A Phase 2, Double-Blind, Randomized, Controlled Study to Evaluate the Efficacy and Safety of JointStem, Autologous Adipose Tissue Derived Mesenchymal Stem Cells, in Treatment of Osteoarthritis
Phase: PHASE2
Conditions: Osteoarthritis, Knee
Sponsor: Nature Cell Co. Ltd.

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Nature Cell Co., Ltd. 
 
 
 
 
A Phase 2, Double-Blind, Randomized, Controlled Study to Evaluate the 
Efficacy and Safety of JointStem, Autologous Adipose Tissue Derived 
Mesenchymal Stem Cells, in Treatment of Osteoarthritis    
 
Protocol Number: JS-OAP2-US01 
 
IND Number: 15,489 
 
Clinical Study Sponsor: 
Nature Cell Co., Ltd. 
5F, 10 Gukhoe-daero 76-gil 
Yeongdeungpo-gu, Seoul 150-870, Korea  
Phone: +82-2-545-4137 
 
 
US Representative: 
KCRN Research, LLC 
20251 Century Blvd. Suite 325 
Germantown, MD 20874 
Phone: 301-540-2600  
 
 
Protocol Version and Date: 
V7.0, May 14, 2018 
 
 
Previous Version and Date: 
V6.0, April 7, 2017 
 
 
Original Version Date: 
V1.0, May 1, 2013 
 
Confidentiality Notice 
 
This document contains confidential information of Nature Cell Co., Ltd. (NC). This document must not be 
disclosed to anyone other than the study staff and members of the scientific review board or independent review 
board. The information in this document cannot be used for any purpose other than the evaluation or conduct of 
the clinical investigation without the prior written consent of NC. If you have questions regarding how this 
document may be used or shared, contact the sponsor. For all study related questions, contact the US 
Representative, KCRN Research (KCRN). 

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Protocol Signature Page 
 
I have carefully read the attached protocol entitled “A Phase 2, Double-Blind, Randomized, Controlled 
Study to Evaluate the Efficacy and Safety of JointStem, Autologous Adipose Tissue Derived Mesenchymal 
Stem Cells, in Treatment of Osteoarthritis” dated May 14, 2018 and agree to its terms in                           
cluding principles of disclosure and confidentiality. 
 
I agree to submit this protocol to the Institutional Review Board to obtain its approval prior to initiation of 
the study. 
 
I also agree to comply with the International Conference of Harmonization (ICH) Tripartite Guidelines on 
good Clinical Practice, and applicable regulations/guidelines set forth in the Code of Federal Regulations 
(CFR), Title 21, Parts 11, 50, 54, 56, and 312. 
 
I agree to ensure that the confidential information contained in this document will not be used for any 
purpose other than the evaluation or conduct of the clinical investigation without the prior written consent 
of NC. 
 
 
 
 
 
 
Signature 
 
 
 
 
Name of Principal Investigator 
 
Date (DD/MMM/YYYY) 
 

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Protocol Synopsis 
 
Title:  
A Phase 2, Double-Blind, Randomized, Controlled Study to Evaluate the Efficacy and 
Safety of JointStem, Autologous Adipose Tissue Derived Mesenchymal Stem Cells, in 
Treatment of Osteoarthritis 
Phase:   
Phase 2 
Indication:   Osteoarthritis (Degenerative Arthritis) 
Study Objective: 
To evaluate the efficacy and safety of autologous adipose tissue derived mesenchymal stem 
cells (AdMSC) for the treatment of osteoarthritis 
 
Study Design: 
This study is a double-blind, randomized, controlled study with two arms to evaluate 
JointStem as a treatment for subjects with osteoarthritis. Following a 2-week screening 
period, approximately 30 subjects will be randomly assigned into one of the following two 
arms in a 2:1 ratio (2 JointStem : 1 positive control): 
• JointStem (1x108 cells/3mL) 
• Positive control: Synvisc-One®  
 
 
After each subject completes 6-month visit (Visit 6) and the data management team 
confirms all individual data have no issue, the individual database will be locked and the 
blinding will be open for the statistical analysis. Only subjects who are randomized to 
JointStem group will then be scheduled for 9-month and 12-month follow-up visits (Visits 
7 and 8).   
 
Long-term follow-up visit will be conducted to collect long-term feedbacks (records of 
medications and treatments) following 2 years after injection for all subjects who complete 
6-month visit and accept the long-term follow-up visit.  
 
Co-Primary Endpoints:  Change of WOMAC score from baseline at Month 6 (JointStem group) 
 
 
 
 Change of VAS score from baseline at Month 6 (JointStem group) 
 
 
 
 MRI improvement evaluation at Month 6 (JointStem group) 
 
 
 
  
Secondary Endpoints: 
1) JointStem group vs. positive control group 
 
 Change of WOMAC score from baseline at Month 6 
 
 Change of VAS score from baseline at Month 6 
 
 Change of KOOS from baseline at Month 6 
 
 Change of Lysholm Knee Scoring Scale from baseline at Month 6 
 
 Change of IKDC from baseline at Month 6 
 
 Change of RAND-36 Score from baseline at Month 6 
 
2) JointStem group 
 
 
 Change of WOMAC score from baseline at Months 9 and 12 
 
 
 Change of VAS score from baseline at Months 9 and 12 
 
 
 Comparison of MRI improvement evaluations between at Month 6 and at Month 
12 
 
 
 Change of Lysholm Knee Scoring Scale from baseline at Months 6, 9 and 12 
 
 
 Change of KOOS from baseline at Months 6, 9 and 12 

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 Change of IKDC from baseline at Months 6, 9 and 12 
 
 Change of RAND-36 Score from baseline at Months 6, 9 and 12 
 
3) Incidence of adverse events and laboratory abnormalities 
 
Exploratory Endpoints: Analysis of all efficacy scales and MRI results and the history of treatments and 
medications following 2 years after injection for all subjects who are injected and 
complete 6-month follow-up visit 
 
Inclusion Criteria: 
1) Subject who can give written informed consent 
2) Male or female of any race, aged 22-60 
3) Subject who had osteoarthritis of knee diagnosed at least six months prior to Screening 
4) Subject who has joint pain ≥ 40mm on VAS (Visual Analog Scale) at Screening 
5) Subject who has swelling, tenderness and active range of motion ≥ Grade I at Screening 
6) Subject who seeks invasive interventions of intra-articular injections 
7) Subject who is willing to discontinue all pain medications for osteoarthritis except rescue medication (< 
acetaminophen 3.25 g per day) at least 72 hours prior to screening and throughout the duration of study 
8) Subject who has radiographic evidence of grade 3 to 4 osteoarthritis based on the Kellgren and Lawrence 
radiographic criteria. 
9) Female subject who meets one of the following criteria: 
a.  Female subject of non-childbearing potential: 
• Post-menopausal for at least 6 months; or 
• Surgically sterile 
b.  Female subject of child-bearing potential: 
• Neither pregnant nor lactating; and 
• Abstinent or use adequate contraception (2 forms of birth control, one of which must be a barrier method) 
10) Subject who is able to comply with lifestyle guidelines, scheduled visits, treatment plan, laboratory tests, and 
other study procedures 
 
Exclusion Criteria: 
1) Subject who has Body Mass Index (BMI) > 35 kg/m2  
2) Subject who has unstable knees 
3) Subject who took any NSAIDs within two weeks from Screening 
4) Subject who had any intra-articular injection therapy in any joint within 2 months from Screening 
5) Subject who has any clinically significant disease, which is judged by the investigator to affect this clinical trial, 
including but not limited to diabetes not adequately controlled, bleeding diathesis or hematologic disease, 
endocrinopathies, cardiovascular disease, renal disease (severe renal impairment), autoimmune disease, 
inflammatory arthritides, and current infectious disease 
6) Subject who has inflammatory arthropathy (rheumatoid, psoriatic, or avascular necrosis), and post traumatic or 
septic arthritis 
7) Subject who has chondrocalcinosis, Paget’s disease, Villonodular synovitis, and other non-OA joint diseases 
8) Subject who has HIV/viral hepatitis 
9) Subject who had knee surgery or radiation therapy in the affected joint within 6 months from Screening 
10) Subject who had CVA attack within 6 months from Screening  
11) Subject for whom the investigator judges the liposuction can cause any problems  

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12) Subject who has significant lab abnormalities for the following parameters (If the value is within 10% of the listed 
laboratory exclusion criterion value and the value is considered not to be clinically significant by the investigator, 
the subject can be considered for enrollment): 
• Serum ALT and AST > 2 x upper limit of normal 
• Serum creatinine out of normal range 
• PT/INR out of normal range 
• Hemoglobin < 10 g/dL for female subject and hemoglobin < 11 g/dL for male subject 
• Platelets out of normal range 
13) Subject who has history of local anesthetic allergy 
14) Subject who took immunosuppressants such as Cyclosporin A or azathioprine within 6 weeks from Screening  
15) (If a subject uses aspirin or plavix) Subject for whom it is determined that it would not be safe to stop the 
aspirin/plavix therapy for 2 weeks prior to Visit 2 
16) Subject who uses anticoagulants which cannot be stopped or corrected 
17) Subject who had oral or intra-muscular corticosteroids within 30 days from Visit 2 
18) Subject who had intra-articular corticosteroid injection in any joint within 30 days from Visit 2 
19) Subject who had intra-articular hyaluronic acid injection within 30 days from Visit 2 
20) Subject who has known hypersensitivity (allergy) to hyaluronan (sodium hyaluronate) preparations 
21) Subject who has knee joint infections or skin diseases or infections in the area of the injection site 
22) Subject who is an active drug/EtOH abuser 
23) Subject who was enrolled in any other clinical trials within 2 months from Screening 
24) Subject who the principal investigator considers inappropriate for the study due to any other reasons than those 
listed above 
25) Subject whose MRI scan results during the screening period do not demonstrate any sign of cartilage damage. 
 
Investigational Product Dosage and Administration:   
One of two treatment groups will receive a single injection of JointStem (1x108 cells/3mL, autologous adipose tissue 
derived mesenchymal stem cells) via intra-articular injection. 
 
Control Group:  
Positive control (Synvisc-One®) via intra-articular injection 
 
Study Procedures:   
Visit 1 (Week -7) – Screening  
Visit 2 (Week -5) – Harvest of Adipose Tissue 
Visit 3 (Week 0) – Baseline (intra-articular injection) 
Visit 4 (Month 1) – 1-month follow-up 
Visit 5 (Month 3) – 3-month follow-up 
Visit 6 (Month 6) – 6-month follow-up (completion of treatment) 
  * Double-blinding will end individually. 
Visit 7 (Month 9) – 9-month follow-up (for only JointStem group) 
Visit 8 (Month 12) – 12-month follow-up (for only JointStem group) 
Long-term Follow-up (Month 24) – 24-month follow-up  
 
Statistical Analysis:   
1. Co-primary Endpoints 

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Using the following three co-primary efficacy variables, the joint functional improvement of knee joint will be 
evaluated and gatekeeping procedures will be used for these three hypothesis tests.  
1) Change of WOMAC score from baseline at Month 6 (JointStem group) 
It will be tested using paired t-test (one-sided test, α=0.05). If change of WOMAC score from baseline at 
Month 6 doesn’t satisfy normal distribution, Wilcoxon signed rank test will be performed.  
2) Change of VAS score from baseline at Month 6 (JointStem group) 
It will be tested using paired t-test (one-sided test, α=0.05). If change of VAS score from baseline at Month 
6 doesn’t satisfy normal distribution, Wilcoxon signed rank test will be performed.  
3) MRI improvement evaluation at Month 6 (JointStem group) 
The frequency and percentage of subjects whose final PI evaluation is ‘improvement’ will be calculated 
(validity criteria: 36%).  
2. Secondary Endpoints 
The comparison of WOMAC score, VAS score, Lysholm Knee Scoring Scale, KOOS, IKDC and RAND-36 score 
between study and control groups will be analyzed using Analysis of Covariance (ANCOVA) with factors of treatment 
and baseline of each variable as a covariate.  
Model-based LS Means of the differences between study and control groups along with 95% CI and p-value will be 
provided.  
In addition, the change of secondary efficacy variables within study group shall be tested using paired t-test. If the 
change of score from baseline at each assessment point doesn’t satisfy normal distribution, Wilcoxon signed rank test 
will be performed.  
In case of MRI, the frequency and percentage of subjects whose PI evaluation is ‘improvement’ at Month 6 will be 
calculated. In addition, MRI improvement evaluation at Month 12 compared to Month 6 will be analyzed using 
McNemar test or Bowker’s test.  
 
Safety variables will be summarized descriptively, by treatment group and visit. 
 
When at least 15 subjects complete 6-month visits (Visit 6, Month 6), one unblinded interim analysis can be performed 
to evaluate the efficacy and safety of JointStem without the suspension of subject’s schedule of assessments. The 
details of this interim analysis will be presented in the statistical analysis plan. 
 
