Evaluation of Safety and Exploratory Efficacy of CARTISTEM®, a Cell Therapy Product for Articular Cartilage Defects: A Phase I/IIa Clinical Trial in Patients With Focal, Full-thickness Grade 3-4 Articular Cartilage Defects of the Knee
Phase: PHASE1
Conditions: Degeneration Articular Cartilage Knee
Sponsor: Medipost, Inc.

CARTISTEM®                                                                                                  page 1 of 137G
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CARTISTEM® PHASE I/IIa 
CLINICAL TRIAL PROTOCOL  
MP-0201-01  
 
 
 
 
Version 3.2 
Date: 15 March, 2017  
 
 
 
 
 
 
 
 
CARTISTEM® PHASE I/IIa 
CLINICAL TRIAL PROTOCOL  

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Name of Company: MEDIPOST Co., Ltd. 
Name of Product: CARTISTEM® (Allogeneic-Unrelated, 
Umbilical Cord Blood-Derived Mesenchymal Stem Cells, Cultured 
Ex vivo, Combined with sodium Hyaluronate) 
Protocol #:  
MP-0201-01 
Protocol Title 
Evaluation of Safety and Exploratory Efficacy of CARTISTEM®, a Cell 
Therapy Product for Articular Cartilage Defects: A Phase I/IIa Clinical Trial 
in Patients with Focal, Full-thickness Grade 3-4 Articular Cartilage Defects 
of the Knee 
Clinical Phase 
Phase I/IIa 
Study Overview 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CARTISTEM® will be administered at doses ranging from 0.5×107 to 
2.25×107 hUCB-MSC (0.25×107 cells/cm2; 0.5 mL/cm2 with 0.5u107 
MSC/mL) to patients with focal, full-thickness, Grade 3-4 articular cartilage 
defects of ആ 2cm2 in size. 
 
Safety: 
Patient safety will be assessed step-wise with increasing levels of total 
hUCB-MSC and HA exposure: a total of 12 patients will be enrolled and 
treated with CARTISTEM® to evaluate whether dose limiting toxicity (DLT) 
is detected. DLT is defined as toxicity or adverse event of Grade 3 or higher 
[80 points or higher for pain] in two or more events at the surgery site among 
swelling, tenderness, range of motion, and pain in any one visit. DLT is also 
defined as adverse drug reaction of Grade 3 or higher in the Common 
Toxicity Criteria Adverse Events (CTCAE), Version 4.0, with the exception 
of the following events and that they are unresolved for 7 consecutive days, 
despite medical interventions: 
 
9 Abnormal results in lab test (Acidosis, Hyponatremia, 
Hyperbilirubinemia, etc.) 
9 Fatigue, defined as not relieved by rest; limiting self-care ADL 
9 Pain, defined as severe pain; limiting self-care ADL 
9 Headache, defined as severe pain in various parts of the head, limiting 
self-care ADL 
9 Fever, defined as > 40.0 degrees C (> 104.0 degrees F) for > 24 hours 
 
Initially, 6 patients with lesion sizes of 2-5 cm2 will be enrolled and treated 
(Dosage A); if dose limiting toxicity is not detected during a 12 week period 
after administration, an additional 6 patients, with lesion sizes of greater than 

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5 cm2, will be enrolled and treated (Dosage B) to further evaluate safety.  
 
Efficacy:  
Efficacy will be evaluated with several validated clinical outcome 
instruments as primary endpoints as well as non-invasive structural 
assessment utilizing high-resolution magnetic resonance imaging with 
cartilage-specific sequences as a secondary endpoint. 
Objectives: 
 
Primary 
Objective 
To evaluate the safety of CARTISTEM® administration 
Secondary 
Objectives 
To evaluate the exploratory efficacy (improvement in Clinical Scores and 
regeneration of defective cartilage as assessed by Radiological images) of 
CARTISTEM®.  
Diagnosis and 
Main Criteria for 
Inclusion 
Patients must meet the following criteria to be eligible for the study; 
y Patients with an intended- to- treat single focal, full-thickness cartilage 
defect (ICRS [International Cartilage Repair Society] Grade 3 or 4) of 
the knee as a result of ageing, trauma, or degenerative diseases. 
y Age ≥ 18 years old 
y Size of the articular cartilage lesion is ≥ 2 cm2  
y Swelling, tenderness and active range of motion ≤ Grade II 
y Joint pain : 20-mm - 60-mm on VAS (Visual Analog Scale) at the time 
of Screening 
y Appropriate blood coagulation, kidney and liver function laboratory 
parameters: 
9 PT(INR) < 1.5, APTT <1.5×control 
9 Creatinine ≤ 2.0 mg/dL, Albumin ≤ trace in urine dipstick test  
9 Bilirubin ≤ 2.0 mg/dL, AST/ALT ≤ 100 IU/L 
y Ligament instability ≤ Grade II 
y Lower extremity alignment within 5 degrees of the neutral weight 
bearing axis 
y No meniscal surgery within the past 3 months and more than 5mm of 
meniscal rim remaining 
y Ability and willingness to fully participate in the post-operative 
rehabilitation program 
y Subject is informed of the investigational nature of this study, 
voluntarily agrees to participate in the study, and signs an IRB-approved 
informed consent prior to performing any of the screening procedures 

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y Body Mass Index (BMI) ≤ 35 kg/m2 
Criteria for 
Exclusion 
x Patients who have been treated previously and are asymptomatic 
x Avascular necrosis/ osteonecrosis 
x Autoimmune or inflammatory joint disease 
x History of infection within the past 6 weeks 
x Surgery or radiation therapy within the past 6 weeks  
x Serious medical co-morbidities, which would otherwise contraindicate 
surgery, as determined by the investigator 
x Currently pregnant or nursing 
x Psychotic diseases, epilepsy, or any history of such diseases 
x Current abuse of alcohol (> 10 drinks weekly) and/or regular exposure to 
other substances of abuse, currently an active smoker 
x Chronic inflammatory articular diseases such as rheumatoid arthritis 
x Enrolled in any other clinical trials within the past 4 weeks 
x Administered immunosuppressants such as Cyclosporin A or 
azathioprine within the past 6 weeks 
x Ligament instability > Grade II  
x Uncorrected significant lower extremity malalignment (i.e. > 5 degrees) 
x  (sub-) Total meniscectomy (<5mm rim remaining) 
x Corticosteroid or viscosupplementation injection to the affected knee in 
the past 3 months 
x Principal investigator considers inappropriate for the clinical trial due to 
any reasons other than those listed above 
Number of 
Patients 
12 patients in total; 6 patients with defect sizes of 2-5 cm2 followed by 6 
patients with defect sizes > 5cm2 
Number of Study 
Centers 
Two 
Concomitant 
Treatment 
Patients should discuss any medications and therapies they are currently 
taking with the study doctor. Patients in this trial must not take the following 
drugs: glucosamine, dietary supplements used as alternative medicine to treat 
osteoarthritis such as chondroitin sulfate and hyaluronan, systemically 
administered corticosteroids (Hydrocortisone, Prednisone, Prednisolone, 
Methylprednisolone, Triamcinolone, Dexamethasone, Paramethasone, 
Betamethasone, Aldosterone, Fludrocortisone ) and immunosuppressants 
(Prednisone, Vincristine, Azathioprine, γ– globulin, Cyclophosphamide, 
Chlorambucil, 6-mercaptopurine, Cyclophosphamide + factor XIII, Rh(D) 
immune globulin, ALG, Actinomycin-D, OKT3, Methotrexate) 

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Study Design 
 
 
 
 
A total of 12 -18 patients will be enrolled and treated with CARTISTEM® to 
evaluate for dose limiting toxicity (DLT). 
Initially, 6 patients with defect sizes of 2 – 5 cm2 will be enrolled in Dosage 
A and treated with 0.5 – 1.25 x 107 hUCB-MSC. If DLT is not detected in 
any patients by 3 months post-administration (time point for first clinical 
efficacy evaluation), then additional 6 patients with defect sizes of above 5 
cm2 will be enrolled in Dosage B and treated with > 1.25 x 107 hUCB-MSC 
to further evaluate safety.  
If DLT is detected in 1 or 2 patients during Dosage A, additional 3 patients 
will be enrolled and assessed at Dosage A. If DLT is detected in 3 or more 
patients during Dosage A period, the study will be stopped. 
In the absence of DLT, a total of 12 patients will, therefore, be evaluated for 
safety and exploratory efficacy. 
 

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Clinical Trial 
Material (CTM)  
CARTISTEM® (human allogeneic-unrelated umbilical cord blood-derived 
mesenchymal stem cells, hUCB-MSC, and sodium hyaluronate) 
CARTISTEM® consists of approximately 7.5 x 106 hUCB-MSC suspended 
in 1.5 mL medium in one vial, and 60 mg sodium hyaluronate provided as a 
lyophilized sponge form in a separate vial. The two vials are mixed at the 
surgical site. Upon admixture of the two vials, the combination forms a 
viscous gel, which is implanted into the articular cartilage defect. 
 
Clinical Trial 
Material Dosage 
and 
Administration 
 
CARTISTEM® will be administered into the articular cartilage defect by 
open surgery at a dose of 0.5 mL/cm2 based upon size of the defect. The 
CARTISTEM® dosage has been selected based on the results derived from 
nonclinical studies and prior human experience (see Investigator’s Brochure 
for further information) 
Surgical  
Technique 
Before application of CARTISTEM®, unstable chondral fragments are 
debrided using a curet and stable shoulders of healthy surrounding cartilage 
are created. After adequate removal of the debris, multiple holes are created 
across the entire articular cartilage defect with a 2~3 mm drill bit spacing the 
holes approximately 3~5 mm apart. CARTISTEM® is applied onto the 
drilled holes first, and then throughout the entire cartilage defect. 
Post-operative 
rehabilitation 
Patients will be started on a continuous passive motion (CPM) device on 
post-operative day 1 with a range of motion of 0-30 degrees initially. This 
will be increased by 10 degrees per day as tolerated to a maximum of 0-90 
degrees. Patients will undergo CPM treatment for 6 hours per day over 6 
weeks. The patient will remain touch-down weight-bearing (TDWB) for 6 
weeks, and then advance to full-weight bearing during the next 6 weeks (up 
to week 12). The patient will refrain from high-impact activities, such as 
running, during the subsequent 8 to 12 weeks (week 20 – 24).  
Reference 
Therapy 
The study does not include a reference compound.   
Approximate 
Duration of 
Patient 
Participation  
Each patient will undergo a 6-week screening period for eligibility and a 12-
month follow-up observation period for both the primary (safety) and 
secondary (efficacy) evaluations following administration of CARTISTEM®. 
Also each patient will undergo a 24-month follow-up visit for a long term 
patient assessment.  

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Approximate 
Duration of 
Study 
The estimated duration of the study for the primary evaluation is 
approximately 12 months, with an additional 12 month extension for the 
long-term patient assessment phase. 
Safety 
Evaluation 
 
 
General 
General safety will be evaluated via the following assessments: AEs, routine 
clinical laboratory tests (hematology, clinical chemistry, and urinalysis), 
thrombin generation (PT and aPTT), immunogenicity tests (T cell subset), 
vital signs, physical exams, ECGs, and MRI for tumorigenicity. 
 
