious adverse events (90 days) that are ongoing at the time of subject discontinuation. 
Monitoring of the serious adverse event may be done by telephone per treating 
investigator discretion. All AEs potentially related to study participation will be followed 
until resolution prior to study completion or early termination of subject. Open AEs that 
are unrelated to the study participation will not be followed beyond study completion or 
subject’s early termination. 
7.2
Subject Withdrawal of Consent 
The investigator/treating physician will make every reasonable effort to keep each subject 
on study.  A subject may withdraw from the study at any time at his/her own request 
without penalty, at any time during the study.  If the subject withdraws consent for 
disclosure of future information, the sponsor may retain and continue to use any data 
collected before such a withdrawal of consent. All subject samples that were obtained 
prior to subject withdrawal will NOT be destroyed and future laboratory testing will be 
performed.
7.3
Lost To Follow Up
All reasonable efforts must be made to locate subjects to determine and report their 
ongoing status.  This includes follow-up with persons authorized by the subject.  Lost to 


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follow-up is defined by the inability to reach the subject after a minimum of three 
documented phone calls, faxes, or emails as well as lack of response by subject to one 
registered mail letter.  All attempts should be documented in the subject’s medical record.  
Should the subject continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
If it is determined that the subject has died, the site will use permissible local methods to 
obtain the date and cause of death.
7.4
Treatment Failure
In order to reduce bias, if subjects require concomitant therapy (i.e. other injections), pain 
scores and subsequent treatment information will continue to be collected through the 1-
year follow up after a subject is declared a treatment failure. 
7.5
Discontinuation of the Clinical Study
The study may be prematurely discontinued by the Sponsor if deemed necessary for any 
reason. If for any reason the study is discontinued early, all subjects should complete the 
End of Study visit and be followed for 90 days for SAEs that were ongoing at the End of 
Study visit. 
8.0
Study Assessments and Procedures
Subjects will have follow-up exams at 1 week, 1 month, 3 months, 6 months, 9 months 
(telephone only) and 1 year.  After subjects complete the screening and consent portion of the 
trial, the subjects will undergo pre-injection MRI and then an additional MRI at 6 and 12 months.  
Additionally, subjects will fill out PROs at each time point.
8.1 
Study Visit Assessments
8.1.1 Screening Visit (Visit 1)

Administer informed consent and HIPAA Authorization

Collect demography

Collect medical and surgical history 

Collect prior and concomitant medications

Collect Knee Osteoarthritis History

Review inclusion and exclusion criteria

Focused knee assessment 

Perform vital signs

Knee MRI (only if the subject is eligible for the study)

Collect subject PROs 

Perform pregnancy test (on female subjects of childbearing potential)

Blood Collection (safety labs)

Once all screening assessments are complete and eligibility has been 
confirmed by the treating investigator, the subject may be randomized. 

Schedule the subject for the appropriate Treatment Visit procedure based 
on randomization


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8.1.2 Treatment Visit (Visit 2, Day 0)

Collect concomitant medications

Focused knee assessment (if required, at the discretion of the treating 
investigator)

Perform vital signs

Assess adverse events

Perform pregnancy test (on female subjects of childbearing potential)

Confirm subject eligibility

Study procedures (depending on subject randomization)
1. Arm 1-BMAC Treatment: bone marrow aspiration, cell processing 
and product release criteria testing
2. Arm 1-CSI Treatment: bone marrow aspiration, cell processing, 
product release criteria testing and CSI preparation
3. Arm 2-SVF Treatment: lipoaspirate procedure, cell processing, and 
product release criteria testing
4. Arm 2-CSI Treatment: lipoaspirate procedure, cell processing, 
product release criteria testing and CSI preparation
5. Arm 3-UCT Treatment: dispense UCT-MSCs, dose preparation, 
and product release criteria testing
6. Arm 3-CSI Treatment: CSI preparation

Perform arthrocentesis and knee injection

Process and store samples for cell characterization (details are described in 
the Laboratory Manual) 

Home physical therapy program to begin post procedure day 8, see 
Appendix 12.1. Instructions for at home physical therapy will be provided 
to the subject by the study staff.
 8.1.3 Week 1 (Visit 3, Day 7) 

Collect concomitant medications and treatments

Focused knee assessment, including observation of knee injection site

Observation of harvest sites (subjects in Arm 1 and Arm 2)

Perform vital signs

Assess adverse events

Review progress of the at home physical therapy plan and encourage 
compliance
8.1.4
Month 1 (Visit 4, Day 30)

Collect concomitant medications and treatments

Focused knee assessment, including observation of knee injection site

Observation of harvest sites (subjects in Arm 1 and Arm 2)

Perform vital signs

PROs

Assess adverse events

Blood Collection (safety labs)

Immunogenicity testing (Arm 3 only)

Review the subject’s at home physical therapy log for compliance 


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8.1.5
Month 3 (Visit 5, Day 90)

Collect concomitant medications and treatments

Focused knee assessment

Perform vital signs

PROs

Assess adverse events
8.1.6
Month 6 (Visit 6, Day 180)