All efficacy variables and the history of treatments and medications, which are measured at a long-term follow-up 
visit (24 months after injection) will be analyzed between treatment groups to see any long-term effects of JointStem. 
Also, MRI results of long-term follow-up visit will be compared to previous MRI results to see any long-term effects 
of JointStem.  

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Schedule of Assessments 
 
 
Screen. Harv. Treat. 
1st Follow-up 
2nd Follow-Up Long-term 
Follow-up 
Blinding 
N/A 
Double Blinding 
Open 7 
Visit 
1 
2 
3 
4 
5 
6 
ET 
7 
8 
N/A 
Week / Month 
W-7 
W-5 
0 
M1 
M3 
M6 <M6 M9 
M12 or 
Final FU6 
M24 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
Medical and Medication History 
X 
X 
 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
 
Complete physical examination 
X 
 
X 
 
X 
X 
X4 
X 
X 
X 
Vital signs and weight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Hematology, serum chemistry, and 
urinalysis 1 
X 
 
X 
X 
X 
X 
X4 
X 
X 
 
Pregnancy test 2 
X 
 
 
 
 
X 
X4 
 
X 
 
HIV test for Screening 
X 
 
 
 
 
 
 
 
 
 
12-lead ECG 
X 
 
X 
 
 
X 
X4 
 
X 
 
X-ray 
X 
 
 
 
 
 
 
 
 
 
Eligibility confirmation  
X 
X 
 
 
 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
Liposuction  
 
X 
 
 
 
 
 
 
 
 
Injection of final drug product 
 
 
X 
 
 
 
 
 
 
 
AE and concomitant medication 
assessment  
 
 
X 
X 
X 
X 
X 
X 
X 
 
Records of Treatment and 
Medications 
 
 
 
 
 
 
 
 
 
X 
MRI scan 3 
X 
 
 
 
 
X 
X5 
 
X 
X 
WOMAC  
 
 
X 
X 
X 
X 
X4 
X 
X 
X 
VAS  
X 
 
X 
X 
X 
X 
X4 
X 
X 
X 
Lysholm  
 
 
X 
X 
X 
X 
X4 
X 
X 
X 
KOOS 
 
 
X 
X 
X 
X 
X4 
X 
X 
X 
IKDC  
 
 
X 
X 
X 
X 
X4 
X 
X 
X 
Quality of Life (RAND-36)  
 
 
X 
 
X 
X 
X4 
X 
X 
X 
1. See Appendix 1 for the complete list of laboratory tests  
2. Serum pregnancy test is performed for all females of childbearing potential (please refer to the relevant inclusion 
criteria)  
3. May be performed the day of Visit 2 or after due to scheduling or re-scanning.  
4. Performed only if the early termination is after V3. 
5. Performed only if the early termination is after V4.  
6. Performed if the follow-up is discontinued after V6.  
7. Only for JointStem group. 

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Glossary and Abbreviations 
 
AdMSC 
Adipose Tissue Derived Mesenchymal Stem Cell 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
eCRF 
Electronic Case Report Form 
ICH 
International Conference of Harmonization 
IKDC 
International Knee Documentation Committee 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
KOOS 
Knee Injury & Osteoarthritis Outcome Score 
LOCF 
Last Observation Carried Forward 
PP 
Per Protocol 
PT-INR 
Prothrombin Time - International Normalized Ratio 
SAE 
Serious Adverse Event 
VAS 
Visual Analog Scale 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 
 

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Table of Contents 
 
Page 
Protocol Synopsis ........................................................................................................................................ 3 
Schedule of Assessments ............................................................................................................................. 6 
Study Glossary and Definitions ................................................................................................................. 7 
1. 
PURPOSE OF STUDY ..................................................................................................................... 12 
2. 
BACKGROUND AND INDICATION ............................................................................................ 13 
2.1 
What is Osteoarthritis (Degenerative Arthritis) ................................................................... 13 
2.2 
Current Treatment for Osteoarthritis and Their Pitfalls ....................................................... 13 
2.3 
Potential Use of Stem Cells in Treatment of Osteoarthritis ................................................. 14 
2.4 
Current Clinical Trials of Treating Osteoarthritis with Stem Cells ...................................... 15 
3. 
INVESTIGATIONAL PLAN ........................................................................................................... 16 
3.1 
Study Design ........................................................................................................................ 16 
3.2 
Selection of Study Population .............................................................................................. 16 
3.2.1 
Inclusion Criteria ................................................................................................ 16 
3.2.2 
Exclusion Criteria............................................................................................... 17 
3.3 
Removal of Subjects from Study ......................................................................................... 19 
3.4 
Premature Termination of Study / Closure of Center .......................................................... 19 
3.5 
Treatment ............................................................................................................................. 20 
3.5.1 
Treatment to be Administered ............................................................................ 20 
3.5.2 
Identity of Investigational Product ..................................................................... 20 
3.5.3 
End of Study ....................................................................................................... 20 
3.5.4 
Selection of Dose in Study ................................................................................. 21 
3.5.5 
Choice of Control/Comparator ........................................................................... 21 
3.5.6 
Blinding .............................................................................................................. 21 
3.5.7 
Prior and Concomitant Treatments .................................................................... 21 
3.5.8 
Treatment Compliance ....................................................................................... 22 
3.6 
Study Endpoints and Variables ............................................................................................ 22 
3.6.1 
Study Endpoints ................................................................................................. 22 
3.6.2 
Efficacy Variables .............................................................................................. 24 
3.6.3 
Safety Variables ................................................................................................. 24 
3.6.4 
Observation and Measurements ......................................................................... 25 
4. 
STUDY PROCEDURES .................................................................................................................. 26 
4.1 
Screening Procedures ........................................................................................................... 26 
4.2 
Treatment Period .................................................................................................................. 26 
4.2.1 
Visit 2 (Week -5) ................................................................................................ 26 
4.2.2 
Preparation of Final Drug Product in Biostar SCRI ........................................... 27 
4.2.3 
Visit 3 (Week 0) ................................................................................................. 27 
4.2.4 
Visit 4 (Month 1 ± 3 days) ................................................................................. 28 

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4.2.5 
Visit 5 (Month 3 ± 1 week) ................................................................................ 28 
4.2.6 
Visit 6 (Months 6 ± 1 week) .............................................................................. 28 
4.2.7 
Visit 7 (Month 9 ± 1 week) ................................................................................ 29 
4.2.8 
Visit 8 (Month 12 ± 1 week) .............................................................................. 29 
4.2.9 
Early Termination Visit ...................................................................................... 30 
4.2.10 
Final Follow-Up Visit ........................................................................................ 30 
4.3 
Data Quality ......................................................................................................................... 31 
4.4 
Documentation ..................................................................................................................... 31 
5. 
ETHICAL AND LEGAL ASPECTS ................................................................................................ 33 
5.1 
Institutional Review Board (IRB) ........................................................................................ 33 
5.2 
Ethical Conduct of the Study ............................................................................................... 33 
5.3 
Regulatory Authority Approvals/Authorizations ................................................................. 33 
5.4 
Subject Information Consent ................................................................................................ 33 
5.5 
Insurance .............................................................................................................................. 34 
5.6 
Confidentiality ..................................................................................................................... 34 
6. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................................. 35 
6.1 
Statistical and Analytical Plans ............................................................................................ 35 
6.1.1 
Analytical Populations ....................................................................................... 35 
6.1.2 
Treatment Group Comparability ........................................................................ 35 
6.1.3 
Significance Level .............................................................................................. 35 
6.1.4 
Primary Efficacy Analyses ................................................................................. 36 
6.1.5 
Secondary Efficacy Analyses ............................................................................. 37 
6.1.6 
Safety Analyses .................................................................................................. 39 
6.1.7 
Missing Data ...................................................................................................... 40 
6.2 
Determination of Sample Size ............................................................................................. 40 
6.3 
Interim Analysis ................................................................................................................... 40 
7. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING .......................................... 41 
7.1 
Definitions ............................................................................................................................ 41 
7.1.1 
Adverse Events................................................................................................... 41 
7.1.2 
Serious Adverse Events ...................................................................................... 41 
7.2 
Reporting Procedures for All Adverse Events ..................................................................... 42 
7.2.1 
Relationship of Adverse Event to Study Drug ................................................... 43 
7.2.2 
Adverse Event Severity ...................................................................................... 43 
7.3 
Serious Adverse Event Reporting Procedures ..................................................................... 43 
8. 
USE OF DATA AND PUBLICATION ............................................................................................ 45 
9. 
REFERENCES ................................................................................................................................. 46 
 
 
 

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APPENDICES 
Appendix 1. Laboratory Parameters ........................................................................................................... 48 
Appendix 2. Kellgren-Lawrence Grading Scale ......................................................................................... 49 
Appendix 3. WOMAC (Western Ontario and McMaster Universities Arthritis Index) ............................. 50 
Appendix 4. VAS (Visual Analogue Scale) for Pain .................................................................................. 55 
Appendix 5. Lysholm Knee Scale ............................................................................................................... 56 
Appendix 6. KOOS (Knee Injury & Osteoarthritis Outcome Score) .......................................................... 58 
Appendix 7. International Knee Documentation Committee (IKDC) Subjective Knee Evaluation ........... 61 
Appendix 8. RAND 36 Questionnaires ....................................................................................................... 63 
Appendix 9. MRI Improvement Score ........................................................................................................ 66 
 

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1. 
PURPOSE OF STUDY 
 
The purpose of this study is to evaluate the efficacy and safety of autologous adipose tissue derived 
mesenchymal stem cells (AdMSC) for the treatment of osteoarthritis.  
 
 
 

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2. 
BACKGROUND AND INDICATION 
 
2.1   What is Osteoarthritis (Degenerative Arthritis) 
 
Osteoarthritis is a group of mechanical abnormalities involving degradation of joints, including 
articular cartilage and subchondral bone. Symptoms may include joint pain, tenderness, stiffness, 
locking, and sometimes an effusion. When bone surfaces become less well protected by cartilage, 
bone may be exposed and damaged. As a result of decreased movement secondary to pain, regional 
muscles may atrophy, and ligaments may become more lax.Wei 2002, Conaghan 2008  
 
Osteoarthritis is the most common form of arthritis, and the leading cause of chronic disability in 
the United States. It affects about 27 million people in the United States. Eighty percent of 
Americans develop osteoarthritis by age 65. Twenty-five percent of all patients of osteoarthritis 
visit to primary care physicians in the US. The total cost of osteoarthritis living with this disease 
is approximately $5,700 annually per person.Maetzel 2004 Osteoarthritis costs the US economy nearly 
$128 billion per year in medical care and indirect expenses, including lost wages and production. 
As population aging progresses and as more young people start taking up active sports, the size of 
the target patient group is growing. 
 
2.2 
Current Treatment for Osteoarthritis and Their Pitfalls 
 
The cartilage is a unique avascular, aneural tissue that has limited capacity of self-repair once 
damaged. Despite ongoing research, treatments to manage the disease remain merely symptom-
relieving, designed to control pain, and improve function and quality of life limiting adverse events. 
An effective treatment for cartilage defects is yet to be discovered.  
 
Treatment generally involves a combination of lifestyle modification, analgesics, nonsteroidal 
anti-inflammatories, and joint injections with steroids or hyaluronan (lubricant). If pain becomes 
debilitating, joint replacement surgery may be used to improve the quality of life, e.g. partial joint 
resurfacing (hip and shoulder), and total joint replacement (hip and knee).Conaghan 2008 Although 
various treatments are currently in use, none of them is to address the root of cause—cartilage 
regeneration. In other words, there has been no cure for osteoarthritis till today. 
 
As a way of regenerating the damaged or defective cartilage tissue, treatment of localized damage 
to articular cartilage using autologous chondrocytes is currently under review. A few studies are 
marketing this method of treatment named “autologous chondrocyte transplant”.Wysocka 2010, Hahn 2010 
The treatment involves the extraction of healthy cartilage tissue from the patient which is then 
cultured and transplanted into the damaged site. However, this treatment requires the extraction of 

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chondrocytes directly from the patient and thus causes new damages in healthy articular cartilage. 
Also, “autologous chondrocyte transplant” cannot be applied to large lesions. Moreover, the effect 
is not satisfactory in patients over 40 years old whose cellular regeneration is slowed-down due to 
aging.  
 
Thus, autologous chondrocyte transplant is rather limited in the number of cells harvested and their 
activation level and is therefore restricted in terms of treatment site, severity of the condition, and 
the size of lesion. Generally speaking, there was no therapy available till today to regenerate 
cartilage for adult. 
 