Adverse Events 
To assess the safety of CARTISTEM®, the course and degree of swelling, 
tenderness, range of motion and pain will be determined. DLT is defined as 
toxicity or adverse event of Grade 3 or higher [80 points or higher for pain] 
in two or more events at the surgery site among swelling, tenderness, range 
of motion, and pain, in any one visit. DLT is also defined as adverse drug 
reaction of Grade 3 or higher in the Common Toxicity Criteria  Adverse 
Events (CTCAE), Version 4.0, with the exception of the following events and 
that they are unresolved for 7 consecutive days, despite medical 
interventions: 
9 Abnormal results in lab test (Acidosis, Hyponatremia, 
Hyperbilirubinemia, etc.) 
9 Fatigue, defined as not relieved by rest; limiting self-care ADL 
9 Pain, defined as severe pain; limiting self-care ADL 
9 Headache, defined as severe pain in various parts of the head, limiting 
self-care ADL 
9 Fever, defined as >40.0 degrees C (> 104.0 degrees F) for > 24 hours 
Efficacy 
Evaluation 
 
 
Primary efficacy outcome parameters will be the postoperative changes in 
subjective knee function as assessed by IKDC (International Knee 
Documentation Committee) score at 12 months. For secondary efficacy 
outcome parameters, patients will answer questionnaires for pain (visual 
analogue scale, VAS), knee specific outcome instruments (Lysholm knee 
scoring, and KOOS [Knee injury and Osteoarthritis Outcome Score]). 
Structural information will be gathered using high-resolution (1.5 or 3 Tesla) 
magnetic resonance imaging (MRI). 

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Statistical 
Methods 
General: all safety and efficacy endpoints will be presented for each dose 
cohort as well as for all patients combined. For safety evaluation, statistical 
homogeneity between dose groups will be performed. For efficacy 
evaluation, statistical comparison (difference) between dose groups will be 
performed.  
 
1) Safety 
Safety will be demonstrated with 95% confidence intervals. Adverse events, 
adverse drug reactions, serious adverse events, and drop-out patients due to 
AE will be presented with frequency and percentage.  Homogeneity 
between dose groups will be analyzed using person’s chi-square test or 
Fisher’s exact test. Descriptive statistics including means, medians, SD 
(standard deviation), minimum and maximum will be used to demonstrate 
the other safety endpoints. 
 
2) Efficacy 
Symptom improvement from the outcome instruments will be demonstrated 
with means and standard deviations. Efficacy results will also be analyzed 
for statistical significance using change from baseline at each efficacy 
endpoint. Statistical difference of continuous variables and categorical 
variables between dose groups will be compared using t-test and Fisher’s 
exact test, respectively.  
Rationale for 
Study Population 
and Number of 
Patients  
CARTISTEM® is administered to the defective joint cartilage region by open 
surgery. Due to ethical considerations, it is not possible to conduct this type 
of procedure in a healthy subject. Therefore, no studies in healthy subjects 
will be performed. 
 
Factors such as number of subjects to acquire statistical data of the 
effectiveness are not considered as critical in this phase I/IIa study. A small 
number of subjects generally participate in this stage of clinical study. 
Accordingly, Dosage A is set based on dose limit of toxicity from non-
clinical study and then Dosage B will be administered. 
 

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Abbreviations 
 
AE  
Adverse Event, Adverse Experience 
ADR 
Adverse Drug Reaction 
ALP 
Alkaline Phosphatase 
ALT(sGPT) 
Alanine aminotransferase (serum Glutamic Pyruvic Transaminase) 
AST(sGOT) 
Aspartate aminotransferase (serum Glutamic Oxaloacetic Transaminase) 
BUN 
Blood Urea Nitrogen 
CK 
Creatine Kinase 
CRP 
C-Reactive Protein 
CTC 
Common Toxicity Criteria 
DLT 
Dose Limiting Toxicity 
ESR 
Erythrocyte Sedimentation Rate 
HCG 
Human Chronic Gonadotropin 
Hb 
Hemoglobin Concentration 
Hct  
Hematocrit 
ICRS 
International Cartilage Repair Society 
IKDC  
International Knee Documentation Committee 
IND 
Investigational New Drug 
KOOS Score 
Knee injury and Osteoarthritis Outcome Score 
LDH 
Lactate dehydrogenase 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MLR 
Mixed Lymphocyte Reaction 
MTD 
Maximal Tolerated Dose 
NCI 
National Cancer Institute 
PT 
Prothrombin Time  
aPTT 
Activated Partial Thromboplastin Time 
RBC 
Red Blood Cell 
ROM 
Range of Motion 
VAS 
Visual Analogue Scale 
WBC 
White Blood Cell 
 

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Table of Contents 
1 
Title and Development of Phase ......................................................................................... 12
1.1 Study Title ........................................................................................................................ 12
1.2 Developmental Phase ...................................................................................................... 12
2
Name and affiliation of principal or coordinating investigators ..................................... 12
2.1 Name and Address of the Research Facilities ................................................................. 12
2.2 Names and Titles of the Coordinating Investigator and the Principal Investigators ....... 12
2.3 Name and Title of the Clinical Trial Pharmacist ............................................................. 12
2.4 Name and Address of the reviewing Institutional Review Board (IRB) ......................... 13
3
Name of the Sponsor ........................................................................................................... 14
4
Background of the Study .................................................................................................... 14
4.1 Cartilage defects .............................................................................................................. 14
4.2 Investigational cellular-surgical combined interventions ................................................ 15
4.3 CARTISTEM® (MEDIPOST Cell Therapy Product) ...................................................... 16
4.4 Sodium Hyaluronate ........................................................................................................ 17
5
Purpose of the Study ........................................................................................................... 18
6
Study Design ......................................................................................................................... 19
6.1 Study Period .................................................................................................................... 19
6.2 Subject Selection Criteria ................................................................................................ 19
6.3 Number of Subjects ......................................................................................................... 21
6.4 Administration Dosage .................................................................................................... 22
6.5 Dose Escalation ............................................................................................................... 24
6.6 Definition of Maximum Permissible Dose and Method of Dose Escalation .................. 26
6.7 Expected Adverse Effects and Usage Considerations ..................................................... 26
6.7.1 Expected Adverse Effects ............................................................................................. 26
6.7.2 Usage Considerations ................................................................................................... 27
7
Investigational Product ....................................................................................................... 27
7.1 Investigational Product .................................................................................................... 27
7.1.1 Trade Name .................................................................................................................. 27
7.1.2 Ingredients .................................................................................................................... 27
7.1.3 Property ........................................................................................................................ 28
7.2 Route of Administration .................................................................................................. 28
7.3 Return and disposal of unused investigational product ................................................... 31
8
Study Method ....................................................................................................................... 32
8.1 Overview of the Study Design ......................................................................................... 32
8.2 Study Flow Chart ............................................................................................................. 33
8.3 Concomitant Medications and Concomitant Non-drug Therapies .................................. 36
8.4 Observation and Evaluation Items ................................................................................... 36
8.4.1
Demographic Background and Medical History of Subjects .................................. 36
8.4.2
Concomitant Medications ........................................................................................ 37
8.4.3
Evaluation of Adverse Events & Toxicity ............................................................... 37
8.4.4
Laboratory Evaluations ............................................................................................ 38
8.4.5
Immunogenicity study ............................................................................................. 38

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8.4.6
IKDC Score ............................................................................................................. 38
8.4.7
100-mm VAS Evaluation ......................................................................................... 39
8.4.8
Lysholm Score ......................................................................................................... 39
8.4.9
KOOS Score ............................................................................................................ 39
8.4.10 MRI Assessment ...................................................................................................... 39
8.5 Early Discontinuation from the Study ............................................................................. 39
9
Definition of Adverse Events .............................................................................................. 40
9.1 Criteria for Safety Assessment ........................................................................................ 40
10
Statistical Analysis ............................................................................................................... 41
10.1Analysis Populations ....................................................................................................... 41
10.1.2 Efficacy Population ................................................................................................. 41
10.2Analysis of Safety Variables and Statistical Evaluation .................................................. 41
10.2.1 Safety Variables ....................................................................................................... 41
10.2.2 Analysis of Safety Endpoints .................................................................................. 42
10.3Analysis of Efficacy Variables and Statistical Evaluation ............................................... 42
10.3.1 Efficacy Variables .................................................................................................... 42
10.3.2 Analysis of Efficacy Endpoints ............................................................................... 43
11
Rehabilitation Protocol ....................................................................................................... 44
12
References ............................................................................................................................ 48
APPENDIX  1. IKDC score ..................................................................................................... 51
APPENDIX  2. LYSHOLM SCORE ....................................................................................... 54
APPENDIX  3. KOOS KNEE SCORE ................................................................................. 55
APPENDIX  4.  CTCAE(Version 4.0) ..................................................................................... 58
APPENDIX  5.  IDMC charter .............................................................................................. 137

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1  Title and Development of Phase 
1.1 Study Title 
Evaluation of Safety and Exploratory Efficacy of CARTISTEM®, a Cell Therapy Product for 
Articular Cartilage Defects: A Phase I/IIa Clinical Trial in Patients with Focal, Full-thickness, 
Grade 3-4 Cartilage Defects of the Knee 
1.2 Developmental Phase 
Phase I/IIa 
2 Name and affiliation of principal or coordinating investigators 
2.1 Name and Address of the Research Facilities 
 
RUSH University Medical Center 
 
1611 W. Harrison Street, Chicago, IL 60612 
       Brigham and Women's Hospital  
850 Boylston St., Chestnut Hill, MA 02467 
2.2 Names and Titles of the Coordinating Investigator and the Principal Investigators 
Coordinating Investigator, Principal Investigator 
Brian J. Cole, MD 
Professor, Department of Orthopedic Surgery 
Professor, Department of Anatomy and Cell Biology 
Section Head of Cartilage Restoration Center  
Principal Investigator 
Andreas H. Gomoll, MD 
Assistant Professor, Department of Orthopedic Surgery 
2.3 Name and Title of the Clinical Trial Pharmacist 
CARTISTEM® consists of umbilical cord blood-derived mesenchymal stem cells (hUCB-
MSC; main component) suspended in a transparent pale pink medium and sodium hyaluronate 

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(device) intended for cartilage regeneration in patients with cartilage defects or injuries. Unlike 
other conventional investigational products, the innate biological properties of the living cells 
in this product limit the shelf-life of the suspension (mixture of hUCB-MSC and HA) to less 
than 72 hours after preparation. Therefore, the investigational product needs to be delivered to 
the test site on the day of the actual surgery so that the on-site preparation and administration to 
the patient can take place shortly after receipt of the two vialed CARTISTEM® components 
(hUCB-MSC and lyophilized HA). Designation of a clinical trial pharmacist is deemed 
unnecessary as the unused portion of the investigational product which is ordered and 
administered on an individual subject basis is to be returned to MEDIPOST after the surgery. 
Therefore, a clinical nurse is given the role of managing the investigational product under 
supervision of the principal investigator and the subinvestigators. 
Moreover, CARTISTEM® does not require a separate compounding or preparation process of 
a clinical trial pharmacist as the product can be mixed and used by the principal investigator in 
the surgery room. Hence, it was decided that it would be acceptable to have an appropriate 
individual designated by the (principal) investigator order, receive the shipment of, and return 
the investigational product to the sponsor. Therefore, a clinical nurse is assigned the role of 
managing the investigational product under the supervision of the investigator. 
2.4 Name and Address of the reviewing Institutional Review Board (IRB) 
 The Institutional Review Board at RUSH University Medical Center 
 Research and Clinical Trials Administration Office 
 1653 W. Congress Parkway, Chicago, IL 60612  
 (Mailing Address: 707 S. Wood Street, Lower Level, Chicago, IL 60612)  
Partners Human research Committee at Brigham and Women’s Hospital  
116 Huntington Avenue, Suite 1002, Boston, MA 02116 
(Website: http://healthcare.partners.org/phsirb) 
 