Collect concomitant medications and treatments

Focused knee assessment 

Perform vital signs

MRI

PROs

Assess adverse events
8.1.7
Month 9 Phone Call (Visit 7, Day 270)

Collect concomitant medications and treatments

PROs

Assess adverse events
8.1.8
Month 12/ (Visit 8, Day 365)

Collect concomitant medications and treatments

Focused knee assessment 

Perform vital signs

MRI

PROs

Assess adverse events

Immunogenicity testing (Arm 3 only)
8.1.9
Unscheduled Visits
Unscheduled visits are allowed as needed and at the discretion of the treating 
investigator for more frequent follow-up than what is required in the protocol. 
The treating investigator will determine the appropriate assessments to be 
conducted during this visit based on the reason for the Unscheduled Visit. Data 
from the Unscheduled visits will be captured in the EDC.
8.1.10  End of Study Visit
If for any reason the study is discontinued early (according to section 7.5), all 
subjects should complete the End of Study visit and be followed for 90 days for 
any SAEs that are ongoing at the End of Study visit. All AEs potentially related to 
study participation will be followed until resolution prior to study completion. 
Open AEs that are unrelated to the study participation will not be followed 
beyond subject’s study completion. Assessments completed during this visit will 
be at the discretion of the treating investigator and what is best for the safety of 
the subjects.  Data from end of study visit will be captured in the EDC.


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8.2
Clinical Assessments and Procedures
8.2.1
Informed consent and HIPAA Authorization
All subjects must agree to participate by signing and dating the informed consent 
and HIPAA Authorization prior to any study specific screening procedures being 
performed. 
Consent must be documented by the subject’s dated signature on a consent and 
HIPAA form along with the dated signature of the person conducting the consent 
discussion. 
A copy of the signed and dated consent form and HIPAA Authorization should be 
given to the subject before participation in the trial. The original documents 
should be filed in the subject’s study chart. 
The initial informed consent form, any subsequent revised written informed 
consent form and any written information provided to the subject must receive the 
IRB’s approval/favorable opinion in advance of use.  The subject should be 
informed in a timely manner if new information becomes available that may be 
relevant to the subject’s willingness to continue participation in the trial. The 
informed consent will adhere to IRB requirements, applicable laws, and 
regulations. 
8.2.2
Assignment of Screening Number
Once informed consent and HIPAA Authorization have been documented, the site 
will assign the subject a screening number. Each site will be responsible for 
maintaining their Screening Log of consented subjects.
8.2.3
Inclusion/Exclusion Criteria
All inclusion and exclusion criteria will be reviewed by the investigator or 
qualified designee to ensure that the subject qualifies for the study. 
8.2.4
Demographics
Subject demographics will be obtained by the investigator or qualified designee.
8.2.5
Medical and Surgical History
A medical and surgical history will be obtained by the investigator or qualified 
designee. Medical history will include all active conditions, and any condition 
deemed clinically relevant by the treating investigator. Surgical history will 
include any past surgeries deemed clinically relevant by the treating investigator.
8.2.6
Prior Medications
The investigator or qualified designee will review prior medication use and record 
any medication taken by the subject within 21 days before signing the informed 
consent. 


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8.2.7
Concomitant Medications and Treatments
The investigator or qualified designee will record any pain medication (including 
anti-inflammatories, NSAIDS, etc.), knee injections and surgeries the subject 
required during the study until the subject’s final study visit.  
8.2.8
Physical Examination
Focused knee assessment will be performed. Please refer to the Operations 
Manual to ensure all required assessments are performed during the exam. At the 
7-day follow-up and 30-day follow-up visits, the assessment will also include 
observation of the knee injection site for all subjects and observation of the 
harvest site for subjects in Arm 1 and Arm 2. 
8.2.9
Vital Signs
The investigator or qualified designee will obtain vital signs. Please refer to the 
Operations Manual for details.
8.2.10 MRI
MRIs will be performed using cartilage mapping sequences for each location 
based on their machines.  The baseline MRI scans and each subsequent MRI scan 
must be performed on the same machine with the same sequence.  Further details 
are described in the MRI protocol.
8.2.11 Patient Reported Outcomes
8.2.11.1  Visual Analog Pain Scale (VAS)
8.2.11.2  Euro-Quality of Life (EQ5D 3L)
8.2.11.3  Knee Injury and Osteoarthritis Outcome Score (KOOS)
8.2.11.4  Patient-Reported Outcomes Measurement Information 
System (PROMIS 29)
8.2.12 Adverse Event Monitoring
The investigator or qualified designee will assess each subject to evaluate for 
potential new or worsening AEs at each study visit and more frequently if 
clinically indicated. Adverse experiences will be graded and recorded throughout 
the study according to CTCAE (Common Terminology Criteria for Adverse 
Events). Toxicities will be characterized in terms regarding seriousness, 
causality/attribution, toxicity grading, and action taken.
Subjects must agree to notify the investigator or study team member as soon as 
possible of any failure of proper use of your birth control method, or if a subject 
becomes pregnant, either of which may result in being withdrawn from the study 
or having limited participation in the study.  Subjects who become pregnant while 
on the study will be followed for AEs/SAEs that may occur for up to 30 days 
following the birth of the child. 