2.3   Potential Use of Stem Cells in Treatment of Osteoarthritis 
 
Over the last ten years, great progresses have been made worldwide in the adult stem cell field.Zuk 
2010 Because of their unlimited capacity for self-renewal and ability to differentiate into multiple 
lineages, human stem cells are a potentially powerful and revolutionary tool for repair of cartilage 
defects. Among different origins of stem cells, marrow-derived stem cells have been considered 
as pluripotenty of mesenchymal stem cells and proved being successful in many clinical trials.Jiang 
2002  
 
However, marrow-derived stem cells are limited and not quite easy to access. Recently many 
groundbreaking articles have been published describing new adult stem cell populations from 
many tissues which were not expected to find stem cells, such as skin, liver, digestive epithelium, 
dental pulp and hair follicles and the adipose tissue derived stem cell has become one of the most 
popular adult stem cell populations being used in the stem cell field. 
 
There are many advantages in using AdMSCs than stem cells isolated from other sources. Firstly, 
unlike embryonic stem cells, the use of adult AdMSCs in research and therapy is not considered 
to be controversial as they are derived from adult tissue samples rather than destroyed human 
embryos. Secondly, adipose tissues represent an abundant and accessible source of adult stem cells, 
especially with the fact that overweight is a common condition in the United States, 68% of the 
American adult population is considered either overweight or obese. Even for normal body weight 
persons and most very lean individuals, 5-20 mL extraction of adipose tissue is not a problem at 
all. Compared with marrow-derived stem cells, more people accept collecting stem cells via 
lipoaspirate than bone marrow punctuation. Thirdly, AdMSCs are true stem cells with the capacity 
of differentiating into multi-lineage mesodermal cells and possible ectodermal and endodermal 
cells.Zuk 2010, Stream 2005  
 

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Finally, autologous cells are obtained from the same individual to whom they will be re-implanted. 
Since the AdMSCs come from the patient’s own body, it has no incidence of graft-versus-host 
rejection and less possibilities of pathogen transmission due to the donor and recipient being the 
same individual. Moreover, treatments using stem cells do not cause damage as “autologous 
chondrocyte transplant” would do to healthy articular cartilage, as AdMSC treatment doesn't 
require the harvesting of healthy cartilage tissues from the patients. 
 
2.4   Current Clinical Trials of Treating Osteoarthritis with Stem Cells 
 
There are no clinical trials to date that have been reported in the USA for humans using AdMSC 
to treat osteoarthritis. Several trials for osteoarthritis treatment using bone marrow derived stem 
cells or umbilical cord blood-derived mesenchymal stem cells are currently registered at the NIH 
clinical trials database. In South Korea, the sponsor completed Phase I and II clinical trials for 
osteoarthritis treatment with injection of autologous AdMSCs, which was proved as a safe and 
effective way and actually regenerated healthy cartilage tissue.  
 
Since there is no therapy available today to regenerate cartilage so to effectively treat osteoarthritis, 
this clinical research has been planned in the USA under the strict regulations required by US FDA 
and IRB, in order to prove the efficacy and safety of AdMSC in the treatment of osteoarthritis joint 
and regeneration of cartilage. 
 
 

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3. 
INVESTIGATIONAL PLAN 
 
3.1   Study Design 
 
This is a double-blind, randomized, controlled study to evaluate the efficacy and safety of 
JointStem for the treatment of osteoarthritis. Two or three investigational centers may be utilized 
in the United States so that a total of approximately 30 subjects will be randomized.  
 
3.2   Selection of Study Population 
 
The study population will be males or females, aged 22 to 60, who have radiographic evidence of 
grade 3 to 4 osteoarthritis based on the Kellgren and Lawrence radiographic criteria.  
 
3.2.1 Inclusion Criteria 
 
1) Subject who can give written informed consent 
 
2) Male or female of any race, aged 22-60 
 
3) Subject who had osteoarthritis of knee diagnosed at least six months prior to Screening   
  
4) Subject who has joint pain ≥ 40mm on VAS (Visual Analog Scale) at Screening  
 
5) Subject who has swelling, tenderness and active range of motion ≥ Grade I at Screening   
 
6) Subject who seeks invasive interventions of intra-articular injections 
 
7) Subject who is willing to discontinue all pain medications for osteoarthritis except rescue 
medication (< acetaminophen 3.25 g per day) at least 72 hours prior to screening and 
throughout the duration of study 
 
8) Subject who has radiographic evidence of grade 3 to 4 osteoarthritis based on the Kellgren and 
Lawrence radiographic criteria. 
 
9) Female subject who meets one of the following criteria 
a.  Female subject of non-childbearing potential: 
•  Post-menopausal for at least 6 months; or 
•  Surgically sterile 

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b.  Female patients of child-bearing potential: 
•  Neither pregnant nor lactating; and 
•  Abstinent or use adequate contraception (2 forms of birth control, one of which must 
be a barrier method) 
 
10) Subject who is able to comply with lifestyle guidelines, scheduled visits, treatment plan, 
laboratory tests, and other study procedures 
 
3.2.2 Exclusion Criteria 
 
1) Subject who has Body Mass Index (BMI) > 35 kg/m2  
 
2) Subject who has unstable knees  
 
3) Subject who took any NSAID within two weeks from Screening   
 
4) Subject who had any intra-articular injection therapy in any joint within 2 months from 
Screening 
 
5) Subject who has any clinically significant disease, which is judged by the investigator to affect 
this clinical trial, including but not limited to diabetes not adequately controlled, bleeding 
diathesis or hematologic disease, endocrinopathies, cardiovascular disease, renal disease 
(severe renal impairment), autoimmune disease, inflammatory arthritides, and current 
infectious disease 
 
6) Subject who has inflammatory arthropathy (rheumatoid, psoriatic, or avascular necrosis), and 
post traumatic or septic arthritis 
 
7) Subject who has chondrocalcinosis, Paget’s disease, Villonodular synovitis, and other non-OA 
joint diseases   
 
8) Subject who has HIV/viral hepatitis   
 
9) Subject who had knee surgery or radiation therapy in the affected joint within 6 months from 
Screening 
 
10) Subject who had CVA attack within 6 months from Screening  
 

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11) Subject for whom the investigator judges the liposuction can cause any problem  
 
12) Subject who has significant lab abnormalities for the following parameters (If a value is within 
10% of the listed laboratory exclusion criterion value and the value is considered not to be 
clinically significant by the investigator, the subject can be considered for enrollment): 
• Serum ALT and AST > 2 x upper limit of normal 
• Serum creatinine out of normal range 
• PT/INR out of normal range 
• Hemoglobin < 10 g/dL for female subject and hemoglobin < 11 g/dL for male subject 
• Platelets out of normal range 
 
13) Subject who has history of local anesthetic allergy 
 
14) Subject who took immunosuppressants such as Cyclosporin A or azathioprine within 6 weeks 
from Screening  
 
15) (If a subject uses aspirin or plavix) Subject for whom it is determined that it would not be safe 
to stop the aspirin/plavix therapy for 2 weeks prior to Visit 2  
 
16) Subject who uses anticoagulants which cannot be stopped or corrected 
 
17) Subject who had oral or intra-muscular corticosteroids within 30 days from Visit 2 
 
18) Subject who had intra-articular corticosteroid injection in any joint within 30 days from Visit 
2  
 
19) Subject who had intra-articular hyaluronic acid injection within 30 days from Visit 2  
 
20) Subject who has known hypersensitivity (allergy) to hyaluronan (sodium hyaluronate) 
preparations 
 
21) Subject who has knee joint infections or skin diseases or infections in the area of the injection 
site 
 
22) Subject who is an active drug/EtOH abuser   
 
23) Subject who was enrolled in any other clinical trials within 2 months from Screening 
 

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24) Subject who the principal investigator considers inappropriate for the study due to any other 
reasons than those listed above 
 
25) Subject whose MRI scan results during the screening period do not demonstrate any sign of 
cartilage damage. 
 
3.3   Removal of Subjects from Study 
 
Subjects may be withdrawn from the study for the following reasons: 
• 
At their own request or at the request of their legally acceptable representative 
• 
If, in the investigator’s opinion, continuation in the study would be detrimental to the subject’s 
well-being 
• 
At the specific request of the sponsor 
 
Also, subjects must be withdrawn for the following reasons: 
• 
A significant violation of the protocol, as determined by the sponsor or the investigator 
• 
Highly significant abnormalities in the laboratory results (Highly significant abnormalities 
generally follow lab related exclusion criteria, but a PI can determine the high significance on 
any abnormalities for the safety of subject) 
• 
Use of any other investigational drugs (including placebo)  
• 
Subjects enrolled in the current trial but taking any prohibited medication/therapy stated in the 
inclusion/exclusion criteria that, in the investigator’s opinion, will interfere with the study 
outcome.  
• 
Subject enrolled in the current trial but having a baby  
 
If a subject prematurely withdraws from the study, the subject must return to the clinical site for 
the early termination visit. In all cases, the reason for withdrawal must be recorded in the electronic 
Case Report Form (eCRF) and in the subject’s medical records. 
 
Contact will be maintained with subjects who are removed due to an adverse event (AE) until it 
has been resolved or stabilized, and the information will be documented in the eCRF and in the 
subject’s medical records. 
 
3.4   Premature Termination of Study / Closure of Center 
 
The sponsor has the right to terminate this study, and the investigator/sponsor has the right to close 
a clinical site, at any time, although this should occur only after consultation between involved 

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parties; the IRB must be informed in any case. Should the clinical site be closed prematurely, all 
study materials (equipment, study medication, etc.) must be returned to the sponsor. 
 
This study will discontinue due to medical or administrative reasons such as: 
• 
Serious adverse events probably related to study drug administration so that the use of study 
drug may no longer be justifiable 
• 
2 or more deaths are observed during any point in the trial 
• 
5 or more adverse drug reactions (NCI-CTCAE ≥ Grade 3) on the injected joint are observed 
during any point in the trial 
• 
Significant change of benefit-risk ratio for the subjects 
• 
Sponsor discontinues the investigation of JointStem for the treatment of osteoarthritis or 
determines that the doses being studied are no longer justifiable 
 
Possible reasons for closing of a clinical site include the following: 
• 
The investigator feels that the number or severity of adverse events is excessive 
• 
A change of technical, administrative, or personal circumstances occurs and the conduct of the 
study no longer meets ICH-GCP guidelines 
• 
In case of evident, significant non-compliance to protocol or poor data quality 
 
3.5   Treatment 
 
3.5.1 Treatment to be Administered 
 
At Visit 2 (Week -5), a subject, who is qualified for this study, will be randomized to one of two 
study groups and the adipose tissue will be harvested via liposuction. At Visit 3 (Week 0, baseline), 
the randomized subject will receive a single intra-articular injection.  
 
3.5.2 Identity of Investigational Product 
 
JointStem is a 5 ml syringe including AdMSCs as 1x108 cells/3mL and is stable at refrigerated 
condition up to 1 week. A positive control syringe including hyaluronic acid will be purchased and 
packed by the aluminum foil pack to be matched with JointStem syringe in appearance to be 
indistinguishable.  
 
3.5.3 End of Study 
 
The efficacy results will be analyzed when the last subject completes Visit 6 (6-month follow-up) 
and this study is finished when the last subject completes Visit 8 (12-month follow-up).  

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Long-term follow-up visit will be conducted to collect long-term feedbacks (records of 
medications and treatments) following 2 years after injection for all subjects who complete 6-
month visit and accept the long-term follow-up visit. 
 
3.5.4 Selection of Dose in Study 
 
The dosage of JointStem was chosen through a phase 1 and 2 study conducted in South Korea.  
 
3.5.5 Choice of Control/Comparator 
 
This study uses hyaluronic acid as a positive control (Synvisc-One®). The purpose of using this 
control is to compare the efficacy of JointStem with current treatment option based on various 
endpoints.   
 
3.5.6 Blinding 
 
As this is a double-blinded study, blinding of the drug contents from the subjects, investigators, 
and other study personnel at each clinical site is necessary. Because two syringes of JointStem and 
positive control are different, one physician must be only assigned to the role of syringe injection 
in order to maintain the double-blinding against other site physicians and staffs.  
 
A subject will be assigned with one randomization code on Visit 2 (Week -5). After each subject 
completes Visit 6 (Month 6) and the data management team confirms all individual data have no 
issue, the randomization code will be open for the statistical analysis.  
 
A code-break envelope for each subject including the randomization code information will be 
retained by each site and can be opened, revealing the randomization information, for emergency 
purposes only. Investigator should note that the occurrence of a SAE should not routinely 
precipitate immediate unblinding. An attempt to contact the sponsor must be made prior to 
unblinding. If unblinding occurs, the subject must be early terminated; a written explanation must 
be prepared immediately. 
 