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3 Name of the Sponsor 
MEDIPOST Co., Ltd. 
21 Daewangpangyo-ro 644-beon-gil, Bungdang-gu, Seongnam-si, Gyeonggi-do 13494, 
Korea 
4 Background of the Study 
4.1 Cartilage defects 
Chondral defects or damage to articular cartilage due to accidents, repetitive trauma or 
arthritis are common disorders. They are major causes of disability, as they can lead to 
osteoarthritis and they rarely heal spontaneously (e.g., Dragoo et al. 2003, Moore et al. 2005). 
As the population ages and as more young people participate in active sports, the size of the 
target patient group is also growing. However, despite ongoing research efforts, clinical 
products directed at cartilage repair remain limited. 
Articular cartilage consists of hyaline cartilage and is a highly differentiated connective 
tissue covering joint surfaces. It is avascular and alymphatic, and it is sheltered from the 
immune system. It also has no nerve supply and is therefore not sensitive to early injuries. 
Articular cartilage also has poor repair properties because there are relatively few cells in the 
tissue, the metabolic rate is low, and the capacity of chondrocytes to divide and migrate within 
articular cartilage is restricted by the dense matrix. As a consequence, it is generally agreed that 
articular cartilage does not repair significantly after damage to the collagen matrix (e.g., Chang 
et al. 2006, Gelse et al. 2003, Hedrick and Daniels 2003, Katayama et al. 2004, Risbud et al. 
2001, Wakitani et al. 2002). Therefore, damage to the tissue as a result of trauma generally 
progresses to osteoarthritis. 
In most cases, the critical limiting step for the induction of spontaneous cartilaginous repair 
is incomplete and leads to the formation of fibrous, or at best fibrocartilage, tissue – a tissue 
intermediate of fibrous mesenchyme and cartilage, depending on the location and size of injury. 
Compared with the native hyaline articular cartilage, fibrous repair tissue has poor mechanical 
qualities and is prone to fail in the long term (Athanasiou et al. 2001, Chuma et al. 2004, Gelse 
et al. 2003, Guo et al. 2004, Mizuta et al. 2004, Moore et al. 2005, Otsuka et al. 1997). It is, 

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therefore, desirable to develop procedures that allow for improved repair of cartilage defects, as 
discussed below.  
4.2 Investigational cellular-surgical combined interventions 
Various different types of treatments are in use, such as drug therapy, arthroscopy, joint 
replacement surgery, marrow stimulation techniques (drilling, abrasion arthroplasty and 
microfracture for stimulation of local MSC), periosteal grafts, and autologous chondrocyte 
transplantation (Athanasiou et al. 2001, Risbud et al. 2001, Smith et al. 2005). However, 
conventional treatment modalities have not been able to provide complete and sustained 
resolution of symptoms following damage to the articular cartilage. Despite the numerous 
techniques available today, complete healing of damaged or defective cartilage or consistent 
reproduction of normal hyaline cartilage does not occur, and continuous drug administration or 
secondary surgeries are common. Thus, functional restoration of diseased and damaged human 
articular cartilage continues to remain one of the most challenging orthopedic problems and the 
clinical need for cartilage repair/regeneration technologies is undisputed (Athanasiou et al. 
2001, Elisseeff 2004, Gelse et al. 2003, Lee et al. 2010, Smith et al. 2005, Yanai et al. 2005). 
The latest attempts to develop clinically useful procedures for repairing damaged articular 
cartilage include the use of cells with the potential for cartilage repair. There are three potential 
cell types that may be utilized: chondrocytes (already used in the autologous chondrocyte 
transplantation technique), adult (somatic) stem cells and embryonic stem cells (Barry 2003, 
Browne et al. 2005, Giannoni et al. 2005, Guo et al. 2004, Otsuka et al. 1997, Yanai et al. 2005).  
Chondrocyte implantation has long been considered as a potential treatment and several 
approaches of chondrocyte implantation are in current clinical use. Implantations of previously 
isolated and in vitro amplified autologous chondrocytes are being performed in current clinical 
practice. The disadvantages of this procedure are the limited proliferative capacity of adult 
chondrocytes, the issue of dedifferentiation in culture and required re-differentiation upon 
implantation, as well as the need for a 2-stage procedure for harvest and implantation. 
The use of stem cells is the most recently developed and investigated method. The most 
promising approaches involve the introduction of MSC /cartilage precursor cells. Bone marrow 

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contains non-hematopoietic progenitor cells capable of differentiating into osteoblasts, 
chondrocytes and adipocytes; because those differentiated cells have mesodermal origin, their 
bone marrow progenitors have been designated MSC.  
The umbilical cord blood is a source of hematopoietic stem cells and is used for 
hematopoietic stem cell transplantation in patients with diseases such as leukemia, aplastic 
anemia, and congenital immune deficiency that require allogeneic hematopoietic stem cell 
transplants.  Over 5,000 cases of umbilical cord blood-derived hematopoietic stem cell 
transplantations have been conducted globally as of 2004, and transplant treatments using 
umbilical cord blood are expected to increase even further in the future.  Umbilical cord blood 
is blood from the placenta and umbilical cord, which can be easily collected from the umbilical 
cord after childbirth, and therefore the collection poses no risk of harm to either the mother or 
the infant. Considering the present US birth rate of about 4,000,000 infants per year, umbilical 
cord blood is one of the most readily available and non-invasive sources of mesenchymal stem 
cells. The mesenchymal stem cell found in umbilical cord blood is characterized by its ability 
to self-replicate as well as its multipotency, or the capability to differentiate into cell lineages 
that compose bone, cartilage, bone marrow stroma, adipocytes, tendon, neurons, and various 
other tissues and organs.  
Research in MSC has had a rapid acceleration over the past decade and MSC-based therapy 
has become one of the objects of investigation for a new branch of medicine termed 
regenerative medicine. This emerging technology shows great promise for producing 
transplantable cartilage constructs to restore the function of degenerated joints. However, 
current treatment options using MSC for articular cartilage repair/regeneration are still at an 
experimental stage of development. Studies with MSC were conducted in various animal 
models while currently only one clinical investigation and two case reports with MSC are 
available (e.g., Wakitani et al. 2002, Wakitani et al. 2010).  
4.3 CARTISTEM® (MEDIPOST Cell Therapy Product) 
CARTISTEM® is intended to be used as a single-dose cellular therapeutic agent for cartilage 
regeneration in human subjects with cartilage defects of the knee as a result of ageing, trauma or 

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degenerative diseases.  
The CARTISTEM® drug product consists of a combination of human umbilical cord blood-
derived mesenchymal stem cells (hUCB-MSC; supplied as a liquid suspension) and lyophilized 
sodium hyaluronate, provided in separate vials for mixing prior to administration. The packaged 
drug product will be shipped and stored as two vials, one vial containing approximately 7.5x106 
hUCB-MSCs suspended in 1.5 mL medium (alpha-MEM) to be mixed with one vial containing 60 
mg sodium hyaluronate (lyophilized). Upon admixture of the two vials, i.e. after distribution of 
the cells in the hyaluronate polymer, the reconstituted product (5x106 cells/mL; 40 mg/mL sodium 
hyaluronate) is formed as a viscous gel which is implanted into the cartilage lesion during open 
surgery. The initial proposed clinical dose is to be 0.5 mL/cm2 (approximately 2.5x106 cells and 
20 mg HA/cm2). Immune phenotype tests using flow cytometer demonstrated that the hUCB-
MSCs are CD45 negative, CD14 negative, HLA-DR negative, CD29 positive, CD73 positive, 
CD105 positive, and CD166 positive. 
hUCB-MSCs, the active ingredient in CARTISTEM®, are expected to induce the regeneration 
of damaged cartilage tissues by repair of the microenvironment with paracrine effects or by 
differentiation towards tissue-specific pathways. Sodium hyaluronate is believed to function as a 
medical device to provide mechanical stability to the hUCB-MSC suspension, enabling the cells 
to remain at the site of the implantation and not disseminate into adjacent areas. 
4.4 Sodium Hyaluronate 
Hyaluronic acid is a natural component of the extracellular matrix in cartilage. The 
glycosaminoglycan is highly conserved and is widely distributed in the body. hUCB-MSCs 
express cell surface receptors (CD44) that bind to hyaluronic acid. Interaction between cells and 
the extracellular matrix regulates many biological processes that are important to cartilage 
homeostasis and repair, including cell attachment, growth, differentiation, and survival (Marcacci 
et al. 2005, Risbud et al. 2001).  
Since the 1970’s, hyaluronic acid has been clinically used as a chondroprotective agent 
(Caplan and Dennis 2006, Watterson and Esdaile 2000). In addition, sodium hyaluronate has been 

CARTISTEM®                                                                                                   page 18 of 137G
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FDA approved for the treatment of osteoarthritis of the knee since 1997 (as an orthopedic device – 
e.g. ORTHOVISC® High Mol, SUPARTZ® Dispo, SYNVISC® (Hylan G-F 20) and HYALGAN®). 
In 2003, HA was approved for injection into the mid to deep dermis for correction of moderate to 
severe facial wrinkles and folds (such as nasolabial folds).  In all cases, the FDA has regulated 
the products as medical devices. 
The sodium hyaluronate in the CARTISTEM® product is believed to provide a stabilizing 
function to the MSC enabling them to remain at the site of the implant and not spill over into 
adjacent areas. In fact, sodium hyaluronate (and its derivatives) has proven to be an ideal molecule 
for use in the delivery of cellular therapies such as autologous chondrocytes or MSC in cartilage 
repair helping to keep the implanted cells in place (e.g., Elisseeff 2004, Marcacci et al. 2005, 
Risbud et al. 2001). In addition, hyaluronic acid has been shown to be both non-toxic and 
biocompatible (Kasahara et al. 2008). Thus, sodium hyaluronate was considered highly desirable 
for use as a scaffold in CARTISTEM®. There is currently no evidence that the presence of sodium 
hyaluronate contributes in any way to the inherent activity of the implanted MSC. Therefore, 
MEDIPOST considers the sodium hyaluronate to be a device in the final administered 
CARTISTEM®. 
 
5 Purpose of the Study 
The primary objective of the proposed single-center phase I/IIa study is to evaluate the safety 
of CARTISTEM®, an allogeneic-unrelated mesenchymal stem cell (hUCB-MSC) suspension 
mixed with sodium hyaluronate, at doses ranging from 0.5×107 to 2.25×107 hUCB-MSC in 
patients with articular cartilage defects that are equal or greater than 2cm2. 
The secondary objective of the study is to evaluate the efficacy (regeneration of defective 
cartilage and decrease of pain) of CARTISTEM®. 
CARTISTEM® will be administered, as a function of the defect size, at a cell density of 
0.25×107 cells/cm2 (0.5 mL/cm2 with 0.5u107 hUCB-MSC/mL) directly into the articular cartilage 
defect by open surgery.  

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A total of 12 patients, initially 6 patients with defect sizes of 2 to 5 cm2 (Dosage A) followed 
by an additional 6 patients with defect sizes of above 5 cm2 (Dosage B), will be enrolled 
sequentially in 2 groups in order to evaluate whether dose-limiting toxicity (DLT) is detected.  
Each patient will undergo a 6-week screening period for eligibility and a 12-month follow-up 
observation period for both the primary (safety) and secondary (efficacy) endpoints of the study. 
There is an additional long term follow-up observation visit at 24 months. The estimated total 
duration of the study is approximately 24 months. 
Prior to administration of CARTISTEM®, the defect will undergo debridement, and following 
appropriate preparation, perforation of the subchondral plate. 
CARTISTEM® is applied directly onto the entire defect site.  
For use at the clinical site, CARTISTEM® will be provided as a cell suspension and lyophilized 
sodium hyaluronate in separate glass vials. 
In terms of post-operative rehabilitation, patients will be started on a continuous passive 
motion (CPM) device on post-operative day 1 and refrain from high-impact activities such as 
running for 20 to 24 weeks. 
 