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8.2.13  Physical Therapy
Subjects will follow an at home physical therapy program, see Appendix 12.1, 
unless otherwise directed by the investigator. Instructions for the at home physical 
therapy will be provided to the subject, by the study team, at the treatment visit. 
The study team will provide subjects with a physical therapy log to track 
compliance with the recommended daily activity (according to Appendix 12.1). 
Subjects will be required to return the log at the 7-day and 30-day follow-up 
visits. The study team will review the log for compliance.
8.2.14  Cell Characterization 
Cell characterization that will be performed includes:

Cell viability assessment including apoptosis assay

Cell phenotype assessment via comprehensive flow cytometry or mass 
cytometry

Single-cell transcriptome analysis

Secretome assessment from both initial aspirate and rescue culture 
supernatant
*Specimen processing, storage and shipment details can be found in the 
Laboratory Manual. 
8.2.15 Local Laboratory Assessments
Laboratory assessments will be collected for subject safety.
8.2.15.1 Hematology
Hematology can be evaluated in either the fed or fasted state and consist 
of a complete blood count with differential count performed as needed at 
the investigator’s discretion.
8.2.15.2 Clinical Chemistry
A comprehensive metabolic panel OR a basic metabolic panel and liver 
function panel will be evaluated in the fed or fasted state Additional 
clinical chemistry testing will be performed as needed at the investigator’s 
discretion. The subject’s ALT and total bilirubin must be evaluated in 
order to determine study eligibility. 
8.2.15.3 Coagulation Assays
Coagulation assays will be evaluated in the fed or fasted state and consist 
of prothrombin time (PT; sec) or international normalized ratio (INR). 
Activated partial thromboplastin time (APTT; sec) may be ordered at the 
discretion of the treating investigator.  


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8.2.15.4 Immunogenicity Testing 
Immunogenicity Testing can be evaluated in either the fed or fasted state 
and consist of a panel reactive antibodies (PRA) on the recipient of the 
umbilical cord tissue at 30 days and at study completion. All subjects in 
Arm 3 will have a blood draw to maintain blinding. 
8.2.16 Pregnancy Testing
Pregnancy testing for human chorionic gonadotrophin (hCG) will be performed 
on female subjects of childbearing potential (refer to eligibility criteria). This may 
be done using a urine or serum sample. Pregnancy testing will be done at two time 
points: 
a) Screening Visit- if the test is positive the subject will be a screen 
failure. 
b) Treatment Visit (prior to procedure/knee injection)- if the test is 
positive, within 7 days of the Treatment Visit, the subject will be 
discontinued from the study.
8.3
Protocol Deviations
Assessments not performed at a required visit per protocol should be documented as a 
deviation from the protocol, regardless of the reason. When a protocol deviation occurs it 
should be discussed with the treating investigator and documented on the Protocol 
Deviation Form detailing the deviation. Protocol Deviation forms will be signed by the 
treating investigator and reviewed by the sponsor’s representative. 
8.4
Adverse Event Reporting and Safety Monitoring
8.4.1
Adverse Events
An adverse event is defined as any untoward or unfavorable medical occurrence 
in human subject, including any abnormal sign, symptom, or disease, temporally 
associated with the subject’s participation in the research, whether or not 
considered related to the subject’s participation in the research. 
The investigator or qualified designee will assess each subject to evaluate for 
potential new or worsening AEs as specified in the SoA and more frequently if 
clinically indicated. Adverse experiences will be graded and recorded throughout 
the study according to CTCAE.
8.4.2
Serious Adverse Events
If the adverse event meets any of the criteria below, it is regarded as a serious 
adverse event (SAE):
a) Led to death
b) Led to serious deterioration in the health of the subject, that either resulted 
in 
a.
A life-threatening illness or injury, or


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b. A permanent impairment of a body structure or a body function, or
c.
In-patient or prolonged hospitalization, or 
d. Medical or surgical intervention to prevent life-threatening illness 
or injury or permanent impairment to a body structure or a body 
function
8.4.3
AE and SAE Collection
All AEs and SAEs will be collected from the signing of the informed consent 
form until the one-year follow-up visit at the time points specified in the SoA 
(Section 1.3) as required by applicable regulation and best practice.
All SAEs will be recorded and reported to the sponsor and the pharmacovigilance 
team at Advanced Clinical  within 24 hours of the study personnel becoming 
aware of the event.  Please utilize the approved SAE data collection forms 
provided by Advanced Clinical to submit the notifications and updates. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it 
being available.
Investigators are not obligated to actively seek AE or SAE after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a 
death, at any time after a subject has been discharged from the study up to a 30 
day follow-up period, and he/she considers the event to be reasonably related to 
the study intervention or study participation, the investigator must promptly notify 
the sponsor. 
8.4.4
Follow-up of AEs and SAEs
After the initial AE/SAE report, the investigator is required to proactively follow 
each subject at subsequent visits/contacts. All AE/SAEs, will be followed until 
resolution, stabilization, the event is otherwise explained, or the subject is lost to 
follow-up (Lost to follow-up is defined in Section Error! Reference source not 
found. of the protocol). 
8.4.5
Adverse Event and Serious Adverse Event Reporting
Adverse events and serious adverse events will be reported to the FDA, the 
Sponsor and IRB in accordance to standard policy. These will be listed per site 
and reviewed by the Site PI, Contract Research Organization (CRO), study 
monitors, Sponsor’s Medical Monitor and the Data Safety Monitoring Board 
(DSMB).
8.4.6
Investigational New Drug (IND) Safety Reports
Written Investigational New Drug (IND) safety reports will be submitted to the 
FDA by the IND sponsor, for serious unexpected adverse reactions within 15 
calendar days of learning of its occurrence. If the event is fatal or is deemed to be 
life threatening, the report will be made within 7 calendar days. 