3.5.7 Prior and Concomitant Treatments 
 
If the use of any concomitant treatment(s) becomes necessary, the treatment(s) must be recorded 
in the eCRF, including the name of the drug or treatment, dose, route of administration, date and 
time of the treatment, and indication. In the event that concomitant medication is administered, the 

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principal investigator or qualified sub-investigator must assess the subject’s eligibility of 
continuing the participation in the study. 
 
The following medications/therapies are not allowed to be taken/used by subjects enrolled in this 
study during the trial (by 6-month follow-up visit): 
• 
Any pain medication for osteoarthritis except rescue medication (< acetaminophen 3.25 g per 
day or narcotic pain medications per investigator discretion in the case all other pain control 
measures have failed. Any pain medication other than acetaminophen 3.25g should only be 
used as last resort and only for a very limited time until symptoms can be controlled by more 
conservative methods). 
• 
Any other injections or invasive procedures (including intra-articular injections) in the affected 
joint  
• 
Any investigational drug (including placebo) 
• 
Any therapy that may affect osteoarthritis, in the judgment of the investigator 
• 
Lidocaine or other numbing agents while making the injection  
 
After the completion of the 6-month follow-up visit, subjects may take pain medication for 
osteoarthritis and all medications will be tracked and recorded. Until the subjects complete the 12-
month follow-up visit, any other treatments/therapies including surgeries (e.g. artificial joint 
replacement surgery) that, in the judgment of the investigator, affect the assessment of 
osteoarthritis will be prohibited.  
 
3.5.8 Treatment Compliance  
 
Only subjects who are randomized to JointStem will return on Visits 4, 5, 6, 7 and 8 (Months 1, 3, 
6, 9 and 12) or at Early Termination. On the other hand, subjects who are randomized to the 
positive control group will only return on Visits 4, 5 and 6 (Months 1, 3 and 6) or at Early 
Termination. 
  
3.6   Study Endpoints and Variables 
 
3.6.1 Study Endpoints 
 
The co-primary endpoints are: 
 
Using the following three co-primary efficacy variables, the joint functional improvement of knee 
joint will be evaluated and gatekeeping procedures will be used for these three hypothesis tests.  
 

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1) Change of WOMAC score from baseline at Month 6 (JointStem group) 
 
2) Change of VAS score from baseline at Month 6 (JointStem group) 
 
3) MRI improvement evaluation at Month 6 (JointStem group) 
 
MRI improvement evaluation will be finally analyzed through the following two steps: 
• Radiologist will compare and analyze MRI results before and after the 
administration of IP and write a report for each subject. 
• Principal Investigator will evaluate MRI results of subjects as one of three 
conditions (a: improvement, b: no change, c: progress) based on the radiologist’s 
report stated above.  
 
The secondary endpoints are: 
 
1) JointStem group vs. positive control group 
 
 Change of WOMAC score from baseline at Month 6 
 Change of VAS score from baseline at Month 6 
 Change of KOOS from baseline at Month 6 
 Change of Lysholm Knee Scoring Scale from baseline at Month 6 
 Change of IKDC from baseline at Month 6 
 Change of RAND-36 Score from baseline at Month 6 
 
2) JointStem group 
 
 Change of WOMAC score from baseline at Months 9 and 12 
 Change of VAS score from baseline at Months 9 and 12 
 Comparison of MRI improvement evaluations between at Month 6 and at Months 12 
 Change of Lysholm Knee Scoring Scale from baseline at Months 6, 9 and 12 
 Change of KOOS from baseline at Months 6, 9 and 12 
 Change of IKDC from baseline at Months 6, 9 and 12 
 Change of RAND-36 Score from baseline at Months 6, 9 and 12 
 
3) Incidence of adverse events and laboratory abnormalities 
 
Exploratory Endpoint is: 
 

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All efficacy variables and the history of treatments and medications, which are measured at a 
long-term follow-up visit (24 months after injection) will be analyzed between treatment groups 
to see any long-term effects of JointStem. Also, MRI results of long-term follow-up visit will be 
compared to previous MRI results to see any long-term effects of JointStem.  
3.6.2 Efficacy Variables 
 
• 
WOMAC score at Visits 3, 4, 5, 6, 7 and 8 (Baseline, M1, M3, M6, M9 and M12) or Early 
Termination (only if the subject is early terminated after Visit 3) or Final Follow-up Up Visit  
• 
VAS at Visits 3, 4, 5, 6, 7 and 8 (Baseline, M1, M3, M6, M9 and M12) or Early Termination 
(only if the subject is early terminated after Visit 3) or Final Follow-up Up Visit 
• 
MRI scan at Visits 1, 6 and 8 (Screening, M6 and M12) or Early Termination (only if the 
subject is early terminated after Visit 4) or Final Follow-up Visit  
• 
KOOS at Visits 3, 4, 5, 6, 7 and 8 (Baseline, M1, M3, M6, M9 and M12) or Early Termination 
(only if the subject is early terminated after Visit 3) or Final Follow-up Up Visit  
• 
Lysholm Knee Scoring Scale at Visits 3, 4, 5, 6, 7 and 8 (Baseline, M1, M3, M6, M9 and M12) 
or Early Termination (only if the subject is early terminated after Visit 3) or Final Follow-up 
Up Visit 
• 
IKDC at Visits 3, 4, 5, 6, 7 and 8 (Baseline, M1, M3, M6, M9 and M12) or Early Termination 
(only if the subject is early terminated after Visit 3) or Final Follow-up Up Visit  
• 
RAND-36 Score at Visits 3, 5, 6, 7 and 8 (Baseline, M3, M6, M9 and M12) or Early 
Termination (only if the subject is early terminated after Visit 3) or Final Follow-up Up Visit  
 
3.6.3 Safety Variables 
 
• 
Hematology, serum chemistry and urinalysis at Visits 1, 3, 4, 5, 6, 7 and 8 (Screening, Baseline, 
M1, M3, M6, M9 and M12) or Early Termination (only if the subject is early terminated after 
Visit 3) or Final Follow-up Visit. See Section Appendix 1 for a complete list of laboratory tests 
to be done. 
• 
ECG evaluation at Visits 1, 3, 6 and 8 (Screening, Baseline, M6 and M12) or Early Termination 
(only if the subject is early terminated after Visit 3) or Final Follow-up Up Visit 
• 
Complete physical examination at Visits 1, 3, 5, 6, 7 and 8 (Screening, Baseline, M3, M6, M9 
and M12) or Early Termination (only if the subject is early terminated after Visit 3) or Final 
Follow-up Up Visit 
• 
Vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight will be 
measured at all visits. 
• 
Data regarding AEs and concomitant medications collected at all visits after randomization  
 

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3.6.4 Exploratory Variables 
 
The following procedures will be performed at 24-month visit (±2 month): 
• 
WOMAC score  
• 
VAS  
• 
MRI scan  
• 
KOOS  
• 
Lysholm Knee Scoring Scale  
• 
IKDC  
• 
RAND-36 score  
• 
Records of treatments and medications since the last visit 
 
3.6.5 Observation and Measurements 
 
The rating scales used in this study are WOMAC (Western Ontario and McMaster Universities 
Arthritis Index), VAS (Visual Analog Scale), Lysholm Knee Scoring Scale, KOOS (Knee Injury 
and Osteoarthritis Outcome Score), IKDC (International Knee Documentation Committee), and 
RAND-36 questionnaires. All questionnaires are subject-administered and should be completed 
by the subjects alone at the beginning of each visit to minimize influences from other procedures 
to be performed at that visit. A short explanation should be given to each subject about the purpose 
and the necessity of these questionnaires. 

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4. 
STUDY PROCEDURES 
 
4.1   Screening Procedures 
 
A signed and dated Institutional Review Board (IRB) approved informed consent must be obtained 
before any study-specific procedures are performed. Once written informed consent has been 
obtained, the subject will be screened to determine eligibility and document adherence to the 
preliminary inclusion/exclusion criteria. 
 
Screening Visit 1 (Week -7) 
 
The following screening assessments/procedures must be performed and the results documented 
within approximately 7 weeks before Baseline visit unless otherwise indicated: 
• 
Record demographic data (i.e., date of birth, race, height, and weight). 
• 
Measure VAS (see Appendix 4). 
• 
Record medical and medication history. 
• 
Perform a complete physical examination. 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature). 
• 
Measure 12-lead ECG. 
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
• 
Perform X-ray for Kellgren-Lawrence scale (see Appendix 2). 
• 
Perform MRI to measure damaged cartilage area (Please follow the instruction separately 
provided by the sponsor). * MRI may be performed the day of Visit 2 or after due to scheduling 
or re-scanning, as long as the results are confirmed prior to injection. 
 
4.2   Treatment Period 
 
4.2.1 Visit 2 (Week -5) 
 
For subjects who are preliminarily eligible for this study based on screening procedures, Visit 2 
will occur within approximately 2 weeks (± 4 days) after Visit 1. During this visit, the following 
assessments/procedures should be performed: 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Confirm medical and medication history. 
• 
Determine the final eligibility.  
• 
Randomize to one of two groups (Please follow the randomization instruction separately 
provided by the sponsor). 
 

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Subjects who are finally eligible will then be taken to the operation room for the procedure of 
liposuction.  
• 
In sterile conditions, approximately 10 – 40 mL of fat will be harvested using the syringe 
liposuction technique with Tumescent (or super-wet) local anesthesia (Please follow the 
liposuction instruction separately provided by the sponsor).  
• 
Ship the packaging box containing the harvested syringe to Biostar SCRI designated by the 
sponsor (pre-labeled). 
• 
Dispense a concomitant medication note. 
 
4.2.2 Preparation of Final Drug Product in Biostar SCRI  
 
The following procedures for the preparation of final drug product will be performed by well-
trained lab technicians at Biostar SCRI. The official package containing the final drug product 
(syringes) will be shipped to the clinical site.   
 
 
 
 
4.2.3 Visit 3 (Week 0)  
 
Visit 3 will occur within 5 weeks after Visit 2. During this visit, the following 
assessments/procedures should be performed: 
• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), IKDC (see 
Appendix 7), and RAND-36 (see Appendix 8).  
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Record any adverse event and any change in concomitant medications.  

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• 
Perform a complete physical examination. 
• 
Measure 12-lead ECG. 
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
• 
Inject the final drug product into the cavity of knee joint (Please follow the intra-articular 
injection instruction separately provided by the sponsor). 
• 
Dispense a concomitant medication note. 
 
4.2.4 Visit 4 (Month 1 ± 3 days)  
 
During this visit, the following assessments/procedures should be performed: 
• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), and IKDC (see 
Appendix 7).  
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Record any adverse event and any change in concomitant medications.  
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
• 
Dispense a concomitant medication note. 
 
4.2.5 Visit 5 (Month 3 ± 1 week) 
 
During this visit, the following assessments/procedures should be performed: 
• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), IKDC (see 
Appendix 7), and RAND-36 (see Appendix 8).  
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Record any adverse event and any change in concomitant medications.  
• 
Perform a complete physical examination. 
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
• 
Dispense a concomitant medication note. 
 
4.2.6 Visit 6 (Months 6 ± 1 week)  
 
During this visit, the following assessments/procedures should be performed: 
• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), IKDC (see 
Appendix 7), and RAND-36 (see Appendix 8). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Record any adverse event and any change in concomitant medications.  

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• 
Perform a complete physical examination. 
• 
Measure 12-lead ECG.  
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
• 
Perform MRI measurement (Please follow the collection instruction separately provided by the 
sponsor).  
• 
Dispense a concomitant medication note. 
 
*  After each subject completes Visit 6 (Month 6) and the data management team confirms all individual 
data have no issue, the individual database will be locked and the blinding will be open for the statistical 
analysis. Only subjects who are randomized to JointStem will be scheduled for Visits 7 and 8 (Months 
9 and 12).  
 
4.2.7 Visit 7 (Month 9 ± 1 week)  
 
Only subjects who are randomized to JointStem group will visit the clinical site for the following 
assessments/procedures: 
• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), IKDC (see 
Appendix 7), and RAND-36 (see Appendix 8). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight.  
• 
Record any adverse event and any change in concomitant medications.  
• 
Perform a complete physical examination.  
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
• 
Dispense a concomitant medication note. 
 
4.2.8 Visit 8 (Month 12 ± 1 week)  
 
Only subjects who are randomized to JointStem group will visit the clinical site for the following 
assessments/procedures: 
• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), IKDC (see 
Appendix 7), and RAND-36 (see Appendix 8). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight.  
• 
Record any adverse event and any change in concomitant medications.  
• 
Perform a complete physical examination.  
• 
Measure 12-lead ECG. 
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
• 
Perform MRI measurement (Please follow the collection instruction separately provided by the 
sponsor).  