6 Study Design 
6.1 Study Period 
1) 24 months from approval of the clinical trial protocol 
2) Recruiting period: 7 months 
3) Follow-up period: 12 months from baseline (week 0) to final visit 
4) Long term follow-up visit: 24 months following administration of CARTISTEM® 
6.2 Subject Selection Criteria 
1) Inclusion Criteria 
A. Patients with an intended- to- treat single focal, full-thickness cartilage defect (ICRS 
[International Cartilage Repair Society] Grade 3 or 4) of the knee as a result of ageing, 

CARTISTEM®                                                                                                   page 20 of 137G
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trauma, or degenerative diseases  
B. Age ≥ 18 years old 
C. Size of the articular cartilage lesion is ≥ 2 cm2  
D. Swelling, tenderness and active range of motion ≤ Grade II 
E. Joint pain : 20-mm - 60-mm on VAS (Visual Analog Scale) at the time of Screening 
F. Appropriate blood coagulation, kidney and liver function laboratory parameters: 
9 PT(INR) < 1.5, APTT <1.5×control 
9 Creatinine ≤ 2.0 mg/dL, Albumin ≤ trace in urine dipstick test  
9 Bilirubin ≤ 2.0 mg/dL, AST/ALT ≤ 100 IU/L 
G.  Ligament instability ≤ Grade II 
H. Lower extremity alignment within 5 degrees of the neutral weight bearing axis 
I.  No meniscal surgery within the past 3 months and more than 5mm of meniscal rim 
remaining 
J. Ability and willingness to fully participate in the post-operative rehabilitation program 
K. Subject is informed of the investigational nature of this study, voluntarily agrees to 
participate in the study, and signs an IRB-approved informed consent prior to 
performing any of the screening procedures 
L. Body Mass Index (BMI) ≤ 35 kg/m2 
 
2) Exclusion Criteria 
A. Patients that have been treated previously and are asymptomatic  
B. Avascular necrosis / osteonecrosis 
C. Autoimmune or inflammatory joint disease 
D. History of infection within the past 6 weeks 
E. Surgery or radiation therapy within the past 6 weeks  
F.  Serious medical co-morbidities which would otherwise contraindicate surgery, as 
determined by the investigator 
G. Currently pregnant or nursing 
H. Psychotic diseases, epilepsy, or any history of such diseases 

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I.   Current abuse of alcohol (> 10 drinks weekly) and/ or regular exposure to other 
substances of abuse; currently an active smoker 
J.   Chronic inflammatory articular diseases such as rheumatoid arthritis 
K. Enrolled in any other clinical trials within the past four weeks 
L. Administered immunosuppressants such as Cyclosporin A or azathioprine within the past 
6 weeks 
M. Ligament instability > Grade II  
N. Uncorrected significant lower extremity malalignment (i.e. > 5 degrees) 
O. (Sub-) Total meniscectomy (<5mm rim remaining) 
P. Corticosteroid or viscosupplementation injection to the affected knee in the past 3 months 
Q. Principal investigator considers inappropriate for the clinical trial due to any reasons other 
than those listed above 
6.3 Number of Subjects  
1) Estimated Number of Patients 
This study requires 12-18 patients (6-9 patients per arm depending on rate of DLT) for two 
different dose ranges (Dosage A: defect sizes of 2-5 cm2 and Dosage B: defect sizes of 
above 5 cm2).  
2) Target Number of Subjects and Rationale 
This is a phase I/IIa clinical trial to evaluate safety and exploratory efficacy of the 
investigational drug product. Therefore, it is not considered critical to base the number of 
subjects on formal statistical power calculations. Six patients at each dose cohort enrolled 
sequentially are considered sufficient for this study. This study will be performed with two 
dose ranges, on the basis of existing pre-clinical test results. Initially, 6 patients with defect 
sizes of 2-5 cm2 will be enrolled in Dosage A. If no DLT is seen during Dosage A, another 6 
patients with larger defect sizes (above 5 cm2) will be recruited for Dosage B of the study. 
There could be a need for an intermediate dose or up to 6 additional patients, based on the 
rate of DLT seen. 

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6.4 Administration Dosage 
1) Initial Administration Dosage and Rationale  
It is somewhat well understood by developers and regulators of living cell therapies that 
for products like CARTISTEM® administered locally into an anatomical defect there is no 
simple extrapolation of a safe starting dose in humans based primarily upon body surface 
area calculations derived from animal studies. 
In addition, dose determinations in this clinical setting should take into account the 
surface area of the cartilage defect such that all NOAEL values should be converted into a 
unit quantity (cells/cm2) at the application site. This approach applies to most therapeutics 
administered into anatomical compartments that have little subsequent distribution outside 
of the compartment; it is recommended that doses are normalized between species according 
to the compartmental volumes and amount of the therapeutic product. 
Support for the range of CARTISTEM® doses (0.5 × 107 cells to 2.25 × 107 cells) to be 
evaluated for safety and efficacy in this phase I/IIa study comes from both preclinical 
studies and clinical results in humans (comprised of a completed Phase I/II study in Korean 
patients with articular cartilage defects (N=7) and an ongoing Phase III study in Korean 
patients (N=50), as follows:  
NOAELs for CARTISTEM® have been determined in the rat (Study No. B04001; 
NOAEL = 3x107 cells per mL; > 1x107 cells per cm2) and the rabbit (Study No. B04004; 
NOAEL = 1.5x107 cells per mL; > 0.3x107 cells per cm2); however, it is possible that the 
design of these studies did not allow for a proper assessment of the NOAEL due to 
limitations on the density of cells administered, and an overall very low toxicity of the 
hUCB-MSC in the species examined.  
No treatment-related SAEs have been reported in seven patients who participated in a 
phase I/II Korean study and 50 patients currently enrolled in an ongoing phase III Korean 
study; all of these patients have received single administrations of 0.25×107 cells/cm2 (0.5 
ml/cm2 with 0.5x107 MSC/mL) up to a maximum of 2.25x107 total MSC; this number of 
cells represents a much higher dose than the NOAEL (10x107 MSC per mL) derived from 

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Study B04001 (GLP repeat-dose toxicology study in rats). 
Based on these findings (for further discussion, please see the Investigator’s Brochure), 
MEDIPOST has selected a single administration of CARTISTEM® at 0.25×107 cells/cm2 
(0.5 mL/cm2 with 0.5x107 hUCB-MSC/mL), with both the volume and total number of 
hUCB-MSC administered to patients being a function of the defect size.  
Similar products available on the market include CARTICEL® manufactured by 
Genzyme Biosurgery, an autologous cultured chondrocyte product approved by the US-FDA. 
Clinical studies of CARTICEL® were conducted at dose levels ranging from 0.64×106 
cells/cm2 up to 3.3×106 cells/cm2 for the 1.2×107 cells/0.4mL product. Meanwhile, 
Chondron, the autologous chondrocyte regeneration therapy of Cellontech, Korea, is a 
1.2×107 cells/0.4mL product which is applied at a ratio of 0.1 mL for every 1 cm2 of 
cartilage defect. For cartilage defects greater than 4 cm2 in size, the entire vial is 
administered. 
Both CARTICEL® and Chondron are autologous chondrocyte therapies, with limits in 
cell proliferation and maximum number of cells that can be achieved in the defect. In other 
words, the limited cell number is a challenge and it is difficult to determine a constant cell 
concentration per unit area in larger defect sizes. Also, there are potentially large differences 
in cell potency since the starting materials/living cells are derived in a patient-specific 
manner and, therefore, typically vary greatly from patient to patient. 
 CARTISTEM® can be differentiated from these two products because it is an off-the-
shelf allogeneic-unrelated cellular therapy that allows a consistent application of the most 
effective cell concentration per area of defect throughout the entire lesion with a constant 
cell concentration. 
Against this background, the most scientific and logical approach for the study would 
be to perform the clinical trial using two different cell concentrations of 0.5×107 cells/mL 
and 1.0×107 cells/mL. However, it was deemed ethically inappropriate to subject a treatment 
group to a relatively-less effective dose.  Therefore, a single cell concentration expected to 
be the more effective of the two was first chosen through a preclinical study and adopted for 

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this clinical trial.  The total volume of administration was determined by size of the lesion. 
CARTISTEM®, consisting of mesenchymal stem cells and sodium hyaluronate, will be 
applied at a dose of 0.5 mL/cm2. The administered dose is, therefore, a function of the defect 
size. It will be administered into the cartilage defect by open surgery. 
The following chart provides determination of CARTISTEM® dosage relative to the 
defect size (derived from nonclinical studies and prior human experience): 
Study 
Phase 
Defect Size 
Volume of Dose 
Total Cell Number 
(hUCB-MSC) 
Device  Dosage 
(Sodium hyaluronate) 
A 
2 cm2 
1.0 mL 
0.5 × 107 cells 
40 mg 
3 cm2 
1.5 mL 
0.75 × 107 cells 
60 mg 
4 cm2 
2.0 mL 
1.0 × 107 cells 
80 mg 
5 cm2 
2.5 mL 
1.25 × 107 cells 
100 mg 
B 
6 cm2 
3.0 mL 
1.5 × 107 cells 
120 mg 
7 cm2 
3.5 mL 
1.75 × 107 cells 
140 mg 
8 cm2 
4.0 mL 
2.0 × 107 cells 
160 mg 
9 cm2~ 
4.5 mL ~ 
2.25 × 107 cells~ 
180 mg ~ 
G
6.5 Dose Escalation 
This clinical trial will employ the following dose escalation scheme: 
A total of 12-18 patients will be enrolled and treated with CARTISTEM® for dose 
limiting toxicity (DLT) evaluation. Initially, 6 patients with lesion sizes of 2 – 5 cm2 will be 
assigned to Dosage A and treated with 0.5 – 1.25x107 MSCs; if dose limiting toxicity is not 
observed at the 3 month time point for the first clinical efficacy evaluation, then another 6 
patients with lesion sizes of above 5 cm2 will be assigned to Dosage B and treated with 
more than 1.25 x 107 MSCs for further safety evaluation. If a DLT occurs to one or two 
patients of the group treated with the dosage A, 3 more patients will be assigned to dosage A. 
If DLT happens to 3 of the patients who were treated with the dosage A or above, this study 
will be halted and the FDA and IRB will be notified. The Independent Data Monitoring 
Committee will perform a comprehensive review of safety (see Section 9.1).  

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If no DLT occurs to any of the dosage A patients, another 6 patients with larger defect 
sizes will be enrolled and assigned to dosage B. In case of no DLT observed, a total of 12 
patients will be enrolled for safety and efficacy evaluation. However, 18 patients could be 
enrolled if DLT occurs to two patients. If DLT occur 3 or more patients treated with Dosage 
B, this study will be halted and the FDA and IRB will be notified. The Independent Data 
Monitoring Committee will perform a comprehensive review of safety (see Section 9.1).  
  
 

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6.6 Definition of Maximum Permissible Dose and Method of Dose Escalation 
 
Dose Limiting Toxicity (DLT): DLT is defined as toxicity or events of Grade 3 or higher (80 
points or higher against pain) in two or more events at the surgery site among swelling, tenderness, 
range of motion, and pain in any one visit. DLT is also defined as adverse drug reaction of Grade 
3 or higher in the Common Toxicity Criteria Adverse Events (CTCAE), Version 4.0, with the 
exception of the following events and that they are unresolved for 7 consecutive days, despite 
medical interventions: 
9 Abnormal results in lab test (Acidosis, Hyponatremia, Hyperbilirubinemia, etc.) 
9 Fatigue, defined as not relieved by rest; limiting self-care ADL 
9 Pain, defined as severe pain; limiting self-care ADL 
9 Headache, defined as severe pain in various parts of the head, limiting self-care ADL 
Fever, defined as > 40.0 degrees C ( > 104.0 degrees F) for > 24 hours 
 
Maximum Tolerated Dose (MTD): If DLT occurs in 2 or fewer patients at the Dosage B level, 
the MTD will be Dosage B. If DLT occurs in 3 or more patients treated with Dosage B then the 
MTD will be Dosage A. If DLT occurs in 3 patients treated with Dosage A then the MTD will not 
have been determined in this study design. 
 