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8.4.7
Unanticipated Problems (Emory IRB Requirement)
The IND sponsor will make an assessment of whether an adverse event 
constitutes an unanticipated problem (UP) posing risks to subjects or others, per 
the Emory IRB Reportable Events guidelines. The IND Sponsor’s assessment will 
be provided to the Emory IRB, which in turn will make a final determination. If 
the Emory IRB determines the event is an UP it will notify the appropriate 
regulatory agencies and institutional officials.  Reporting of the Emory IRB’s 
final determination should be submitted to the site’s IRB of record per their 
policies and guidelines. See MILES Study Operations Manual for further details 
regarding reporting process. 
9.0
Statistical Considerations
9.1
Statistical Hypothesis
An experienced statistician trained in multicenter clinical trials has provided statistical 
justification. De-identified early pilot data, outside of this study, from the Emory 
Department of Orthopedics provided sample data for estimation.
Rigorous statistical analyses were performed based on the preliminary data with 
autologous MSC cell injections and data in the literature to design a randomized 
controlled study that will provide sufficient power to compare data from four different 
sites. The collaborative work will involve recruitment sites with an established track 
record in using stem cells for the treatment of knee osteoarthritis. In addition, these sites 
have a large clinical volume to complete the study as proposed.
While 120 subjects per site would provide sufficient power to achieve statistical 
differences, this number reflects a conservative estimate compared to the number of 
subjects that each site recruits for stem cell injections per year based on retrospective 
evaluations. The sample size of 120 subjects amongst 4 sites for each of the four arms is 
substantially greater than the other less rigorously controlled trials and the number also 
accounts for reasonably unlikely yet unforeseen variability between recruitments.
9.2
Sample Size Determination
The total estimated sample size for the proposed intention-to treat, parallel-group, 
multicenter, randomized, controlled trial is 480 subjects. The primary endpoints are 
Visual Analog Scale (VAS) pain score and the pain subsection of the Knee Injury and 
Osteoarthritis Outcomes (KOOS). The sample size calculations are based on 
improvements (from baseline to 1-year) in the visual analog scale (VAS) pain score and 
total KOOS. Total KOOS was used as a proxy and should ensure that the study is amply 
powered. 
Assuming a decline of 1 point on average in pain in the Control arm (corticosteroids) and 
a decline on average of 2.5 points in a treatment arm (mesenchymal stem cells) and an 
estimated standard deviation on change of 3.5, the proposed sample sizes (n=121 subjects 


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per group or 484 total subjects) will provide 91% power to detect a difference on change 
of 1.5 points at the two-sided 5% significance level if the true difference between 
treatment groups is 1.5 points (two-sided two-sample equal variance t-test).
Assuming an increase of 10 points on average in total KOOS  in the Control arm 
(corticosteroids) and an increase on average of 20 points in a treatment arm 
(mesenchymal stem cells) and an estimated standard deviation on change of 20, the 
proposed sample sizes (n=121 subjects per group or 484 total subjects) will provide 97% 
power to detect a difference on change of 10 points at the two-sided 5% significance 
level if the true difference between treatment groups is 10 points (two-sided two-sample 
equal variance t-test).
Each of the four participating sites will accrue 30 subjects to each of the 4 treatment 
groups.  Cohort retention is expected to be 90% at 1-year.
9.3
Efficacy Analyses
The statistical analysis plan (SAP) has been developed and describes the subject 
populations to be included in the analyses, and procedures for accounting for missing, 
unused, and spurious data. This section is a summary of the planned statistical analyses of 
the primary and secondary endpoints.
The primary analysis of the data will be performed according to subjects’ original 
treatment assignment (i.e., intention-to-treat analyses) regardless of their compliance to 
treatment and the inclusion of all data from all subjects randomized in the final analysis.  
9.3.1
Efficacy Variables
Primary efficacy variables:

Visual Analog Scale (VAS) pain score

KOOS Pain Score
Secondary efficacy variables:

Total KOOS Score

KOOS Symptoms Score

KOOS ADL Score

KOOS Sports/Recreation Score

KOOS Quality of Life (QoL) Score

European Quality of life Score (EQ5D 3L) Index
9.3.2    Primary and Secondary Efficacy Analyses
Eight separate repeated-measures analysis will be performed on the eight efficacy 
variables described above. Each of the eight variables will be used as a dependent 
variable. The following model building method will be used for each analysis. 
Using Statistical Analysis System (SAS) MIXED Procedure (version 9.4; SAS 
Institute, Cary, NC), a linear mixed model will be fit on each efficacy variable. 
The model will include site, treatment arm, time on study (baseline and 1, 3, 6, 9 


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and 12 months on study), and treatment arm by time interaction as fixed effects. 
Subject ID will be the random effect. A compound-symmetric variance-
covariance form in repeated measurements will be assumed and robust estimates 
of the standard errors of parameters will be used to perform statistical tests and 
construct 95% confidence intervals. The model-based means are unbiased with 
unbalanced and missing data, assuming missing data are non-informative. A P-
value ≤0.05 will be considered statistically significant for all the terms in the 
mixed model. The statistical test for interaction between time on study and 
treatment will be the overall hypothesis test to determine whether efficacy 
variables in the four treatment arms changed significantly during 12 months of 
follow-up If mean scores in the treatment arms are consistently different or 
similar over time (i.e., no statistical interaction) then the main effect test for 
treatment will be used as the primary hypothesis test to compare the  treatment 
arms.  The primary study results from this model will be the mean score and 95% 
confidence interval for each of the 4 treatment arms and the treatment mean 
differences and 95% confidence intervals.   
Assuming a significant treatment effect on efficacy score change is identified (i.e., 
the interaction test is significant at P = 0.05) then the six pairwise treatment 
comparisons on pain score change will be performed. A Bonferroni correction 
(p=0.05/6=0.0083) for multiple comparisons will be applied. Specific statistical 
tests on efficacy score change will be done within the framework of the mixed 
effects linear model.  All statistical tests will be 2-sided and adjusted for multiple 
comparisons. The same Bonferroni method will be used if the statistical 
interaction between treatment group and time on study is not significant but the 
main effect test for treatment is significant.
Missing values will be excluded from the repeated measures analyses. Unknown 
values for ethnicity and gender will be included as a separate unknown category 
in the models if they represent more than 5% of the subjects. 
9.3.3
Efficacy Analyses across Subgroups
The heterogeneity of treatment effects across age, sex, and ethnicity will be 
evaluated using a statistical test for interaction terms. Specifically, effects of 
treatment in subgroups will be determined by including the additional interaction 
terms between treatment and the three subgroups (age, sex, and ethnicity) in the 
repeated measures model described above for the eight efficacy variables.
The following variables will be treated as categorical variables in all of the linear 
mixed models.

Treatment arms: CSI (reference), BMAC, ADP, UCT

Age: ≤65 (reference) vs. >65

Sex: female vs male (reference)


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
Ethnicity: Hispanic vs non-Hispanic

Time: 0, 1, 2, 3, 4, 5 representing baseline and 1, 3, 6, 9 and 12 months 
follow-up visits
9.4
Safety Analyses
9.4.1
Trial Drug Exposure
Descriptive statistics will be summarized for cell count, cell viability, endotoxin 
completion status, and 14-day sterility testing status by BMAC, UCT and SVF 
treatment arms. The treatment data for BMAC, UCT, SVF and CSI arms will be 
provided in four separate data listings. Cell count and cell viability data will also 
be included in the listings for BMAC, UCT and SVF treatment arms. 
9.4.2
Adverse Events
All adverse events (AEs) and serious adverse events (SAEs) will be classified by 
System Organ Class (SOC) and Preferred Term (PT) according to the Medical 
Dictionary of Regulatory Activities (MedDRA) version 21.1 for the safety 
population.  The number and percentage of subjects reporting AEs, as well as the 
number of events, in each treatment group will be tabulated by SOC and PT; by 
SOC, PT, and maximum severity; and in relationship to study treatment, SOC and 
PT. If a subject has multiple occurrences of the same SOC and PT, then the 
subject will be counted only once for the SOC and PT using the most sever 
occurrence for the summarization by maximum severity. Presentation by SOC 
and PT will display SOC sorted alphabetically and PT by descending frequency 
within SOC. 
9.4.3
Continuous Monitoring of Specific Adverse Events
In addition, the incidence of specific safety related events of concern will be 
continuously monitored separately in each treatment arm at each center 
throughout the study to determine if any of their observed subject-based 
incidence rates exceed a threshold incidence rate of concern pre-specified for 
each particular event (for example infection and allergic reaction related to 
study harvest procedure and/or knee injection).
These rules will be implemented by Advanced Clinical continuously 
monitoring the occurrence of any events to determine if the currently 
observed rate of each exceeds the corresponding threshold rate of concern 
with a pre-specified level of confidence.  The stopping rule will be considered 
to be met if the lower 95% confidence limit on the observed incidence rate 
exceeds the corresponding threshold level of concern for that event.  If any 
stopping rule is met, enrollment and randomization will be suspended pending 
expedited DSMB review.
The following table describes the minimum number of events out of the 
selected numbers of subjects randomized to each treatment arm at each site 