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4.2.9 Early Termination Visit  
 
If a subject will drop-out the study before Visit 6 (Month 6), the clinical site will try to schedule 
an early termination visit (one of two types)  
 
1) If a subject will drop-out the study before Visit 4 (Month 1), the following assessments and 
procedures should be performed for the early termination visit: 
 
• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), IKDC (see 
Appendix 7), and RAND-36 (see Appendix 8). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight.  
• 
Record any adverse event and any change in concomitant medications.  
• 
Perform a complete physical examination.  
• 
Measure 12-lead ECG. 
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
 
2) If a subject will drop-out the study after Visit 4 (Month 1), the following assessments and 
procedures should be performed for the early termination visit: 
 
• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), IKDC (see 
Appendix 7), and RAND-36 (see Appendix 8). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight.  
• 
Record any adverse event and any change in concomitant medications.  
• 
Perform a complete physical examination.  
• 
Measure 12-lead ECG. 
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
• 
Perform MRI measurement (Please follow the collection instruction separately provided by the 
sponsor).  
 
4.2.10 Final Follow-Up Visit  
 
If a subject will discontinue follow-up after Visit 6 (Month 6), the clinical site will try to schedule 
the final follow-up visit to perform the following assessments and procedures: 
 

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• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), IKDC (see 
Appendix 7), and RAND-36 (see Appendix 8). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight.  
• 
Record any adverse event and any change in concomitant medications.  
• 
Perform a complete physical examination.  
• 
Measure 12-lead ECG. 
• 
Collect blood and urine samples for hematology, serum chemistry, and urinalysis.  
• 
Perform MRI measurement (only if this final follow-up visit is conducted at least 1 month after 
Visit 6). 
 
4.2.11 Long-term Follow-up Visit (Month 24 ± 2 month)  
 
Subjects who complete 6-month visit and accept the long-term follow-up visit will visit the clinical 
site for the following assessments/procedures: 
• 
The following questionnaires/procedures will be completed: WOMAC (see Appendix 3), VAS 
(see Appendix 4), Lysholm scale (see Appendix 5), KOOS (see Appendix 6), IKDC (see 
Appendix 7), and RAND-36 (see Appendix 8). 
• 
Collect records of treatments and medications since the last visit. 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight.  
• 
Perform a complete physical examination.  
• 
Perform MRI measurement (Please follow the collection instruction separately provided by the 
sponsor).  
 
4.3   Data Quality 
 
Monitoring and auditing procedures defined/agreed by the sponsor will be followed in compliance 
with current GCP guidelines. Each center will be visited at regular intervals by a monitor to ensure 
compliance with the study protocol, GCP guideline, and other regulatory aspects. This will include 
on-site review of the eCRF for completeness and clarity, consistency with source documents, and 
clarification of administrative matters. 
 
4.4 
Documentation 
 
Entries made in the eCRF must be either verifiable against source documents or have been directly 
entered into the eCRF, in which case the entry in the eCRF will be considered as the source data. 
The source data parameter to be verified and the identification of the source document must be 

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documented. The study file and all source data should be retained/archived until notification by 
the sponsor for change of archive site or destruction. 

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5. 
ETHICAL AND LEGAL ASPECTS 
 
5.1 
Institutional Review Board (IRB) 
 
Documented approval from the IRB will be obtained for all participating trial center(s)/clinic(s) 
prior to study start, according to GCP and applicable laws and regulations. When necessary, an 
extension, amendment, or renewal of the IRB approval must be obtained and also forwarded to the 
sponsor. The IRB must supply to the sponsor, upon request, a list of the IRB members involved in 
the vote and a statement to confirm that the IRB is organized and operates according to GCP and 
applicable laws and regulations.  
 
5.2 
Ethical Conduct of the Study 
 
The procedures set out in this protocol, pertaining to the conduct, evaluation, and documentation 
of this study, are designed to ensure that the sponsor and investigator abide by GCP guidelines and 
under the guiding principles detailed in the Declaration of Helsinki. The study will also be carried 
out in keeping with applicable local laws and regulations. This may include an inspection by the 
sponsor representatives and/or Regulatory Authority representatives at any time. The investigator 
must agree to the inspection of study-related records by the Regulatory Authority/sponsor 
representatives, and must allow direct access to source documents to the Regulatory 
Authority/sponsor representatives. 
 
Modifications to the study protocol will be implemented by the investigator only after sponsor’s 
approval. However, the investigator may implement a deviation form, or change of the protocol to 
eliminate any immediate hazard(s) to the trial subjects without prior IRB/sponsor approval. The 
implemented deviation or change, the reasons for it and, if appropriate, the proposed amendment 
should be submitted to the IRB/sponsor as soon as possible. Any deviations from the protocol must 
be fully explained and documented by the investigator. 
 
5.3 
Regulatory Authority Approvals/Authorizations 
 
Regulatory Authority approvals/authorizations/notifications, where required, will be in place and 
fully documented prior to the study’s start. 
 
5.4 
Subject Information Consent 
 
A core information and Informed Consent Form will be provided. Prior to the beginning of the 
study, the investigator must have the IRB written approval of the Informed Consent Form and any 

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other written information that will be provided to the subjects. The written approval of the IRB 
with the approved Informed Consent Form must be in the study files.  
 
Written informed consent must be obtained before any study specific procedure takes place. 
Participation in the study and date of informed consent given by the subject should be documented 
appropriately in the subject’s files. 
 
5.5 
Insurance 
 
All subjects participating in the study will have insurance coverage by the sponsor, which is in line 
with applicable laws and/or regulations. 
 
5.6 
Confidentiality 
 
All records identifying the subject will be kept confidential and, to the extent permitted by the 
applicable laws and/or regulations, will not be made publicly available.  
 
Subject names will not be supplied to the sponsor. Only the subject number and subject initials 
will be recorded in the eCRF, and if the subject name appears on any other document (e.g. 
pathologist report), it must be obliterated before a copy of the document is supplied to the sponsor. 
Study findings stored on a computer will be stored in accordance with local data protection laws. 
The subjects will be informed in writing that representatives of the sponsor, IRB, or Regulatory 
Authorities may inspect their medical records to verify the information collected, and that all 
personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws. 
 
Even if the results of the study are published, the subject’s identity will remain confidential. The 
investigator will maintain a list to enable subjects’ records to be identified.  

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6. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
 
6.1 
Statistical and Analytical Plans 
 
6.1.1 Analytical Populations 
 
6.1.1.1 
Intent-to-Treat Population 
 
An intent-to-treat (ITT) population will include subjects who received the intra-articular injection 
and have at least post-injection efficacy measurements. This cohort will be evaluated for all 
efficacy variables. 
 
6.1.1.2 
Per-Protocol Population 
 
All subjects valid for ITT who completed Visit 6 (Month 6) will be ‘valid per protocol’ (also called 
‘valid for efficacy’). Additional criteria may be added prior to unblinding the study database. As 
with the ITT population, this per-protocol (PP) cohort will also be evaluated for all efficacy 
variables. 
 
6.1.1.3 
Safety Population 
 
Any subject who was randomized and completed Visit 2 (Week -5) will be included in the 
evaluation of safety.  This cohort will be evaluated for all safety variables. 
 
6.1.2 Treatment Group Comparability 
 
Demographic variables, medical history, treatment duration, and efficacy variables at baseline will 
be summarized by treatment group for the subjects valid for potential safety analysis. Because, in 
theory, the goal of randomization is to balance out the patient characteristics, statistical tests are 
not planned for these variables. 
 
6.1.3 Significance Level 
 
The primary efficacy hypothesis tests will be performed using a 5% significance level (but, for the 
MRI improvement evaluation, it shall meet the validity criteria). For the secondary efficacy 
endpoints, hypothesis tests will be performed individually at the 5% significance level. All 
hypothesis tests except for the primary efficacy hypothesis tests will be performed with two-sided 
alternative hypotheses.  
 

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6.1.4 Primary Efficacy Analyses 
 
For primary efficacy endpoints, the joint functional improvement of knee joint will be evaluated 
using the following three co-primary efficacy variables and gatekeeping procedures will be used 
for these three hypothesis tests.  
 
Three hypothesis tests will be performed in the following order: 1) Change of WOMAC score 
within study group, 2) Change of VAS score within study group and 3) MRI improvement 
evaluation in the study group. If null hypothesis is dismissed at 5% significance level for the first 
hypothesis test, the second hypothesis will also be tested at 5% significance level. Then, for MRI 
improvement evaluation, the test will be performed to confirm if the percentage of subjects whose 
final PI evaluation is ‘improvement’ meets the validity criteria. If null hypothesis is not dismissed 
at 5% significance level or it is lower than the validity criteria, the hypothesis test is stopped and 
it is concluded only previous item of which null hypothesis is dismissed is significant.  
 
1) Change of WOMAC score from baseline at Month 6 (JointStem group) 
 
Change of WOMAC score from baseline at Month 6 will be tested using paired t-test (one-
sided test, α=0.05) with the null hypothesis equal to zero. If change of WOMAC score from 
baseline at Month 6 doesn’t satisfy normal distribution, Wilcoxon signed rank test will be 
performed.  
 
If null hypothesis is dismissed, the conclusion that the function of knee joint is improved 
from at least subjects who administer IP can be drawn.    
 
2) Change of VAS score from baseline at Month 6 (JointStem group) 
 
Change of VAS score from baseline at Month 6 will be tested using paired t-test (one-sided 
test, α=0.05) with the null hypothesis equal to zero. If change of VAS score from baseline 
at Month 6 doesn’t satisfy normal distribution, Wilcoxon signed rank test will be performed.  
 
If null hypothesis is dismissed, the conclusion that the pain of degenerative arthritis is 
reduced from at least subjects who administer IP can be drawn.    
 
3) MRI improvement evaluation at Month 6 (JointStem group) 
 
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• Radiologist will compare and analyze MRI results before and after the 
administration of IP and write a report for each subject. 
• Principal Investigator will evaluate MRI results of subjects as one of three 
conditions (a: improvement, b: no change, c: progress) based on the radiologist’s 
report stated above.  
 
 The frequency and percentage of subjects whose final PI evaluation is ‘improvement’ 
will be calculated per group. 
 
If the percentage of subjects whose final PI evaluation is at least 36%, the conclusion that 
the damaged cartilage of knee joint is improved in the subjects who administer JointStem 
can be drawn.  
 
6.1.5 Secondary Efficacy Analyses 
 
1) WOMAC Score 
 
 Change of WOMAC score from baseline at Month 6 (JointStem group vs. positive 
control group) 
 
; This secondary efficacy endpoint will be analyzed with an ANCOVA with factors of 
treatment and the baseline of WOMAC score as a covariate. Model-based LS Means 
of the differences between study and control groups, along with 95% CI and p-value 
will be provided. 
 
 Change of WOMAC score from baseline at Months 9 and 12 (JointStem group) 
; Change of WOMAC score from baseline at Months 9 and 12 will be analyzed using 
paired t-test. If change of WOMAC score from baseline at Months 9 and 12 doesn’t 
satisfy normal distribution, Wilcoxon signed rank test will be performed. 
 
2) VAS Score 
 
 Change of VAS score from baseline at Month 6 (JointStem group vs. positive control 
group) 
 
; This secondary efficacy endpoint will be analyzed with an ANCOVA with factors of 
treatment and the baseline of VAS score as a covariate. Model-based LS Means of the 
differences between study and control groups, along with 95% CI and p-value will be 
provided. 
 

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 Change of VAS score from baseline at Months 9 and 12 (JointStem group) 
; Change of VAS score from baseline at Months 9 and 12 will be analyzed using paired 
t-test. If change of VAS score from baseline at Months 9 and 12 doesn’t satisfy normal 
distribution, Wilcoxon signed rank test will be performed. 
 
3) MRI 
 
 Comparison of MRI improvement evaluations between at Month 6 and at Month 12  
(JointStem group) 
; MRI improvement evaluation at Month 12 compared to Month 6 will be analyzed 
using McNemar test or Bowker’s test. 
 
4) Lysholm Knee Scoring Scale 
 
 Change of Lysholm Knee Scoring Scale from baseline at Month 6 (JointStem group 
vs. positive control group) 
 
; This secondary efficacy endpoint will be analyzed with an ANCOVA with factors of 
treatment and the baseline of Lysholm Knee Scoring Scale as a covariate. Model-
based LS Means of the differences between study and control groups, along with 95% 
CI and p-value will be provided. 
 
 Change of Lysholm Knee Scoring Scale from baseline at Months 6, 9 and 12 
(JointStem group) 
; Change of Lysholm Knee Scoring Scale from baseline at Months 6, 9 and 12 will be 
analyzed using paired t-test. If change of Lysholm Knee Scoring Scale from baseline 
at Months 6, 9 and 12 doesn’t satisfy normal distribution, Wilcoxon signed rank test 
will be performed. 
 