6.7 Expected Adverse Effects and Usage Considerations  
6.7.1 Expected Adverse Effects 
There has not been any expected adverse effect that is directly related to the administration 
of CARTISTEM®, however, mild increase in temperature, pain, nausea, and headache may 
occur in a response to the administration of allogenic mesenchymal stem cells. In general, 
adverse effects that may be observed following arthrotomy accompanied by the use of 
anesthesia include the followings: 
 
- Implant site pain, pruritus, and warmth 
- Nausea 

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- Constipation 
- Dyspepsia 
- Headache 
- Dysuria 
- Dizziness 
 
6.7.2 Usage Considerations 
1) Sterility should be strictly maintained as the product involves injection into human knee 
joint cavity. 
2) Should any serious adverse events occur during the administration period or within 14 
days after final injection, the principal investigator must, regardless of whether or not 
the adverse reaction is thought to be related to the study drug, report the incident to the 
clinical trial review committee and MEDIPOST Co., Ltd. personnel within 24 hours of 
occurrence.  
3) This drug should not be administered intravenously. 
4) Before mixing the constituting substances of the drug, tap the vial with the fingers to 
make sure that the cells and the preserving solution mix properly. Do not vortex.  
5) In order to prevent the intrusion of any foreign materials into the syringe, wipe the 
needle point and insertion area of the vial with ethanol before inserting the needle into 
the vial. 
 
7 Investigational Product 
7.1 Investigational Product 
7.1.1 Trade Name 
 CARTISTEM® 
7.1.2 Ingredients 
- hUCB-MSCs: Human umbilical cord blood-derived mesenchymal stem cell suspension 
in pale pink and transparent medium 
-  Sodium hyaluronate: white or gray-white lyophilized sponge form 

CARTISTEM®                                                                                                   page 28 of 137G
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7.1.3 Property 
A viscous gel matrix formed by mixing umbilical cord blood-derived mesenchymal 
stem cell suspension and white lyophilized sodium hyaluronate 
7.1.4 Storage and Handling Conditions 
-  Storage condition: 2 – 10 ºC (36 – 50 ºF) 
-  Shelf-life of hUCB-MSC suspension: 72 hours from the time of manufacturing 
-  CARTISTEM® after combining with sodium hyaluronate is recommended to use 
within 12 hours from time of the combination. 
7.2 Route of Administration 
7.2.1. Anesthetize a patient. 
7.2.2. Gently finger-tap hUCB-MSC vial to mix and transfer 1.5 mL of the cell suspension 
using a sterile syringe to the HA vial. Gently mix using a sterile spatula and leave the mixture 
stationary until the sodium hyaluronate is completely swollen for at least 30 minutes at room 
temperature. 
7.2.3. Perform arthroscopy to obtain more accurate measurement of the defect size. 
7.2.4. Expose the cartilage defect through routine knee arthrotomy, based on defect location 
(medial or lateral parapatellar arthrotomy). 
 

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7.2.5. Debride the cartilage defect back to stable shoulders using a curet to remove any 
unstable or degenerated (soft and fissured) cartilage, following standard guidelines as used for 
microfracture or autologous chondrocyte implantation. After debridement, measure size of the 
defect to calculate required the dose of CARTISTEM®. 

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7.2.6. Create multiple holes across the entire base of the articular cartilage defect with a 
2~3mm drill bit spacing the holes approximately 3~5 mm apart. If active bleeding is encountered, 
the defect may be packed with epinephrine soaked sponges. Alternatively, thrombin (5000 Units) 
or thrombin spray may be used.  The defect base should be without any active bleeding at the 
time of implantation. 
7.2.7. Fill the holes with CARTISTEM® first and across the entire cartilage defect.  
7.2.8. Deflate the tourniquet, achieve hemostasis, and close the wound. 
7.2.9. Put a knee immobilizer and a standard cold-therapy device onto the leg of a patient. 
 

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7.3 Return and disposal of unused investigational product 
After administration of CARTISTEM®, the amount of any empty containers or remaining 
drug shall be documented on a designated form and returned to the Contract Manufacturing 
Organization (CMO). 
The CMO will then verify the amount of any remaining drugs indicated on the form and 
store them frozen for one year after its receipt of the returned investigational product. 
Thereafter, the CMO will dispose the returned drug per its operating procedure.  
 

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8 Study Method 
8.1 Overview of the Study Design 
This study is a phase I/IIa open-label clinical trial with the objective of assessing the safety 
and exploratory efficacy of a single administration of CARTISTEM®, an allogeneic-unrelated 
umbilical cord blood-derived mesenchymal stem cell product, in patients with articular 
cartilage defects. 

CARTISTEM®                                                                                                                                                       page 33 of 137G
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8.2 Study Flow Chart  
 
Screening 
(Week –
6~Week 0) 
Baseline 
(Day -2) 
(±2d) 
Treatment 
(Day 0) 
Week 2 
(±5d) 
Week 4 
(±5d) 
Week 8 
(±5d) 
Week 12 
(±7d) 
Week 24 
(±14d) 
Month 
12 
(±30d) 
Month 
24 
(±30d) 
Visits 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Informed Consent 
z 
 
 
 
 
 
 
 
 
 
Physical Examination1) 
z 
 
 
z 
z 
z 
z 
z 
z 
z 
Medical History, 
Medication History1) 
z 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
Criteria 
z 
 
 
 
 
 
 
 
 
 
Pregnancy Test (Serum 
HCG) 
z 
z 
 
 
 
 
 
 
 
 
Vital Signs/Temperature 
z 
z 
z 
z 
z 
z 
z 
z 
z 
z 
Laboratory Tests2) 
z3) 
 
 
z4) 
z 
z 
z 
z 
z 
z 
Immunogenicity tests 
(T cell subset) 
z5) 
 
 
 
 
 
 
z 
z 
z 
X-ray of the Joint 
z 
 
 
 
 
 
 
 
z 
 
MRI (T2 mapping) 
z6) 
 
 
 
 
 
 
z 
z7) 
z7) 
Administration of 
the Investigational 
Product8) 
 
 
z 
 
 
 
 
 
 
 
IKDC Score9) 
z 
z 
 
 
z 
z 
z 
z 
z 
z 

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Screening 
(Week –
6~Week 0) 
Baseline 
(Day -2) 
(±2d) 
Treatment 
(Day 0) 
Week 2 
(±5d) 
Week 4 
(±5d) 
Week 8 
(±5d) 
Week 12 
(±7d) 
Week 24 
(±14d) 
Month 
12 
(±30d) 
Month 
24 
(±30d) 
Lysholm Score 
 
z 
 
 
z 
z 
z 
z 
z 
z 
KOOS Score 
 
z 
 
 
z 
z 
z 
z 
z 
z 
100-mm VAS 
Evaluation10) 
 
z 
 
z11) 
z 
z 
z 
z 
z 
z 
Check for Concomitant 
Medications 
 
z 
 
z 
z 
z 
z 
z 
z 
z 
Check for Adverse 
Events/Toxicity 
 
 
 
z 
z 
z 
z 
z 
z 
z 
 
 
Name, gender, date of birth, address, height, body weight, medical history, concomitant medications  
 
Hematology: Hematocrit, Hemoglobin, MCV, MCH, MCHC, RBC, WBC, Platelet, Differential count (Neutro, Eosino, Baso, 
Lympho, Mono) 
Blood Chemistry: GOT (AST), GPT (ALT), Alkaline Phosphatase, Glucose, Urea (BUN), Creatinine, Direct bilirubin, CK, LDH, 
Uric acid, Albumin, and Total Protein 
Blood Coagulation: PT, aPTT 
Electrolytes: Sodium, Potassium, Chloride 
Urinalysis: Color, Specific gravity, pH, Leucocytes, Nitrite, Protein, Glucose, Ketone, Urobilinogen, Bilirubin, RBC, Microscopy 
 
Lab test at Screening can be used as the pre-treatment baseline. 
 
Lab Tests for patient at Week 2 can be omitted if the lab tests within the window period for Week 2 (i.e. 9 to 19 days after operation) 
are available. 
 
Immunogenicity test at Screening can be used as the pre-treatment baseline. 
 
MRI (T2 mapping) performed for at Screening may be skipped if MRI (T2 mapping) within the past 6 months is available. MRI (T2 
mapping) at Screening can be used as the pre-treatment baseline. 
 
MRI performed at Week 24 and Months 12 and 24 will also evaluate for tumorigenicity at focal lesion of the knee administration 

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site. 
 
Administration of the Investigational Product: 500 PL/cm2 of defect size 
 
From baseline to Week 24, only subjective knee evaluation form must be filled in. 
 Use of NSAIDs must be discontinued for 6 weeks prior to treatment and may be resumed following the treatment. Use of NSAIDs 
and any other analgesics must be discontinued for 48 hours and 24 hours, respectively, prior to VAS evaluation at Weeks 4, 8, 12, 
and 24, and Months 12 and 24.  
 Patient may be allowed to take analgesics within 24 hours prior to VAS evaluation at Week 2.  
 
The subject must visit the center on the scheduled visitation date±5 days for Weeks 2, 4, and 8; ±7 days for Week 12, ±14 days for Week 
24 after the administration of the investigational product. For the long term follow-up patient assessment, the subject must visit the 
center on the scheduled visitation date±30 days at Months 12 and 24.

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8.3 Concomitant Medications and Concomitant Non-drug Therapies 
 
Concomitant treatment with systemic corticosteroids or immunosuppressants is not 
permitted, but co-administration of any other drugs that have no effect on the efficacy 
assessment is allowed. If there is a concomitant medication, the name of the drug’s active 
ingredient (name of the product in case of a combination drug), dosage, starting/ending 
date of administration, and the reasons for administration are to be recorded on the case 
report form (CRF). Information on any concurrent therapies (ex: physiotherapy) are also 
required to be documented on the CRF (type, duration, etc.). All concomitant medications 
and therapies are to be recorded at baseline and during the trial.  
 
The following drugs are not permitted: glucosamine, dietary supplements used as 
alternative medicine to treat osteoarthritis such as chondroitin sulfate and hyaluronan, 
systemically administered corticosteroids (Hydrocortisone, Prednisone, Prednisolone, 
Methylprednisolone, Triamcinolone, Dexamethasone, Paramethasone, Betamethasone, 
Aldosterone, Fludrocortisone ) and  immunosuppresant (Prednisone, Vincristine, 
Azathioprine, γ– globulin, Cyclophosphamide, Chlorambucil, 6-mercaptopurine, 
Cyclophosphamide + factor XIII, Rh(D) immune globulin, ALG, Actinomycin-D, OKT3, 
Methotrexate 
8.4 Observation and Evaluation Items 
 
8.4.1 Demographic Background and Medical History of Subjects 
The patients will be screened by survey of demographic background and medical 
history to determine their eligibility for enrollment. 
9 Demographic background: the patient’s initials, date of birth, age, gender, body 
weight, height, ethnicity, etc. 
9 Medical history: the patient’s current or past diseases of substantial significance 
9 Vital Signs and Physical Examination: vital signs will be monitored and recorded 
at screening, after administration of the investigational product, and at each 
follow-up visit. 
9 Vital signs: blood pressure, pulse 
9 Physical examinations: general condition, nutritional condition, skin/mucosa, eye, 
ENT, thyroids, lungs, cardiovascular system, abdomen, kidney, spine/extremities, 

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peripheral circulation, neuro-psychiatric system, lymphatic system, etc 
8.4.2 Concomitant Medications 
Each participating subject must be inquired at baseline and throughout the treatment 
period and at each follow up visit whether he or she is on any concomitant medications. 
And detailed information of the medication such as the name of the drug’s active 
ingredients (name of the product for a combination drug), dosage, start and end dates of 
the administration, and a reason for the administration should be documented on case 
report form. 
8.4.3 Evaluation of Adverse Events & Toxicity 
Any adverse events (AE) or toxic reactions of each participating subject will be 
evaluated throughout the course of the study and at each follow up visit (from Day -2 to 
the end-of-study visit). Any adverse events or serious adverse events will be managed, 
investigated, and reported according to the procedures described in the following 
sections: 
9 Adverse Events 
When an adverse event is either observed by the investigator or reported by a subject, 
the investigator, regardless of the relationship of the AE to the investigational product, 
will record name and type of the adverse event, the severity, dates of onset and 
resolution of the event, the investigator’s opinion on the relationship between the 
investigational product and the adverse event, and whether or not the event was an SAE 
(serious adverse event) on the case report form (CRF). 
The principal investigator or the trial coordinator will carry out follow-up 
observations for all subjects with adverse events until the symptoms subside and the 
abnormal clinical test results are returned to normal, or until a satisfactory explanation 
can be given for the observed changes. If and when there is such a request from the 
sponsor, a progress report on the adverse event will be submitted to the trial coordinator.  
9 Serious Adverse Events 
A serious adverse event is defined as any untoward medical occurrence at any dose 
that causes death, life-threatening condition, in-patient hospitalization or prolongation 
of existing hospitalization, persistent or significant disability/incapacity, a congenital 
anomaly/birth defect, or another important medical event (see below). 