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which, if equaled or exceeded, would satisfy the stopping rule for each event 
of concern.
Table 1.  Study Termination Rules for Infection and Allergic Reaction: 
Minimum Number of Subjects with Events Meeting Stopping Rule for Infection and Allergic 
Reaction (infections and/or allergic reactions must be related to the harvesting procedure and/or 
knee injection) for Selected Numbers of Subjects Randomized Per Treatment Arm at each Center 
Using a Threshold Incidence Rate of Concern of 10%
Number of 
Subjects
with Event
Number of 
Randomized
Subjects Total
Incidence Rate
Lower 95% 
Confidence Limit, 
Wilson score 
method
1
5
20%
4%
2
5
40%
12%
1
10
10%
2%
2
10
20%
6%
3
10
30%
11%
4
10
40%
17%
4
20
20%
8%
5
20
25%
11%
6
20
30%
15%
5
30
17%
7%
6
30
20%
10%
7
30
23%
12%
Examples above illustrate threshold number of events that exceed the stopping rule (highlighted 
in bold); non-highlighted entries illustrate the observed incidence rate and the lower 95% 
confidence limit that does not exceed the stopping rule threshold of 10%
For each treatment arm at each center: if the lower confidence interval for the estimated infection 
and allergic reaction rate is 10% or higher, then enrollment and randomization will be suspended 
pending DSMB review. Infection and/or allergic reactions must be related to the harvesting 
procedure and/or knee injection. 
9.4.4
Analysis of Adverse Events
Additionally, the following AE-related specific analysis will be performed.
1. Frequency and percentages of each event will be summarized by treatment 
arm for the following:


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
AEs

AE in relationship to study treatment (not-related, possibly related, or 
related)

AE Severity

SAEs

SAE in relationship to study treatment (not-related, possibly related or 
related)

SAE Severity

Any Laboratory Toxicities
2. Allergic reaction and infection will be summarized as one category and 
corresponding number and proportions will be provided for each CTCAE 
grade level by treatment arm. These AEs will be counted only once per 
subject as the most severe level (i.e., maximum severity) reported across the 
six study assessments/visits during the 1-year follow-up period and compared 
between treatment arms with a chi-square or Fisher’s exact test.  The 95% 
confidence intervals will also be provided for the proportions.
3. Estimates of infection at harvest site or treated/targeted knee by treatment 
arms and time on study will be estimated and compared by performing a 
generalized estimating equations (GEE) analysis of the repeated binary 
responses within participant. The subjects will be clustered within center. This 
analysis will be implemented via the SAS GENMOD Procedure, using an 
exchangeable correlation structure for the repeated data within subjects 
(binomial-logit model).  Infection rates and 95% confidence intervals will be 
used to summarize the data by treatment group and clinical visit.
4. Subjects who become pregnant while on the study will be followed for 
AEs/SAEs that may occur for up to 30 days following the birth of the child.
9.5
Interim Analyses and Data Monitoring
No formal interim analyses for efficacy will be performed for this study. A Data Safety 
and Monitoring Committee (DSMB) will review safety data bi-annually throughout the 
course of this study with one possible additional meeting within the second 6-month 
period. The DSMB objectives and operational details are detailed in the DSMB charter. 
10.0 Ethical Considerations and Compliance with Good Clinical Practice
10.1
Statement of Compliance
This study will be conducted in accordance with this protocol, the International 
Conference on Harmonization (ICH) GCP, 21 Code of Federal Regulations (CFR), and 
applicable national and local regulatory requirements.
Before enrollment of subjects into this study, the IRB will review and approve/give 
favorable opinion on the protocol, ICF, any promotional material/advertisements, and any 
other written information to be provided to the subjects. The IB/IFU will be provided to 


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the IRB for review. The IRB’s composition or a statement that the IRB’s composition 
meets applicable regulatory criteria will be documented.
If the protocol or any other information given to the subject is amended, the revised 
documents will be reviewed and approved/given favorable opinion by the IRB, where 
applicable. The protocol amendment will only be implemented upon the sponsor’s receipt 
of approval and, if required, upon the sponsor’s notification of applicable regulatory 
authority(ies).  Amendments to the protocol that eliminate an apparent immediate hazard 
to subjects do not require pre-approval by the IRB.
10.2
Participating Centers
Participating clinical sites must have an appropriate IRB governance since they are 
actively engaged in research and provide informed consent. The protocol and consent 
forms will be approved for the sponsor by a central IRB review prior to release to 
participating sites. Health Insurance Portability and Accountability Act (HIPAA) and 
applicable local regulations will be followed by each participating institution in 
accordance with each institution’s requirements. The participating sites will obtain 
approval from their corresponding review boards in accordance with their local 
procedures and institutional requirements.
The investigator is required to keep accurate records to ensure the conduct of the study is 
fully documented. 
The investigational sites participating in this study will maintain the highest degree of 
confidentiality permitted for the clinical and research information obtained from subjects 
participating in this study. Unless required by the laws permitting copying of records, 
only the coded identity associated with documents or other subject data may be copied 
(obscuring any personally identifying information). Authorized representatives, as noted 
above, are bound to maintain the strict confidentiality of medical and research 
information that may be linked to identify individuals. The investigational site will 
normally be notified in advance of auditing visits. 
10.3    Informed Consent 
Written informed consent will embody the elements of informed consent as described in 
the Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance 
with all applicable laws and regulations. Investigators will enroll subjects according to 
the study eligibility criteria and in compliance with 21 CFR 50. The investigator will 
exercise no selectivity so that no bias is introduced from this source.
10.4    Study Subject Confidentiality
The investigator will comply with applicable subject privacy regulations/guidance as 
described as per HIPAA and any additional local regulations.