5) KOOS 
 
 Change of KOOS from baseline at Month 6 (JointStem group vs. positive control 
group) 
 
; This secondary efficacy endpoint will be analyzed with an ANCOVA with factors of 
treatment and the baseline of KOOS as a covariate. Model-based LS Means of the 
differences between study and control groups, along with 95% CI and p-value will be 
provided. 
 
 Change of KOOS from baseline at Months 6, 9 and 12 (JointStem group) 

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; Change of KOOS from baseline at Months 6, 9 and 12 will be analyzed using paired 
t-test. If change of KOOS from baseline at Months 6, 9 and 12 doesn’t satisfy normal 
distribution, Wilcoxon signed rank test will be performed. 
 
6) IKDC 
 
 Change of IKDC from baseline at Month 6 (JointStem group vs. positive control 
group) 
 
; This secondary efficacy endpoint will be analyzed with an ANCOVA with factors of 
treatment and the baseline of IKDC as a covariate. Model-based LS Means of the 
differences between study and control groups, along with 95% CI and p-value will be 
provided. 
 
 Change of IKDC from baseline at Months 6, 9 and 12 (JointStem group) 
; Change of IKDC from baseline at Months 6, 9 and 12 will be analyzed using paired 
t-test. If change of IKDC from baseline at Months 6, 9 and 12 doesn’t satisfy normal 
distribution, Wilcoxon signed rank test will be performed. 
 
7) RAND-36 Score 
 
 Change of RAND-36 Score from baseline at Month 6 (JointStem group vs. positive 
control group) 
 
; This secondary efficacy endpoint will be analyzed with an ANCOVA with factors of 
treatment and the baseline of RAND-36 Score as a covariate. Model-based LS Means 
of the differences between study and control groups, along with 95% CI and p-value 
will be provided. 
 
 Change of RAND-36 Score from baseline at Months 6, 9 and 12 (JointStem group) 
; Change of RAND-36 Score from baseline at Months 6, 9 and 12 will be analyzed 
using paired t-test. If change of RAND-36 Score from baseline at Months 6, 9 and 12 
doesn’t satisfy normal distribution, Wilcoxon signed rank test will be performed. 
 
6.1.6 Safety Analyses 
 
AE rates will be summarized by treatment group and overall, and will be broken down by severity, 
seriousness and relation to study drug. Statistical tests are not planned for safety variables. 
 

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6.1.7 Missing Data 
 
Last observation carried forward (LOCF) imputation method will be used for efficacy variables, 
but no adjustments for missing data and no imputation methods are planned for safety variables .  
 
6.2 
Determination of Sample Size 
 
There was no formal sample size calculation since this is a proof-of-concept study and is not a 
hypothesis-driven study.  The number of enrolled subjects is predefined at n=30, for 20 subjects 
per study group and 10 subjects per control group. 
 
6.3 
Interim Analysis 
 
When at least 15 subjects complete 6-month visits (Visit 6, Month 6), one unblinded interim 
analysis can be performed to evaluate the efficacy and safety of JointStem without the suspension 
of subject enrollment. The details of this interim analysis will be presented in the statistical analysis 
plan.  No adjustment on the overall alpha-level will be made, as this is not a statistically powered 
study. 
 
6.4 
Long-term Follow-up Analysis 
 
All efficacy variables and the history of treatments and medications, which are measured at a long-
term follow-up visit (24 months after injection) will be analyzed between treatment groups to see 
any long-term effects of JointStem. Also, MRI results of long-term follow-up visit will be 
compared to previous MRI results to see any long-term effects of JointStem. The details of this 
long-term follow-up analysis will be presented in the statistical analysis plan.  
 

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7. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING 
 
7.1 
Definitions 
 
7.1.1 Adverse Events 
 
An adverse event is defined in the 21 CFR 312.32(a) as “Adverse event means any untoward 
medical occurrence associated with the use of a drug in humans, whether or not considered drug 
related.” 
 
An adverse event (also referred to as an adverse experience) can be any unfavorable and 
unintended sign (e.g., an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a drug, without any judgment about causality. An adverse event can arise from any 
use of the drug (e.g., off-label use, use in combination with another drug) and from any route of 
administration, formulation, or dose, including an overdose. Worsening of a pre-existing medical 
condition (e.g., diabetes, migraine headaches, and gout) after the drug administration should be 
considered an adverse event if there is either an increase in severity, frequency, or duration of the 
condition or an association with significantly worse outcomes. 
 
The investigator is responsible for reviewing laboratory test results and determining whether an 
abnormal value in an individual study subject represents a change from baseline values. Abnormal 
laboratory findings without clinical significance (based on the investigator's judgment) should not 
be recorded as adverse events; however, laboratory value changes requiring therapy or adjustment 
in prior therapy are considered adverse events. 
 
Adverse events will be reviewed continuously throughout the study. 
 
7.1.2 Serious Adverse Events 
 
A serious adverse event (SAE) is defined as an adverse event that 
• 
is fatal 
• 
is life threatening (places the subject at immediate risk of death) 
• 
requires in-patient hospitalization or prolongation of existing hospitalization 
• 
results in persistent or significant disability/incapacity 
• 
is a congenital anomaly/birth defect 
• 
other significant medical hazard 
 

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Life threatening:  The term life-threatening in the definition of ‘serious’ refers to an AE in which 
the subject was at risk of death at the time of the event. It does not see an AE that hypothetically 
might have caused death if it were more severe.  
 
Hospitalization: Any adverse event leading to hospitalization or prolongation of hospitalization 
will be considered as ‘serious’, UNLESS at least one of the following exceptions is met: 
• 
the admission results in a hospital stay of less than 12 hours OR 
• 
the admission is pre-planned (i.e., elective or scheduled surgery arranged prior to the start 
of the study) OR 
• 
a medical intervention that requires hospitalization (e.g., blood product transfusion or 
central line insertion) will be not considered a serious adverse event 
 
However, it should be noted that invasive treatment during any hospitalization may fulfill the 
criteria of ‘medically important’ and as such may be reportable as a SAE dependent on clinical 
judgment.   
 
Disability means a substantial disruption of a person’s ability to conduct normal life functions. 
 
Important medical event: Any AE may be considered serious because it may jeopardize the patient 
and may require intervention to prevent another serious condition. As guidance for determination 
of important medical events see the ‘WHO Adverse Reaction Terminology – Critical Terms List’. 
These terms either see or might be indicative of a serious disease state. 
 
Such reported events warrant special attention because of their possible association with a serious 
disease state and may lead to more decisive action than reports on other terms. 
 
7.2 
Reporting Procedures for All Adverse Events 
 
The investigator is responsible for ensuring that all adverse events (as defined in Section 7.1) 
observed by the investigator or reported by subjects after the first dose of each subject are properly 
captured in the subject’s medical records and reported on the eCRF. 
 
Documentation must be supported by an entry in the subject’s file. A laboratory test abnormality 
considered clinically relevant, e.g., causing the subject to withdraw from the study, requiring 
treatment or causing apparent clinical manifestations, or judged relevant by the investigator, 
should be reported as an adverse event. Each event should be described in detail along with start 
and stop dates, severity, relationship to investigational product, action taken, and outcome 
 

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7.2.1 Relationship of Adverse Event to Study Drug 
 
The following adverse event attributes must be assigned by the investigator:  adverse event 
diagnosis or syndrome(s) (if known, signs or symptoms if not known); event description (with 
detail appropriate to the event); dates of onset and resolution; severity; assessment of relatedness 
to study drug and action taken. The investigator may be asked to provide follow-up information, 
discharge summaries, and extracts from medical records or eCRFs. 
 
If applicable, the relationship of the adverse event to the study drug will be assessed by means of 
the question: “Is there a reasonable possibility that the event may have been caused by the study 
drug?”  The investigator should respond to this question with either Yes or No. 
 
7.2.2 Adverse Event Severity 
 
The severity of adverse events should be graded as follows: 
• 
Mild – Usually transient in nature and generally not interfering with normal activities 
• 
Moderate – Sufficiently discomforting to interfere with normal activities 
• 
Severe – Prevents normal activities 
 
Medically significant adverse events considered related to the study drug by the investigator or 
Sponsor will be followed until resolved or considered stable. 
 
It will be left to the investigator’s clinical judgment to determine whether an adverse event is 
related and of sufficient severity to require the subject’s removal from treatment or from the study. 
A subject may also voluntarily withdraw from treatment due to what he or she perceives as an 
intolerable adverse event. If either of these situations arises, the subject should be strongly 
encouraged to undergo an end-of-study assessment and be under medical supervision until 
symptoms cease or the condition becomes stable. 
 
7.3 
Serious Adverse Event Reporting Procedures 
 
Serious adverse events will be collected and recorded from the drug administration to 3-month 
follow-ups.  
 
Serious Adverse Events, including laboratory test abnormalities fulfilling the definition of serious, 
after the first dose, and during follow-up period must immediately (within 24 hours of the 
investigator’s awareness) be reported to the person/parties as detailed in the study file. A Serious 
Adverse Event form must also be completed within 1 day of the investigator’s awareness and 

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forwarded to the designated person/parties as detailed in the study file. Each Serious Adverse 
Event must be followed up until resolution or stabilization by submission of updated reports to the 
designated person/parties.  
 
Serious adverse events also will be collected and reported within 1 working day of discovery or 
notification of the event if it occurs 7 days after the last dose of study drug or after the end of the 
study and is thought to be possibly related to study drug. 
 
For all deaths, available autopsy reports and relevant medical reports should be faxed to Sponsor 
or their designee. For this reporting process, subject assessments must be made 7 days after 
administration of the last dose of study drug. 
 
If a subject is permanently withdrawn from the study because of a serious adverse event, this 
information must be included in the initial or follow-up Serious Adverse Event Report Form as 
well as the End of Study Case Report Form. 
 
When required, and according to local law and regulations, serious adverse events must be reported 
to the institutional review board and Regulatory Authorities. 
 

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8. 
USE OF DATA AND PUBLICATION  
 
All data and results and all intellectual property rights in the data and results derived from the 
study will be the property of the sponsor, who may utilize the data in various ways, such as for 
submission to government regulatory authorities or disclosure to other investigators. The 
investigator, while free to utilize data derived from the study for scientific purposes, must discuss 
any publication with the sponsor prior to release and obtain written consent of the sponsor on the 
intended publication. The sponsor recognizes the right of the investigator to publish the results 
upon completion of the study. However, the investigator must send a draft manuscript of the 
publication or abstract to the sponsor thirty days in advance of submission in order to obtain 
approval prior to submission of the final version for publication. This will be reviewed promptly 
and approval will not be withheld unreasonably. In case of a difference of opinion between the 
sponsor and the investigator(s), the contents of the publication will be discussed in order to find a 
solution that satisfies both parties. 
 
The investigator is encouraged to participate in the evaluation of the data for scientific purposes 
but is expected to work with the sponsor in the development of any scientific presentation or 
publication. Since the sponsor authors will be included, it is expected that all co-authors of the 
manuscripts will have an opportunity for feedback in the content and conclusions. The technical 
and editorial resources of the sponsor will be available to assist in the development of abstracts, 
presentations, and publications regarding this study and it is expected that drafts will be sent to the 
sponsor with adequate time for input and revisions prior to submission.  
 

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9. 
REFERENCES  
 
Wei N, Delauter SK, and J Beard S. Arthroscopic debridement and visco-supplementation: a 
minimally invasive treatment for symptomatic osteoarthritis involving the base of the thumb. J 
Clin Rheumatol. 2002 Jun;8(3):125-9. 
 
Conaghan PG and Brooks P. How to manage musculoskeletal conditions. Best Pract Res Clin 
Rheumatol. 2008 Jun;22(3):387-94. 
 
Maetzel A. Defining therapeutic success in rheumatoid arthritis clinical trials: from statistical 
significance to clinical significance. J Rheumatol. 2004 Mar;31(3):411-2. 
 
Wysocka A, Mann K, Bursig H, Dec J, and Gaździk TS. Chondrocyte suspension in fibrin glue. 
Cell Tissue Bank. 2010 May;11(2):209-15.  
 
Hahn DB, Aanstoos ME, and Wilkins RM. Osteochondral lesions of the talus treated with fresh 
talar allografts. Foot Ankle Int. 2010 Apr;31(4):277-82. 
 
Zuk PA. The adipose-derived stem cell: looking back and looking ahead. Mol Biol Cell. 2010 Jun 
1;21(11):1783-7.  
 
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, 
Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, and 
Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature. 2002 
Jul 4;418(6893):41-9.  
 
Strem BM, Hicok KC, Zhu M, Wulur I, Alfonso Z, Schreiber RE, Fraser JK, and Hedrick MH. 
Multipotential differentiation of adipose tissue-derived stem cells. Keio J Med. 2005 
Sep;54(3):132-41. 
 