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Important medical events that do not result in death, are not life-threatening, or do not 
require hospitalization may be considered SAEs when, based on appropriate medical 
judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. Examples of such medical 
events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in in-patient 
hospitalization, or development of drug dependency or drug abuse. If a serious adverse 
event occurs, the investigator must, regardless of the relationship of the SAE to the 
investigational product/treatment, report the event to the responsible Institutional 
Review Board/Independent Ethics Committee and to the sponsor within 24 hours of 
awareness of the event by the investigator or, at the latest, by the next working day. 
If an unexpected fatal or life-threatening adverse event occurs, the sponsor must 
report to the FDA by telephone or fax within seven days and report in writing of 
unexpected and serious adverse events within 15 days as required under 21CFR312.32. 
8.4.4 Laboratory Evaluations 
Laboratory evaluations will be performed at screening, after final administration of the 
investigational product and at every follow-up visit. 
1) Hematology: Hematocrit, Hemoglobin, MCV, MCH, MCHC, RBC, WBC, 
Platelet, Differential count (Neutro, Eosino, Baso, Lympho, Mono) 
2) Blood Chemistry: GOT(AST), GPT(ALT), Alkaline Phosphatase, Glucose, 
Urea(BUN), Creatinine, Direct bilirubin, CK, LDH, Uric acid, Albumin, Total 
Protein  
3) Blood coagulation test: PT, aPTT 
4) Electrolytes: Sodium, Potassium, Chloride 
5) Urinalysis: Color, Specific gravity, pH, Leucocytes, Nitrite, Protein, Glucose, 
Ketone, Urobilinogen, Bilirubin, RBC, Microscopy 
8.4.5 Immunogenicity study 
T cell subset for immunogenicity evaluations will be performed at Screening, at 24-
week 12-month, and 24-month visit. 
8.4.6 IKDC Score 

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The subjects will undergo a self-assessment of knee function using IKDC subjective 
knee evaluation score before and after the drug administration in order to determine the 
efficacy of the investigational product. The IKDC assessment will be performed at the 4, 
8, 12, 24 weeks and 12 and 24 months after the drug treatment in an exploratory 
fashion but the IKDC score from the 12 month time point will be used as a primary 
result of the post-operative change.  
8.4.7 100-mm VAS Evaluation 
 
The subjects will undergo a self-assessment of joint pain using 100 mm VAS before 
and the 2, 4, 8, 12, 24 weeks and 12 and 24 months after the drug administration for the 
efficacy evaluation. Use of NSAIDs must be discontinued for 6 weeks prior to 
treatment and may be resumed following the treatment. Use of NSAIDs and any other 
analgesics must be discontinued for 48 hours and 24 hours, respectively, prior to VAS 
evaluation at Weeks 4, 8, 12, and 24, and Months 12 and 24. Patient may be allowed to 
take analgesics within 24 hours prior to VAS evaluation at Week 2.  
8.4.8 Lysholm Score 
The subjects will undergo a self-assessment of knee function using Lysholm Score 
before and the 4, 8, 12, 24 weeks and 12 and 24 months after the drug administration 
for the efficacy evaluation. 
8.4.9 KOOS Score 
The subjects will undergo a self-assessment of knee function and knee-related quality-
of-life (QoL) using KOOS Score before and the 4, 8, 12, 24 weeks and 12 and 24 
months after the drug administration for the efficacy evaluation. 
8.4.10 MRI Assessment 
Structural information will be gained using high-resolution (1.5 or 3 Tesla) magnetic 
resonance imaging (MRI) at Screening, week 24, month 12, and month 24 in order to 
evaluate the clinical symptom improvement. The MRI evaluations at week 24, month 
12 and month 24 will also evaluate for tumorigenicity at focal lesion. 
8.5 Early Discontinuation from the Study 
 
Drop-out or withdrawal of a subject from the study can be determined at any time point 
during the study period by reporting to the trial coordinator or the principal investigator. 

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Should a patient voluntarily decide to withdraw, the decision will be respected and 
accepted without any questions.  
Purpose of this study is to evaluate the safety and the efficacy of the investigational 
product. Therefore, any subjects who want to withdraw from the study on a voluntary 
basis or due to the adverse events will be replaced with new subjects as long as the drug 
administration in the dosage group that the withdrawn subject was in is not complete. The 
study data obtained from such a subject until the point of drop out will be, where possible, 
included in the data pool for analysis at the final evaluation stage. 
 
9 Definition of Adverse Events  
An adverse event (AE) is defined as any undesired clinical responses or complication 
experienced by a subject. All operative and postoperative adverse events, whether related 
or not, will be documented on the AE case report form (CRF). 
9.1 Criteria for Safety Assessment 
 
Vital sign monitoring, physical examination (swelling, tenderness, range of motion, and 
pain), and laboratory evaluations will be carried out to determine the safety of the 
investigational product. When an adverse event occurs, the type, the severity, dates of the 
onset and resolution of the adverse event, and the relationship between the investigational 
product and the adverse event will be investigated and documented on the case report form. 
Causality of the adverse events will be determined according to the following criteria: 
9 Not related: the adverse experience is definitely not related to the investigational 
product 
9 Unlikely: there are other, more likely causes and the investigational product is not 
suspected as a cause 
9 Suspected, reasonable possibility: the direct cause and effect relationship between 
the drug and the adverse event has not been demonstrated but there is a reasonable 
possibility that the event was caused by the drug. 
9 Probable: there probably is a direct cause and effect relationship between the 
adverse event and the investigational product 

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Certainty of causal relationship between the adverse event and the investigational 
product (or any other reasons – progression of an underlying disease, concomitant therapy, 
etc.) will be determined on the basis of how well the adverse event could be explained in 
light of the following factors: 
9 Known pharmacological effect and mechanism of the investigational product 
9 Similar events previously reported for the investigational product or other 
substances of the same class  
9 Drug reactions frequently reported with similar medications 
9 Events that are temporally associated with the investigational product (events that 
are resolved once the drug is discontinued but reappear with the next administration) 
The study will be under ongoing periodic reviews by an assigned Independent Data 
Monitoring Committee (IDMC). An IDMC will independently review data on a periodic 
basis as detailed in the IDMC charter. Serious AEs will be reported to the IDMC as outlined 
in the IDMC charter. The IDMC will make recommendations to the Sponsor as to whether 
the trial should be revised or closed. 
 
10 Statistical Analysis 
10.1 Analysis Populations 
10.1.1 Safety Population  
 The safety analysis for all clinical and laboratory adverse experiences will be based on 
all enrolled patients who are administered the investigational product. 
10.1.2 Efficacy Population 
The efficacy population will be defined as all patients who met the eligibility criteria 
and received at least one dose of the investigational product, and had been assessed at 
least once for at least one efficacy endpoint. 
10.2 Analysis of Safety Variables and Statistical Evaluation 
10.2.1 Safety Variables 
  All adverse events will be coded according to the latest version of MedDRA and the 
classification according to the System Organ Class of MedDRA using preferred term. 
  All adverse events will be summarized and analyzed.  

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  Serious adverse events and drop-out patients due to adverse events will be described 
in details.  
  Descriptive statistics including means, medians, SD (standard deviation), minimum 
and maximum will be used to present the other safety endpoints, laboratory tests 
including routine hematology and chemistry, thrombin generation (PT and aPTT), vital 
signs, autoimmune disease test (T-cell subset) and ECGs. For laboratory data, the 
number of subjects who deviated from the normal range will be presented for each 
analyte, by visit, and by dosage phase. The results will be also classified into normal, 
decreased, or increased in relation to the normal range.  
10.2.2 Analysis of Safety Endpoints 
  Analysis of the adverse events, adverse drug reactions, and serious adverse events 
will be presented with number of case (# of subject who experienced), number of 
adverse events, and percentage.  
  Analysis of the adverse events will include the severity, the seriousness and the 
relationship with the study medication. It will be presented with number of event and 
percentage.  
  Incidence rates of the adverse events including adverse drug reactions and serious 
adverse events occurred in each dose group will be presented with frequency, 
percentage, and 95% confidence interval of the rates. Homogeneity between dose 
groups will be analyzed using person’s chi-square test or Fisher’s exact test. 
  Incidence rates of the adverse drug reaction by SOC between two dose groups will 
be analyzed for homogeneity using pearson’s chi-square test or Fisher’s exact test. 
10.3 Analysis of Efficacy Variables and Statistical Evaluation 
10.3.1 Efficacy Variables 
 Data such as subjective knee function of each category will presented using criteria 
for the IKDC, the Lysholm score and the KOOS assessment, and the improvement 
level of pain will be analyzed using the 100-mm VAS. Structural information will be 
gained through the use of high-resolution (1.5 or 3 Tesla) magnetic resonance 
imaging (MRI) with cartilage-specific sequences (T2-mapping). 
9 Primary efficacy endpoint: post-operative change in subjective knee function will 
be obtained from the IKDC score at the 12-month time point as the primary 

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efficacy endpoint.  
9 Secondary efficacy endpoint: the Lysholm Score and the KOOS score will be used 
as the secondary efficacy endpoint to measure post-operative change of the knee 
function.  
9 Improvement degree of joint pain will be measured using a 100-mm VAS (Visual 
Analogue Scale).   
9 Grade of the cartilage regeneration and morphological constitution of the cartilage 
repair area will be assessed using high-resolution (1.5 or 3 Tesla) magnetic 
resonance imaging (MRI).  
10.3.2 Analysis of Efficacy Endpoints  
The descriptive statistics of the categorical variables will be presented with 
percentage and frequency and that of the continuous variables such as mean, median, 
standard deviation, and interquartile range. The primary efficacy endpoint will be 
analyzed using the t-test. As for the secondary efficacy endpoints, differences of the 
continuous variables and the categorical variables between the two groups will be 
analyzed using the t-test and Fisher’s exact test, respectively. 

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11 Rehabilitation Protocol 
All patients must participate in the following standardized rehabilitation program after 
receiving treatment. Rehabilitation program will vary according to the defect location of 
each subject.  
Stage 1- Proliferative Phase (Week 1 to 6) 
 
Femoral Condyle Defect 
 
   
PRIMARY GOALS 
DO NOT OVERLOAD GRAFT 
INCREASE TIBIOFEMORAL AND PATELLOFEMORAL MOBILITY 
RESTORE QUADRICEPS CONTROL 
 
BRACE 
Knee immobilizer with ambulation, until good quads control/SLR (approximately 
Week 3 to 6) 
GAIT 
Heel-toe TDWB with crutches 
ROM 
Full AROM and gentle AAROM.  
 CPM ≥ 6 to 8 hours daily for 6 weeks. Start at 0-40 degrees, progress range as 
tolerated. 
 Goal: minimum 90 degrees flexion for the first 2 weeks, 110 degrees for the next 4 
weeks (the 6 week time point of post-op) 
THEREX 
Quad sets, SLR in knee immobilizer as needed, leg curl/heel slides, hip abduction 
 Stationary bicycle with no resistance once 90 degrees knee flexion obtained (~ 4 
weeks). 
 90 degree leg dangle hourly to improve ROM 
THERAPY 
Gentle multi-directional patella mobilization starts immediately after surgery. 

Cryotherapy and compression stockings/TEDS for swelling and pain control. 

E-stim for VMO/quadriceps muscle re-education/biofeedback encouraged 
early after surgery if needed. 
 
Gentle massage/deep friction to hamstring insertions, suprapatellar quadriceps, 
medial/lateral gutters, and infrapatellar fat pad region at 2-3 weeks post-op. 
 