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The investigational sites participating in this study will maintain the highest degree of 
confidentiality permitted for the clinical and research information obtained from subjects. 
Medical and research records will be maintained at each site in the strictest confidence, 
however, as a part of the quality assurance and legal responsibilities of an investigation, 
the investigational site must permit authorized representatives of the sponsor(s) and 
regulatory agencies to examine (and when required by applicable law, to copy) records 
for the purposes of quality assurance reviews, audits and evaluation of the study safety 
and progress. Unless required by the laws permitting copying of records, only the coded 
identity associated with documents or other subject data may be copied (obscuring any 
personally identifying information). Authorized representatives, as noted above, are 
bound to maintain the strict confidentiality of medical and research information that may 
be linked to identify individuals. Study records with the study subject’s information for 
internal use at the clinical sites will be secured at the study site during the study. At the 
end of the study, all records will continue to be kept in a secure location for at least 2 
years post market approval in the applicable region. There are no plans to destroy the 
records
10.5
Study Documentation and Case Report Forms (CRFs)
The data collection tool for this study will be sponsor defined eCRFs to be completed by 
study-site personnel. The investigator will maintain complete and accurate study 
documentation in a separate file. Study documentation may include medical records, 
records detailing the progress of the study for each subject, signed informed consent 
forms, drug disposition records, correspondence with the Institutional Review Board 
(IRB) and the study monitor/sponsor, screening and consent information, CRFs, SAE 
reports, laboratory reports, subject diaries, data clarifications requested by the sponsor or 
designee, and any other documentation deemed relevant and pertinent to the study and 
the study subjects. Subject data necessary for analysis and reporting will be entered into a 
validated database or data system in accordance with Title 21 of the Code of Federal 
Regulations (21 CFR) Part 11. Clinical data management will be performed by Advanced 
Clinical in accordance with applicable data management standards and data cleaning 
procedures. The investigator is responsible for the procurement of data and for the quality 
of data recorded on the eCRFs. The eCRF will be electronically signed by the 
investigator listed on Form FDA 1572.
The handling of data by the sponsor and the data management vendor (Advanced 
Clinical), including data quality assurance, will comply with regulatory guidelines and 
the standard operating procedures of the sponsor or designee. Data management and 
control processes specific to the study will be described in the Data Management Plan as 
created for this study by Advanced Clinical CRO.  
10.6
Monitoring of the Study
Advanced Clinical will be responsible for data monitoring, data integrity, and data 
analysis. The study will be routinely monitored to ensure compliance with the study 
protocol and the overall quality of data collected. Throughout the course of the study, the 


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study monitor will make frequent contacts with the investigator through telephone calls 
and on-site visits. During the on-site visits, source documentation and the eCRFs will be 
reviewed for completeness and adherence to the protocol. As part of the data audit, 
source documents will be made available for review by the study monitor. The study 
monitor may periodically request review of the investigator study file to assure the 
completeness of documentation in all respects of clinical study conduct.
The study monitor will verify that each subject has proper consent documentation from 
the subject for study procedures and for the release of medical records to the sponsor, 
FDA, other regulatory authorities, and the IRB. The investigator or appointed delegate 
will receive the study monitor during these on-site visits and will cooperate in providing 
the documents for inspection and respond to inquiries. In addition, the investigator will 
permit inspection of the study files by authorized representatives of the regulatory 
agencies. 
Upon completion of the study, the study monitor will arrange for a close out visit, at each 
participating site, as defined in the Clinical Monitoring Plan (CMP). Study files should be 
secured for the appropriate time period. 
10.7 Direct Access to Source Data/Documents
The investigator/study site will cooperate and provide direct access to study documents 
and data, including source documentation for monitoring by the study monitor, audits by 
the sponsor or sponsor’s representatives, review by the Ethics Committee, and 
inspections by applicable regulatory authorities. If contacted by an applicable regulatory 
authority, the investigator will notify the sponsor of contact, cooperate with the authority, 
provide the sponsor with copies of all documents received from the authority, and allow 
the sponsor to comment on any responses.
10.8
Medical Monitor and Data Safety Monitoring Board (DSMB)
All adverse events will be recorded on the adverse event forms, and the treatment related 
SAEs will be sent to the IRB, per their reporting requirements, and to sponsor. The study 
medical monitor or designee will review all adverse event reports. Further details are 
captured in the study medical monitoring plan, data management plan, and safety 
management plan created for this study by Advanced Clinical and maintained in the 
study Trial Master File.
The DSMB is responsible for monitoring the safety of the trial subjects, and data integrity 
during periodic and ad hoc reviews. The DSMB will meet every 6 months; it can 
recommend to the sponsor and the study executive committee the continuation of study 
as planned, modification of the protocol, or the stopping of the study.
The sponsor will ensure the timely communication of the safety and efficacy data to the 
DSMB according to the agreed upon schedules or within reasonable time if requested for 