 
 
 

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APPENDICES  
 
Appendix 1. Laboratory Parameters 
 
Appendix 2. Kellgren-Lawrence Grading Scale 
 
Appendix 3. WOMAC (Western Ontario and McMaster Universities Arthritis Index) 
 
Appendix 4. VAS (Visual Analogue Scale) for Pain 
 
Appendix 5. Lysholm Knee Scale 
 
Appendix 6. KOOS (Knee Injury & Osteoarthritis Outcome Score) 
 
Appendix 7. International Knee Documentation Committee (IKDC) Subjective Knee Evaluation 
 
Appendix 8. RAND 36 Questionnaires 
 
Appendix 9. MRI Final Evaluation  
 
 
 
 
 
 

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Appendix 1. Laboratory Parameters 
 
Blood and urine samples for complete laboratory evaluation (hematology, serum chemistry, and 
urinalysis) at Visits 1, 3, 4, 5, 6, 7 and 8 (Screening, Baseline, M1, M3, M6, M9 and M12) or Early 
Termination or Final Follow-up Visit.   
 
HEMATOLOGY 
CHEMISTRY 
URINALYSIS 
Hemoglobin 
Hematocrit 
RBC 
WBC 
MCV 
MCH 
MCHC 
Neutrophils (absolute) 
Lymphocytes (absolute) 
Monocytes (absolute) 
Eosinophils (absolute) 
Basophils (absolute) 
Platelets 
PT-INR 
Total bilirubin 
Alkaline phosphatase 
ALT (SGPT) 
AST (SGOT) 
Blood urea nitrogen (BUN) 
Creatinine 
Glucose 
Albumin 
Total protein 
Sodium 
Potassium 
Chloride 
Bicarbonate 
Calcium 
HCG *  
HIV ** 
 
Color 
Appearance 
Specific gravity 
pH  
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Leukocyte esterase 
WBC 
RBC 
Epithelial cell 
Bacteria 
Hyaline casts 
 
 
*  HCG (pregnancy test) only for all females of childbearing potential (please refer to the relevant inclusion 
criteria) at Visits 1, 6 and 8 or Early Termination or Final Follow-Up Visit. 
**  Visit 1 only 
 

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Appendix 2. Kellgren-Lawrence Grading Scale 
 
Kellgren-Lawrence Grading Scale 
 
The Kellgren-Lawrence grading system is radiological classification of knee osteoarthritis. It is based on 
x-rays and consists of normal, Grade 1, Grade 2, Grade 3, and Grade 4. 
 
Grade 1:  Unlikely narrowing of the joint space, possible osteophytes 
Grade 2:  Small osteophytes, possible narrowing of the joint 
Grade 3:  Multiple, moderately sized osteophytes, definite joint space narrowing, some sclerotic areas, 
possible deformation of bone ends 
Grade 4:  Multiple large osteophytes, severe joint space narrowing, marked sclerosis and definite bony 
end deformity. 
 
 
 

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Appendix 3. WOMAC (Western Ontario and McMaster Universities Arthritis Index) 
 
Section A 
 
PAIN 
 
Think about the pain you felt in your                             (study joint) caused by your arthritis 
during the last 48 hours. 
 
(Please mark your answers with an “x”.) 
QUESTION: How much pain have you had … 
 
1. when walking on a flat surface?  
none          mild          moderate          severe          extreme     
☐              ☐ 
            ☐                  ☐                 ☐ 
 
 
2. when going up or down stairs? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
3. at night while in bed? (that is – pain that disturbs your sleep) 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
4. while sitting or lying down? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
5. while standing? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
Study Coordinator 
Use Only 
 
 
PAIN1     __________ 
 
 
 
 
PAIN2     __________ 
 
 
 
 
PAIN3     __________ 
 
 
 
 
PAIN4     __________ 
 
 
 
 
PAIN5     __________ 
 
 
 
 
 
 
 
 
 
 

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Section B 
 
STIFFNESS 
 
Think about the stiffness (not pain) you felt in your                             (study joint) caused by your 
arthritis during the last 48 hours. 
 
Stiffness is a sensation of decreased ease in moving your joint. 
 
(Please mark your answers with an “x”.) 
 
6. How severe has your stiffness been after you first woke up  
in the morning? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
 
 
 
7. How severe has your stiffness been after sitting or lying down or 
while resting later in the day? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
Study Coordinator 
Use Only 
 
 
STIFF6    __________ 
 
 
 
 
 
 
 
 
STIFF7    __________ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Section C 
 
DIFFICULTY PERFORMING DAILY ACTIVITIES 
 
Think about the difficulty you had in doing the following daily physical activities caused by the 
arthritis in your                             (study joint) during the last 48 hours. By this we mean your 
ability to move around and take care of yourself. 
 
(Please mark your answers with an “x”.) 
QUESTION: How much difficulty have you had … 
 
8. when going down the stairs?  
none          mild          moderate          severe          extreme     
☐              ☐ 
            ☐                  ☐                 ☐ 
 
 
9. when going up the stairs? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
10. when getting up from a sitting position? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
11. while standing? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
12. when bending to the floor? 
none          mild          moderate          severe          extreme     
☐              ☐ 
            ☐                  ☐                 ☐ 
 
 
13. when walking on a flat surface? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
Study Coordinator 
Use Only 
 
 
PFTN8     __________ 
 
 
 
 
PFTN9     __________ 
 
 
 
 
PFTN10   __________ 
 
 
 
 
PFTN11   __________ 
 
 
 
 
PFTN12   __________ 
 
 
 
 
PFTN13   __________ 
  
  
 
 
 
 
 
 

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DIFFICULTY PERFORMING DAILY ACTIVITIES 
 
Think about the difficulty you had in doing the following daily physical activities caused by the 
arthritis in your                             (study joint) during the last 48 hours. By this we mean your 
ability to move around and take care of yourself. 
 
(Please mark your answers with an “x”.) 
QUESTION: How much difficulty have you had … 
 
14. getting in or out of a car, or getting on or off a bus?  
none          mild          moderate          severe          extreme     
☐              ☐ 
            ☐                  ☐                 ☐ 
 
 
15. while going shopping? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
16. when putting on your socks or panty hose or stockings? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
17. when getting out of bed? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
18. when taking off your socks or panty hose or stockings? 
none          mild          moderate          severe          extreme     
☐              ☐ 
            ☐                  ☐                 ☐ 
 
 
19. while lying in bed? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
Study Coordinator 
Use Only 
 
 
PFTN14   __________ 
 
 
 
 
PFTN15   __________ 
 
 
 
 
PFTN16   __________ 
 
 
 
 
PFTN17   __________ 
 
 
 
 
PFTN18   __________ 
 
 
 
 
PFTN19   __________ 
  
 
 
 
 
 
 
 
 

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DIFFICULTY PERFORMING DAILY ACTIVITIES 
 
Think about the difficulty you had in doing the following daily physical activities caused by the 
arthritis in your                             (study joint) during the last 48 hours. By this we mean your 
ability to move around and take care of yourself. 
 
(Please mark your answers with an “x”.) 
QUESTION: How much difficulty have you had … 
 
20. when getting in or out of the bathtub?  
none          mild          moderate          severe          extreme     
☐              ☐ 
            ☐                  ☐                 ☐ 
 
 
21. while sitting? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
22. when getting on or off the toilet? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
23. while doing heavy household chores? 
none          mild          moderate          severe          extreme     
  ☐              ☐ 
            ☐                  ☐                 ☐ 
 
24. while doing light household chores? 
none          mild          moderate          severe          extreme     
☐              ☐ 
            ☐                  ☐                 ☐ 
 
Study Coordinator 
Use Only 
 
 
PFTN20   __________ 
 
 
 
 
PFTN21   __________ 
 
 
 
 
PFTN22   __________ 
 
 
 
 
PFTN23   __________ 
 
 
 
 
PFTN24   __________ 
 
 
 
 
Study Coordinator: 
 
 
Signature: __________________________ Date: __________________ 
 
 
 
 
 

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Appendix 4. VAS (Visual Analogue Scale) for Pain 
 
Site No: __ 
Subject No: __ __ 
Subject Initials: __ __ __ 
 
Visit (circle one):   Baseline    M1    M3    M6    M9    M12    ET (      /        /         )    Final FU (      /        /         ) 
                                                                 
 
Pain 100mm Visual Analogue Scale 
 
Please mark on the scale below how you feel your pain rates today as the following example: 
 
Example: 
 
  
 
 No Pain                                                                        Worst Pain Ever 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
      0         
 
 
 
 
 
 
  100 (mm)  
 
 
 
 
 
                                                                        Marked Length (mm)   _______________ 
 
 
Study Coordinator: 
 
 
Signature: __________________________ Date: __________________ 
 
 
No Pain 
Worst pain ever 

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Appendix 5. Lysholm Knee Scale 
 
Site No: __ 
Subject No: __ __ 
Subject Initials: __ __ __ 
 
Visit (circle one):   Baseline    M1    M3    M6    M9    M12    ET (      /        /         )    Final FU (      /        /         ) 
 
This questionnaire has been designed to give your Physical Therapist information as to how your knee pain has 
affected your ability to manage everyday life. Below are common complaints that people frequently have with their 
knee problems. Please answer every section and mark only ONE box which best describes your condition at this 
moment.  
 
I. LIMP: 
 ___ I have no limp when I walk. (5) 
 ___ I have a slight or periodical limp when I walk. (3) 
 ___ I have a severe and constant limp when I walk. (0)  
 
II. USING CANE OR CRUTCHES:  
___ I do not use a cane or crutches. (5)  
___ I use a cane or crutches with some weight-bearing. (2) 
___ Putting weight on my hurt leg is impossible. (0)  
 
III. LOCKING SENSATION IN THE KNEE:  
___ I have no locking and no catching sensations in my knee. (15)  
___ I have catching sensations but no locking sensations in my knee. (10) 
___ My knee locks occasionally. (6)  
___ My knee locks frequently. (2)  
___ My knee feels locked at this moment. (0)  
 
IV. GIVING WAY SENSATION FROM THE KNEE:  
___ My knee never gives way. (25)  
___ My knee rarely gives way only during athletics or other vigorous activities. (20)  
___ My knee frequently gives way during athletics or other vigorous activities and in turn, I am unable to participate 
in these activities. (15)  
___ My knee often gives way during daily activities. (5)  
___ My knee gives way every step I take. (0)  
 
V. PAIN:  
___ I have no pain in my knee. (25)  
___ I have intermittent or slight pain in my knee during vigorous activities. (20)  
___ I have marked pain in my knee during vigorous activities. (15)  
___ I have marked pain in my knee during or after walking more than 1 mile. (10)  
___ I have marked pain in my knee during or after walking less than 1 mile. (5)  
___ I constant pain in my knee. (0)  
 
VI. SWELLING:  
___ I have no swelling in my knee. (10)  
___ I have swelling in my knee only after vigorous activities. (6)  
___ I have swelling in my knee after ordinary activities. (2)  
___ I have swelling constantly in my knee. (0)  
 

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VII. CLIMBING STAIRS:  
___ I have no problems climbing stairs. (10)  
___ I have slight problems climbing stairs. (6) 
___ I can climb stairs only one at a time. (2)  
___ Climbing stairs is impossible for me. (0)  
 
VIII. SQUATTING:  
___ I have no problems squatting. (5)  
___ I have slight problems squatting. (4) 
___ I cannot squat beyond a 90 degree bend in my knee. (2) 
___ Squatting is impossible because of my knee(s). (0)  
 
 
Thank you very much for completing all the questions in this questionnaire. 
 
_____________________________________________________________________________________________ 
 
Score (by Study Coordinator): 
 
 
TOTAL: _________ (Maximum: 100) 
 
 
 
Signature: __________________________ Date: __________________ 
 
 

J S -O A P 2 -U S 0 1  
V er si o n 7. 0, M a y 1 4, 2 0 1 8  
 
P a g e 5 8  of 6 6  
 
 
C O N FI D E N TI A L  
N at ur e C ell C o., Lt d.
 
A p pe n di x 6. K O O S ( K nee I nj ur y & Oste o a rt hritis O utc o me Sc ore)  
 
Site N o: _ _  
S u bject N o : _ _ _ _  
S u bject I niti als: _ _ _ _ _ _  
 
Visit  (circle o ne):   B aseli ne     M 1    M 3    M 6    M 9    M 1 2    E T (      /        /         )    Fi n al F U (      /        /         )  
 
I N S T R U C TI O N S:  
T his s ur ve y as ks f or y o ur vie w a b o ut y o ur k nee. T his i nf or mati o n will hel p us kee p trac k of h o w y o u feel a b o ut y o ur 
k nee a n d h o w well y o u are a ble t o perf or m y o ur us ual acti vities. A ns wer e ver y q uesti o n b y tic ki n g t he a p pr o priate 
b o x, o nl y o ne  b o x f or eac h q uesti o n. If y o u are u ns ure a b o ut h o w t o a ns wer a q uesti o n, pl ease gi ve t he best a ns wer 
y o u ca n.  
 