Pool therapy recommended 2-3 weeks post-op to enhance motion. 
 

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Stage 2- Transitional Phase (Week 7 to 12) 
 
Femoral Condyle Defect 
 
   
PRIMARY GOALS 
DO NOT OVERLOAD GRAFT 
INCREASE TIBIOFEMORAL AND PATELLOFEMORAL MOBILITY 
RESTORE QUADRICEPS CONTROL 
 
BRACE 
Knee brace may be discontinued once independent SLR achieved 
GAIT 
Week 7 & 8: 50% weight-bearing, week 9+: full weight-bearing  
ROM 
Full AROM and gentle PROM exercises 
 Progress towards full ROM until the 12 week time point.  
THEREX 
Low weight (max 10-20lbs.) open-chain leg extension and curl 
 Stationary bicycle with gradual increased tension per level of comfort 
 Continue quad sets, SLR in brace, leg curl and heel slides 
 Strengthen quadriceps, hamstrings, and hip abductors/extensors using ankle 
weights and/or elastic band resistance through full ROM as tolerated    
 Gentle closed-chain terminal knee extension 0 to 40 degrees (TKE) permitted 
starting from the nine or ten week time point as tolerated per weight bearing 
restriction 
THERAPY 
Gentle multi-directional patella mobilization 
 Cryotherapy and compression stockings/TEDS for swelling and pain control 
 E-stim for VMO/quadriceps muscle re-education/biofeedback encouraged 
 Gentle massage/deep friction to hamstring insertions, suprapatellar quadriceps,  
 
 
medial/lateral gutters, and infrapatellar fat pad region  
 Pool therapy recommended to enhance motion 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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-- or for trochlear defects -- 
Stage 1- Proliferative Phase (Week 0 to 6) 
 
Trochlear Defect 
 
   
PRIMARY GOALS 
DO NOT OVERLOAD GRAFT 
INCREASE TIBIOFEMORAL AND PATELLOFEMORAL MOBILITY 
RESTORE QUADRICEPS CONTROL 
 
BRACE 
 
Bledsoe Hinge knee brace for ambulation (locked) and at night 
 Out of brace for CPM.  
 
No brace, but towel/pillow behind heel when lying down   
PRECAUTIONS 
Full weightbearing in full extension (locked brace)  
ROM 
Gentle AROM flexion as tolerated 3x/day.  Only PROM extension allowed. 
 
CPM ˻ 6 to 8 hours daily. Starting from 0 to 40 degrees, progress range as 
tolerated after the first 2 weeks. 
 
Minimum 90 degrees flexion for the first 2 weeks, 110 degrees for the next 4 
weeks 
THEREX 
Quad sets, SLR with brace locked, leg curl/heel slides, hip abduction 
 
Stationary bicycle with no resistance once 90 degrees knee flexion obtained (> 
4wks). 
 90 Degree Leg dangle hourly to improve ROM 
THERAPY 
Gentle multi-directional patella mobilization right after surgery 
 
Cryotherapy and compression stockings/TEDS for swelling and pain control. 
 
E-stim for VMO/quadriceps muscle re-education/biofeedback encourage early 
after surgery if necessary. 
 
Gentle massage/deep friction to hamstring insertions, suprapatellar quadriceps, 
medial/lateral gutters, and infrapatellar fat pad region at the two to three week time 
point post-op. 
 
Pool therapy recommended two to three weeks post-op to enhance motion. 
 
 
 
 
 
 
 
 
 
 

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Stage 2- Transitional Phase (Week 7 to 12) 
 
Trochlear Defect 
 
   
PRIMARY GOALS 
DO NOT OVERLOAD GRAFT 
INCREASE TIBIOFEMORAL AND PATELLOFEMORAL MOBILITY 
RESTORE QUADRICEPS CONTROL 
 
BRACE 
Hinged knee brace may be discontinued once independent SLR achieved 
GAIT 
Full weight-bearing as tolerated  
ROM 
Gentle A/AAROM flexion and extension permitted 
 Progress towards full ROM until week 12.  
THEREX 
Stationary bicycling without resistance at short intervals (5 min, 2-3x/day) as 
tolerated 
   Strengthening of quadriceps, hamstrings, and hip abductors/extensors using elastic 
band isometrics and closed-chain terminal knee extension 0-40 degrees only 
 Backward treadmill walking with safety bars recommended to reduce 
patellofemoral compressive forces
 Pool exercise using kickboard allowed. Flutter/straight leg scissor kick only (no 
whip kick)
 No open-chain strengthening permitted until 6 months after surgery. 
 No closed-chain leg pressing or squatting 
THERAPY 
Gentle multi-directional patella mobilization 
 Cryotherapy and compression stockings/TEDS for swelling and pain control 
 E-stim for VMO/quadriceps muscle re-education/biofeedback encouraged 
 Gentle massage/deep friction to hamstring insertions, suprapatellar quadriceps, 
medial/lateral gutters, and infrapatellar fat pad region  
 Pool therapy recommended to enhance motion 
 
G
G
G
G
  
 
 
 
 
 

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12 References 
Athanasiou KA, Shah AR, Hernandez RJ, LeBaron RG. Basic science of articular cartilage 
repair. Clin Sports Med. 2001 Apr;20(2):223-47. 
Barry FP. Mesenchymal stem cell therapy in joint disease. Novartis Found Symp. 
2003;249:86-96; discussion 96-102, 170-4, 239-41. 
Browne JE, Anderson AF, Arciero R, Mandelbaum B, Moseley JB Jr, Micheli LJ, Fu F, 
Erggelet C. Clinical outcome of autologous chondrocyte implantation at 5 years in US 
subjects. Clin Orthop Relat Res. 2005 Jul;(436):237-45. 
Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006 
Aug 1;98(5):1076-84. 
Chang CH, Kuo TF, Lin CC, Chou CH, Chen KH, Lin FH, Liu HC. Tissue engineering-based 
cartilage repair with allogenous chondrocytes and gelatin-chondroitin-hyaluronan tri-
copolymer scaffold: A porcine model assessed at 18, 24, and 36 weeks. Biomaterials. 2006 
Mar;27(9):1876-88. Epub 2005 Nov 8. 
Chuma H, Mizuta H, Kudo S, Takagi K, Hiraki Y. One day exposure to FGF-2 was sufficient 
for the regenerative repair of full-thickness defects of articular cartilage in rabbits. 
Osteoarthritis Cartilage. 2004 Oct;12(10):834-42. 
Dragoo JL, Samimi B, Zhu M, Hame SL, Thomas BJ, Lieberman JR, Hedrick MH, Benhaim 
P. Tissue-engineered cartilage and bone using stem cells from human infrapatellar fat pads. J 
Bone Joint Surg Br. 2003 Jul;85(5):740-7. 
Elisseeff J. Injectable cartilage tissue engineering. Expert Opin Biol Ther. 2004 
Dec;4(12):1849-59. 
Gelse K, Söder S, Eger W, Diemtar T, Aigner T. Osteophyte development--molecular 
characterization of differentiation stages. Osteoarthritis Cartilage. 2003 Feb;11(2):141-8. 
Giannoni P, Pagano A, Maggi E, Arbicò R, Randazzo N, Grandizio M, Cancedda R, Dozin B. 
Autologous chondrocyte implantation (ACI) for aged patients: development of the proper cell 
expansion conditions for possible therapeutic applications. Osteoarthritis Cartilage. 2005 
Jul;13(7):589-600. 
Guo X, Wang C, Zhang Y, Xia R, Hu M, Duan C, Zhao Q, Dong L, Lu J, Qing Song Y. 
Repair of large articular cartilage defects with implants of autologous mesenchymal stem 
cells seeded into beta-tricalcium phosphate in a sheep model. Tissue Eng. 2004 Nov-
Dec;10(11-12):1818-29. 
Hedrick MH, Daniels EJ. The use of adult stem cells in regenerative medicine. Clin Plast 
Surg. 2003 Oct;30(4):499-505. 
Kasahara Y, Iwasaki N, Yamane S, Igarashi T, Majima T, Nonaka S, Harada K, Nishimura S, 
Minami A. Development of mature cartilage constructs using novel three-dimensional porous 

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scaffolds for enhanced repair of osteochondral defects. J Biomed Mater Res A. 2008 
Jul;86(1):127-36. 
Katayama R, Wakitani S, Tsumaki N, Morita Y, Matsushita I, Gejo R, Kimura T. Repair of 
articular cartilage defects in rabbits using CDMP1 gene-transfected autologous mesenchymal 
cells derived from bone marrow. Rheumatology (Oxford). 2004 Aug;43(8):980-5. Epub 2004 
Jun 8. 
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KH. Articular cartilage imaging by the use of phase-contrast tomography in a collagen-
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Pederzini L, Rosa D, Sacchetti GL, Stefani G, Zanasi S. Articular cartilage engineering with 
Hyalograft C: 3-year clinical results. Clin Orthop Relat Res. 2005 Jun;(435):96-105. 
Mizuta H, Kudo S, Nakamura E, Otsuka Y, Takagi K, Hiraki Y. Active proliferation of 
mesenchymal cells prior to the chondrogenic repair response in rabbit full-thickness defects 
of articular cartilage. Osteoarthritis Cartilage. 2004 Jul;12(7):586-96. 
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trials of celecoxib in osteoarthritis and rheumatoid arthritis: systematic review and meta-
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2005;7(3):R644-65. Epub 2005 Mar 24. 
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by chondrocytes on a biocompatible hydrogel: implications for engineering cartilage tissue. 
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Smith GD, Knutsen G, Richardson JB. A clinical review of cartialge repair techniques. J 
Bone Joint Surg[Br]. 2005;87-B:445-9 
Wakitani S, Imoto K, Yamamoto T, Saito M, Murata N, Yoneda M. Human autologous 
culture expanded bone marrow mesenchymal cell transplantation for repair of cartilage 
defects in osteoarthritic knees. Osteoarthritis Cartilage. 2002 Mar;10(3):199-206. 
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Kato H, Uematsu K, Kuroda R, Kurosaka M, Yoshiya S, Hattori K, Ohgushi H. Safety of 
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Watterson JR, Esdaile JM. Viscosupplementation : Therapeutic mechnisms and clinical 
potential in osteoarthritis of the knee. J Am Acad Orthop Surg. 2000;8:277-284. 

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Yanai T, Ishii T, Chang F, Ochiai N. Repair of large full-thickness articular cartilage defects 
in the rabbit: the effects of joint distraction and autologous bone-marrow-derived 
mesenchymal cell transplantation. J Bone Joint Surg Br. 2005 May;87(5):721-9.  

CARTISTEM®                                                                                          page 51 of 137G
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APPENDIX  1. IKDC score 
 

CARTISTEM®                                                                                          page 52 of 137G
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IKDC PATIENT REPORTED 
 
SYMPTOMS*: 
*Grade symptoms at the highest activity level at which you think you could function without significant symptoms, even if 
you are not actually performing activities at this level. 
 
1. What is the highest level of activity that you can perform without significant knee pain? 
Very strenuous activities like jumping or pivoting as in basketball or soccer 
Strenuous activities like heavy physical work, skiing or tennis 
Moderate activities like moderate physical work, running or jogging 
Light activities like walking, housework or yard work 
Unable to perform any of the above activities due to knee pain 
 
2. During the past 4 weeks, or since your injury, how often have you had pain? 
Never 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Constant 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
3. If you have pain, how severe is it? 
Never 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Worst Pain 
Imaginable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4. During the past 4 weeks, or since your injury, how stiff or swollen was your knee? 
Not at all 
Mildly 
Moderately 
Very 
Extremely 
 
5. What is the highest level of activity you can perform without significant swelling in your knee? 
Very strenuous activities like jumping or pivoting as in basketball or soccer 
Strenuous activities like heavy physical work, skiing or tennis 
Moderate activities like moderate physical work, running or jogging 
Light activities like walking, housework, or yard work 
Unable to perform any of the above activities due to knee swelling 
 
6. During the past 4 weeks, or since your injury, did your knee lock or catch? 
Yes   
No 
 
7. What is the highest level of activity you can perform without significant giving way in your knee? 
Very strenuous activities like jumping or pivoting as in basketball or soccer 
Strenuous activities like heavy physical work, skiing or tennis 
Moderate activities like moderate physical work, running or jogging 
Light activities like walking, housework or yard work 
Unable to perform any of the above activities due to giving way of the knee 

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IKDC Subjective Knee Evaluation Form cont. 
 