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an ad hoc analysis. The DSMB will meet bi-annually and ad hoc as specified in its 
charter.
Data accrual will be performed continuously as the study is being performed. Advanced 
Clinical, LLC, is the CRO that is responsible for the data management plan and integrity 
of the study data. The study medical monitor will be working continuously with 
Advanced Clinical to assess the data in regard to safety concerns and will recommend ad 
hoc review by the DSMB as necessary.
10.9
Publication Policy
Manuscript submission for publication of the results of this study, or any aspect of work 
directly related to the study, will be decided by the investigators.  Any investigator can 
submit a publication concept proposal including proposed authorship order to the rest of 
the investigators for review, which will take place within 30 days after a proposal has 
been submitted.
10.10 Maintenance and Retention of Records
The investigator will retain study documentation and data (electronic case report forms) 
in accordance with applicable regulatory requirements, institutional policy and the 
document and data retention policy, as described in the Data Management Plan or other 
supporting documents as applicable.
Signed consent forms for each subject will be coded with the subject’s unique study 
identification number and stored locally at each clinical site.  


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11.0
References
1.  Kim, Jae-Do, et al. "Clinical outcome of autologous bone marrow aspirates 
concentrate (BMAC) injection in degenerative arthritis of the knee." European 
Journal of Orthopaedic Surgery & Traumatology 24.8 (2014): 1505-1511.
2.  Jo, Chris Hyunchul, et al. "Intra-articular Injection of Mesenchymal Stem Cells for 
the Treatment of Osteoarthritis of the Knee: A 2-Year Follow-up Study." The 
American journal of sports medicine 45.12 (2017): 2774-2783.
3.  Shapiro, Shane A., et al. "A prospective, single-blind, placebo-controlled trial of 
bone marrow aspirate concentrate for knee osteoarthritis." The American journal of 
sports medicine 45.1 (2017): 82-90.
4. Buckwalter, Joseph A., et al. “The Impact of Osteoarthritis: Implications for 
Research.” Clinical Orthopaedics and Related Research (1976-2007): October 2004-
Volume 427-Issue-pp S6-S15
5. Micromedix:  Bone Marrow Harvesting-General Information. Accessed through 
Sanford Health CareNotes August 2, 2018
6. Cheng, Jiango, M.D., Ph.D. and Abdi, Salahadin, M.D., PhD. “Complications of 
Joint, Tendon, and Muscle Injections.” Tech Reg Anesth Pain Manag. 2007 Jul; 
11(3): 141-147
7. Micromedix:  Magenetic Resonance Imaging-General Information. Accessed through 
Sanford Health CareNotes August 2, 2018 
8. Illoouz, Yves-Gerard., and Aris Sterodimas, eds. Adipose Stem Cells and 
Regenerative Medicine. New York: Springer Heidelberg Dordrecht, 2011. Print


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12.0
Appendices
12.1 Joint Rehab
Establishing any home physical therapy program requires incorporating anticipated 
physiological changes with expected joint dysfunction. The following is a guideline to 
help you with your home physical therapy program following biologic injections to 
weight bearing joints. These guidelines were developed from research findings, 
therapist and patient feedback and clinical experience from physicians who routinely 
utilize stem cells.
Post Procedure Day
Precautions
Home Program
1-7
• WBAT (Weight Bearing As Tolerated), but 
PWB (Partial Weight Bearing) with crutches 
is allowed for patients with moderate to 
severe pain
• Avoid any heavy loading activities such as 
hiking, running, or heavy weight lifting
• Bracing if indicated by physician
• Gentle ROM (range of motion) if pain is not 
severe
8-14
• WBAT
• Avoid impact activities
• Avoid heavy weight lifting to affected joint
• Follow the Knee Range of Motion and 
Strengthening Post-Procedure Days 8-14 
instructions provided to you by the study 
team
• May start swimming and biking (low 
resistance)
15-28
• Avoid impact activities 
• Follow the Knee Range of Motion and 
Strengthening Post-Procedure Days 15-28 
instructions provided to you by the study 
team
• Can increase biking/ swimming activities
• May resume light aerobic activities such as 
walking
• Weight lifting/ strength training as tolerated 


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12.2 Lab Value Reference Ranges
Please refer to your site’s local laboratory reference ranges.