SPORTS ACTIVITIES: 
 
8. What is the highest level of activity you can participate in on a regular basis? 
Very strenuous activities like jumping or pivoting as in basketball or soccer 
Strenuous activities like heavy physical work, skiing or tennis 
Moderate activities like moderate physical work, running or jogging 
Light activities like walking, housework or yard work 
Unable to perform any of the above activities due to knee 
 
9. How does your knee affect your ability to: 
 
 
Not difficult 
at all 
Minimally 
difficult 
Moderately 
Difficult 
Extremely 
difficult 
Unable 
to do 
a. 
Go up stairs 
 
 
 
 
 
b. 
Go down stairs 
 
 
 
 
 
c. 
Kneel on the front of your knee 
 
 
 
 
 
d. 
Squat 
 
 
 
 
 
e. 
Sit with your knee bent 
 
 
 
 
 
f. 
Rise from a chair 
 
 
 
 
 
g. 
Run straight ahead 
 
 
 
 
 
h. 
Jump and land on your involved leg 
 
 
 
 
 
i. 
Stop and start quickly 
 
 
 
 
 
 
FUNCTION: 
10. How would you rate the function of your knee on a scale of 0 to 10 with 10 being normal, excellent function and 0 being 
the inability to perform any of your usual daily activities which may include sports? 
 
FUNCTION PRIOR TO YOUR KNEE INJURY: 
Cannot perform 
daily activities  
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No limitation
 
 
 
 
 
 
 
 
 
 
 
 
 
CURRENT FUNCTION OF YOUR KNEE: 
Cannot perform 
daily activities 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No limitation
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

CARTISTEM®                                                                                          page 54 of 137G
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APPENDIX  2. LYSHOLM SCORE 
G
 

CARTISTEM®                                                                                          page 55 of 137G
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APPENDIX  3. KOOS KNEE SCORE 
 

CARTISTEM®                                                                                          page 56 of 137G
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CARTISTEM®                                                                                          page 57 of 137G
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CARTISTEM®                                                                                          page 58 of 137G
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APPENDIX  4.  CTCAE(Version 4.0) 
1. CTCAE 4.0  
Common Terminology Criteria for 
Adverse Events (CTCAE) 
Version 4.0 
 
U.S.DEPARTMENT OF HEALTH AND HUMAN SERVICES 
National Institutes of Health 
National Cancer Institute 
 

CARTISTEM®                                                                                          page 59 of 137G
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CARTISTEM®                                                                                          page 60 of 137G
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CARTISTEM®                                                                                          page 61 of 137G
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CARTISTEM®                                                                                          page 62 of 137G
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CARTISTEM®                                                                                          page 63 of 137G
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CARTISTEM®                                                                                          page 64 of 137G
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Congenital, familial and genetic disorders 4. Congenital, familial and genetic disorders  
 
 
 
Grade  
 
 
Adverse Event  
1  
2  
3  
4  
5  
Congenital, familial and 
genetic disorders - Other, 
specify  
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated  
Moderate; minimal, local 
or noninvasive intervention 
indicated; limiting age-
appropriate instrumental 
ADL  
Severe or medically 
significant but not 
immediately life-
threatening; hospitalization 
or prolongation of existing 
hospitalization indicated; 
disabling; limiting self care 
ADL  
Life-threatening 
consequences; urgent 
intervention indicated  
Death  
 
CTCAE 4.0 - May 28, 2009 : Congenital, familial and genetic disorders 7  

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CARTISTEM®                                                                                          page 66 of 137G
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CARTISTEM®                                                                                          page 67 of 137G
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CARTISTEM®                                                                                          page 68 of 137G
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CARTISTEM®                                                                                          page 69 of 137G
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CARTISTEM®                                                                                          page 70 of 137G
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CARTISTEM®                                                                                          page 71 of 137G
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CARTISTEM®                                                                                          page 72 of 137G
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CARTISTEM®                                                                                          page 73 of 137G
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CARTISTEM®                                                                                          page 74 of 137G
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CARTISTEM®                                                                                          page 75 of 137G
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CARTISTEM®                                                                                          page 76 of 137G
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CARTISTEM®                                                                                          page 77 of 137G
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CARTISTEM®                                                                                          page 78 of 137G
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CTCAE 4.0 - May 28, 2009 : Gastrointestinal disorders 21  

CARTISTEM®                                                                                          page 79 of 137G
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CARTISTEM®                                                                                          page 80 of 137G
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CARTISTEM®                                                                                          page 81 of 137G
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CARTISTEM®                                                                                          page 82 of 137G
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CTCAE 4.0 - May 28, 2009 : Hepatobiliary disorders 25 CTCAE 4.0 - May 28, 2009 : Immune system disorders 26  

CARTISTEM®                                                                                          page 83 of 137G
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CARTISTEM®                                                                                          page 84 of 137G
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CARTISTEM®                                                                                          page 85 of 137G
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CARTISTEM®                                                                                          page 86 of 137G
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CARTISTEM®                                                                                          page 87 of 137G
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CARTISTEM®                                                                                          page 88 of 137G
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CARTISTEM®                                                                                          page 89 of 137G
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CARTISTEM®                                                                                          page 90 of 137G
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CARTISTEM®                                                                                          page 91 of 137G
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CARTISTEM®                                                                                          page 92 of 137G
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CARTISTEM®                                                                                          page 93 of 137G
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CARTISTEM®                                                                                          page 94 of 137G
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CARTISTEM®                                                                                          page 95 of 137G
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CARTISTEM®                                                                                          page 96 of 137G
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CARTISTEM®                                                                                          page 97 of 137G
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CTCAE 4.0 - May 28, 2009 : Injury, poisoning and procedural complications 40  

CARTISTEM®                                                                                          page 98 of 137G
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CARTISTEM®                                                                                          page 99 of 137G
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CARTISTEM®                                                                                          page 100 of 137G
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CTCAE 4.0 - May 28, 2009 : Investigations 43  

CARTISTEM®                                                                                          page 101 of 137G
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CARTISTEM®                                                                                          page 102 of 137G
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CTCAE 4.0 - May 28, 2009 : Metabolism and nutrition disorders 45  

CARTISTEM®                                                                                          page 103 of 137G
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CARTISTEM®                                                                                          page 104 of 137G
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CARTISTEM®                                                                                          page 105 of 137G
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CARTISTEM®                                                                                          page 106 of 137G
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CTCAE 4.0 - May 28, 2009 : Musculoskeletal and connective tissue disorders 49 CTCAE 4.0 - May 28, 2009 : Neoplasms benign, malignant and unspecified (incl cysts and polyps) 50  

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CARTISTEM®                                                                                          page 108 of 137G
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CARTISTEM®                                                                                          page 109 of 137G
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CARTISTEM®                                                                                          page 110 of 137G
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CARTISTEM®                                                                                          page 111 of 137G
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CARTISTEM®                                                                                          page 112 of 137G
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CARTISTEM®                                                                                          page 113 of 137G
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CTCAE 4.0 - May 28, 2009 : Nervous system disorders 55 CTCAE 4.0 - May 28, 2009 : Pregnancy, puerperium and perinatal conditions 56  
 

CARTISTEM®                                                                                          page 114 of 137G
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CARTISTEM®                                                                                          page 115 of 137G
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CTCAE 4.0 - May 28, 2009 : Psychiatric disorders 58  

CARTISTEM®                                                                                          page 116 of 137G
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CARTISTEM®                                                                                          page 117 of 137G
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CTCAE 4.0 - May 28, 2009 : Renal and urinary disorders 60  

CARTISTEM®                                                                                          page 118 of 137G
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CARTISTEM®                                                                                          page 119 of 137G
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CARTISTEM®                                                                                          page 120 of 137G
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CARTISTEM®                                                                                          page 121 of 137G
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CARTISTEM®                                                                                          page 122 of 137G
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CARTISTEM®                                                                                          page 123 of 137G
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CARTISTEM®                                                                                          page 124 of 137G
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CARTISTEM®                                                                                          page 125 of 137G
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CARTISTEM®                                                                                          page 126 of 137G
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CARTISTEM®                                                                                          page 127 of 137G
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CTCAE 4.0 - May 28, 2009 : Respiratory, thoracic and mediastinal disorders 70  

CARTISTEM®                                                                                          page 128 of 137G
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CARTISTEM®                                                                                          page 129 of 137G
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CARTISTEM®                                                                                          page 130 of 137G
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CARTISTEM®                                                                                          page 131 of 137G
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CARTISTEM®                                                                                          page 132 of 137G
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CTCAE 4.0 - May 28, 2009 : Skin and subcutaneous tissue disorders 74 CTCAE 4.0 - May 28, 2009 : Social circumstances 75 CTCAE 4.0 - May 28, 2009 : Surgical and medical 
procedures 76  
 

CARTISTEM®                                                                                          page 133 of 137G
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Surgical and medical procedures 26. Surgical and medical procedures  
 
 
 
 
Grade  
 
 
Adverse Event  
1  
2  
3  
4  
5  
Surgical and medical 
procedures - Other, specify  
Asymptomatic or mild 
symptoms; clinical or 
diagnostic observations 
only; intervention not 
indicated  
Moderate; minimal, local or 
noninvasive intervention 
indicated; limiting age-
appropriate instrumental 
ADL  
Severe or medically 
significant but not 
immediately life-
threatening; hospitalization 
or prolongation of existing 
hospitalization indicated; 
disabling; limiting self care 
ADL  
Life-threatening 
consequences; urgent 
intervention indicated  
Death  
 

CARTISTEM®                                                                                          page 134 of 137G
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CARTISTEM®                                                                                          page 135 of 137G
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CARTISTEM®                                                                                          page 136 of 137G
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CTCAE 4.0 - May 28, 2009 : Vascular disorders 78  
28. Publication Information  
 
NIH Publication No. 03-5410 
Revised May 2009 
Reprinted May 2009 
 
 
 

CARTISTEM®                                                                                          page 137 of 137G
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APPENDIX  5.  IDMC charter 
 
1. Composition of Data Safety Monitoring Boards (DSMB) 
In the present clinical trial study for Evaluation of Safety and Exploratory Efficacy of 
CARTISTEM®, Data Safety Monitoring Boards (DSMB) consists of 3 members who are 
experts in the area of orthopedics, cell therapies or biostatistics. The members will be 
independent from the sponsor, IRB, regulatory agencies, principal investigator, co-principal 
or sub-principal investigator, site investigator, site sub-investigator, steering committee 
membership, advisory board membership, CEC membership, clinical care of the study 
subjects, or any other capacity related to the present clinical trial operations. 
 
2. Frequency of DSMB meetings 
DSMB meets periodically to review aggregate and individual subject data related to 
safety, data integrity and overall conduct of the trial. DSMB meetings will be organizational 
face-to-face and quarterly teleconferences. However, given the small sample size for the 
present clinical study, the DSMB meetings will be flexible and based on enrollment of 
patients.    
According to the schedule, the DSMB meetings will be required 1) for protocol 
revision, 2) before the dosage B started and 3) to review a draft final report after 12 month 
follow-up period.  
 
3. Information to be reviewed at each meeting  
In order for the DSMB members to review all the information at each meeting, 
guidance for the conduct of safety and effectiveness analyses, protocol modification if 
applicable, and guidelines/stopping rules will be established prior to the DSMB’s first 
evaluation of data. The DSMB will review data unblinded fashion.  
The DSMB will also consider data from other studies or external sources during its 
deliberations, if available, as these results may have a profound impact on the status of the 
patients and design of the present study.