S Y M P T O M S  
 
T hese q uesti o ns s h o ul d be a ns were d t hi n ki n g of y o ur k nee s y m pt o ms d uri n g t he l ast w ee k. 
 
 
 
0  
1  
2  
3  
4  
S 1  D o y o u ha ve s welli n g i n y o ur k nee?  
� Ne ver  � Rarel y  � S o meti mes  � Ofte n  � Al wa ys  
S 2  D o y o u feel gri n di n g, hear clic ki n g or a n y ot her t y pe 
of n oise w he n y o ur k nee m o ves?  
� Ne ver  � Rarel y  � S o meti mes  � Ofte n  � Al wa ys  
S 3  D oes y o ur k nee catc h or ha n g u p w he n m o vi n g?  
� Ne ver  � Rarel y  � S o meti mes  � Ofte n  � Al wa ys  
S 4  Ca n y o u strai g hte n y o ur k nee f ull y?  
� Ne ver  � Rarel y  � S o meti mes  � Ofte n  � Al wa ys  
S 5  Ca n y o u be n d y o ur k nee f ull y?  
� Ne ver  � Rarel y  � S o meti mes  � Ofte n  � Al wa ys  
 
Stiff ness: T he f oll o wi n g q uesti o ns c o ncer n t he a m o u nt of j oi nt stiff ness y o u ha ve e x perie nce d d uri n g t he l ast w ee k 
i n y o ur k nee. Stiff ness is a se nsati o n of restricti o n or sl o w ness i n t he ease wit h w hic h y o u m o ve y o ur k nee j oi nt. 
 
 
 
0  
1  
2  
3  
4  
S 6  H o w se vere is y o ur k nee j oi nt stiff ness after first 
wa ke ni n g i n t he m or ni n g?  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
S 7  H o w se vere is y o ur k nee stiff ness after sitti n g, l yi n g 
or resti n g later i n t he da y?  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
 
P AI N  
 
 
 
0  
1  
2  
3  
4  
P 1  H o w ofte n d o y o u e x perie nce k nee pai n?  
� Ne ver  � M o nt hl y  � W ee kl y  
� Dail y  � Al wa ys  
 
W hat a m o u nt of k nee pai n ha ve y o u e x perie nce d t he last wee k d uri n g t he f oll o wi n g acti vities?  
 
 
 
0  
1  
2  
3  
4  
P 2  T wisti n g/ pi v oti n g o n y o ur k ne e  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
P 3  Strai g hte ni n g k nee f ull y  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
P 4  B e n di n g k nee f ull y  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
P 5  W al ki n g o n flat s urface  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
P 6  G oi n g u p or d o w n stairs  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
P 7  At ni g ht w hile i n be d  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
P 8  Sitti n g or l yi n g  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
P 9  Sta n di n g u pri g ht  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  

J S -O A P 2 -U S 0 1  
V er si o n 7. 0, M a y 1 4, 2 0 1 8  
 
P a g e 5 9  of 6 6  
 
 
C O N FI D E N TI A L  
N at ur e C ell C o., Lt d.
 
A D L  
 
F u ncti o n, d ail y li vi n g : T he f oll o wi n g q uesti o ns c o ncer n y o ur p h ysical f u ncti o n. B y t his we mea n y o ur a bilit y t o m o ve 
ar o u n d a n d t o l o o k after y o urs elf. F or eac h of t he f oll o wi n g acti vities please i n dicate t he d e gree of diffic ult y y o u ha ve 
e x perie nce d i n t he l ast w ee k d ue t o y o ur k nee.  
 
 
 
0  
1  
2  
3  
4  
A 1  Desce n di n g stairs  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 2  Asce n di n g stairs  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
 
F or eac h of t he f oll o wi n g acti vities please i n dicate t he de gre e of diffic ult y y o u ha ve e x perie nce d i n t he last wee k d ue 
t o y o ur k nee. 
 
 
 
0  
1  
2  
3  
4  
A 3  Risi n g fr o m sitti n g  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 4  Sta n di n g  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 5  B e n di n g t o fl o or/ pic k u p a n o bj ect  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 6  W al ki n g o n flat s urface  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 7  Getti n g i n/ o ut of car  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 8  G oi n g s h o p pi n g  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 9  P utti n g o n s oc ks/st oc ki n gs  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 1 0  Risi n g fr o m be d  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 1 1  T a ki n g off s oc ks/st oc ki n gs  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 1 2  L yi n g i n be d (t ur ni n g o ver, mai ntai ni n g k nee 
p ositi o n)  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 1 3  Getti n g i n/ o ut of bat h  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 1 4  Sitti n g  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 1 5  Getti n g o n/ off t oilet  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
 
F or eac h of t he f oll o wi n g acti vities please i n dicate t he de gre e of diffic ult y y o u ha ve e x perie nce d i n t he last wee k d ue 
t o y o ur k nee. 
 
 
 
0  
1  
2  
3  
4  
A 1 6  Hea v y d o mestic d uties ( m o vi n g hea v y b o xes, 
scr u b bi n g fl o ors, etc.) 
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
A 1 7  Li g ht d o mestic d uties (c o o ki n g, d usti n g, etc.) 
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
 
S P O R T/ R E C  
 
F u ncti o n, s p orts a n d recre ati o n al acti vities  
T he f oll o wi n g q uesti o ns c o nc er n y o ur p h ysical f u ncti o n w h e n bei n g acti ve o n a hi g her le vel. T he q uesti o ns s h o ul d 
be a ns were d t hi n ki n g of w hat de gree of diffic ult y y o u ha ve e x perie nce d d uri n g t he  l ast wee k d ue t o y o ur k nee.  
 
 
 
0  
1  
2  
3  
4  
S P 1  S q uatti n g  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
S P 2  R u n ni n g  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
S P 3  J u m pi n g 
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
S P 4  T wisti n g/ pi v oti n g o n y o ur i nj ure d k nee  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  
S P 5  K neeli n g  
� N o ne  � Mil d  
� M o derate  � Se vere  � E xtre me  

J S -O A P 2 -U S 0 1  
V er si o n 7. 0, M a y 1 4, 2 0 1 8  
 
P a g e 6 0  of 6 6  
 
 
C O N FI D E N TI A L  
N at ur e C ell C o., Lt d.
 
 
Q U AI T Y O F LI F E  
 
 
 
0  
1  
2  
3  
4  
Q 1  H o w ofte n are y o u a ware of y o ur k nee 
pr o ble m?  
� Ne ver  
� 
M o nt hl y  
� W ee kl y  
� Dail y  
� C o nsta ntl y  
Q 2  Ha ve y o u m o difie d y o ur life st yle t o a v oi d 
p ote ntiall y da ma gi n g acti vities t o y o ur 
k nee?  
� N ot at all  � Mil dl y  � M o deratel y  � Se verel y  � T otall y  
Q 3  H o w m uc h are y o u tr o u ble d wit h lac k of 
c o nfi de nce i n y o ur k nee?  
� N ot at all  � Mil dl y  � M o deratel y  � Se verel y  � E xtre mel y  
Q 4  I n ge neral, h o w m uc h diffic ult y d o y o u 
ha ve wit h y o ur k nee?  
� N o ne  
� Mil d  
� M o derate  
� Se vere  
� E xtre me  
 
 
T ha n k y o u ver y m uc h f or c o m pleti n g all t he q uesti o ns i n t his q uesti o n naire.  
 
_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
S c ore ( b y S t u d y C o or di n at or): 
 
 
K O O S S y m pt o ms  
1 0 0 – ( Mea n sc ore of S 1 t o S 7 _ _ _ _ _ _ _ _ _ x 2 5)  =  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
K O O S Pai n   
  
1 0 0 – ( Mea n sc ore of P 1 t o P 9 _ _ _ _ _ _ _ _ _ x 2 5)  =  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
K O O S A D L   
  
1 0 0 – ( Mea n sc ore of A 1 t o A 1 7 _ _ _ _ _ _ _ _ _ x 2 5)  =  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
K O O S S p ort/ Rec   
1 0 0 – ( Mea n sc ore of S P 1 t o S P 5 _ _ _ _ _ _ _ _ _ x 2 5)  =  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
K O O S Q O L   
  
1 0 0 – ( Mea n sc ore of Q 1 t o Q 4 _ _ _ _ _ _ _ _ _ x 2 5)  =  _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ 
 
 
 
Si g nat ure: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ Date: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 

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Appendix 7. International Knee Documentation Committee (IKDC) Subjective Knee 
Evaluation 
 
Site No: __ 
Subject No: __ __ 
Subject Initials: __ __ __ 
 
Visit (circle one):   Baseline    M1    M3    M6    M9    M12    ET (      /        /         )    Final FU (      /        /         ) 
 
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? 
4  Very strenuous activities like jumping or pivoting as in basketball or soccer 
3  Strenuous activities like heavy physical work, skiing or tennis 
2  Moderate activities like moderate physical work, running or jogging 
1  Light activities like walking, housework or yard work 
0  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? 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
Never 
 
 
 
 
 
 
 
 
 
 
   Constant 
 
3. If you have pain, how severe is it? 
    
  0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
No pain   
 
 
 
 
 
 
 
 
 
  Worst pain 
 
 
4. During the past 4 weeks, or since your injury, how stiff or swollen was your knee? 
4  Not at all 
3  Mildly 
2  Moderately 
1  Very 
0  Extremely 
 
5. What is the highest level of activity you can perform without significant swelling in your knee? 
4  Very strenuous activities like jumping or pivoting as in basketball or soccer 
3  Strenuous activities like heavy physical work, skiing or tennis 
2  Moderate activities like moderate physical work, running or jogging 
1  Light activities like walking, housework, or yard work 
0  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? 
0 Yes    1 No 
 
7. What is the highest level of activity you can perform without significant giving way in your knee? 
4  Very strenuous activities like jumping or pivoting as in basketball or soccer 
3  Strenuous activities like heavy physical work, skiing or tennis 
2  Moderate activities like moderate physical work, running or jogging 
1  Light activities like walking, housework or yard work 
0  Unable to perform any of the above activities due to giving way of the knee 

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SPORTS ACTIVITIES: 
 
8. What is the highest level of activity you can participate in on a regular basis? 
4  Very strenuous activities like jumping or pivoting as in basketball or soccer 
3  Strenuous activities like heavy physical work, skiing or tennis 
2  Moderate activities like moderate physical work, running or jogging 
1  Light activities like walking, housework or yard work 
0  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 
4  
3  
2  
1  
0  
b. Go down stairs 
4  
3  
2  
1  
0  
c. Kneel on the front of your knee 
4  
3  
2  
1  
0  
d. Squat 
4  
3  
2  
1  
0  
e. Sit with your knee bent 
4  
3  
2  
1  
0  
f. Rise from a chair 
4  
3  
2  
1  
0  
g. Run straight ahead 
4  
3  
2  
1  
0  
h. Jump and land on your involved leg 
4  
3  
2  
1  
0  
i. Stop and start quickly 
4  
3  
2  
1  
0  
 
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  
 
 
 
                     No limitation daily activities 
 0 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
10    
 
 
 
 
 
 
 
 
 
 
    
 
CURRENT FUNCTION OF YOUR KNEE: 
Cannot perform daily activities  
 
 
 
                     No limitation daily activities 
 
 0 
 1 
 2 
 3 
 4 
 5 
 6 
 7 
 8 
 9 
10    
 
 
 
 
 
 
 
 
 
 
    
 
Thank you very much for completing all the questions in this questionnaire. 
_____________________________________________________________________________________________ 
 
Score (by Study Coordinator)  
 
IKDC Score = (Sum of Items: ___________ ) / (Maximum Possible Score: 87) x 100 = __________________ 
 
* The response to Item 10a is not included in the overall score.  
 
Signature: __________________________ Date: __________________ 

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CONFIDENTIAL 
Nature Cell Co., Ltd. 
Appendix 8. RAND 36 Questionnaires 
 
Site No: __ 
Subject No: __ __ 
Subject Initials: __ __ __ 
 
Visit (circle one):   Baseline     M3     M6    M9     M12     ET (      /        /         )     Final FU (      /        /         ) 
 
1.  In general, would you say your health is: (circle one) 
     Excellent (1)   Very good (2)   Good (3)   Fair (4)   Poor (5) 
 
2.  Compared to one year ago, how would you rate your health in general now? (circle one) 
     Much better now than one year ago (1) 
Somewhat better now than one year ago (2) 
    About the same as one year ago (3) 
Somewhat worse than one year ago (4) 
 
 Much worse than one year ago (5) 
 
The following items are about activities you might do during a typical day. Does your health now limit you in these 
activities? If so, how much? (circle one number on each line) 
 
ACTIVITIES 
Yes, Limited 
A Lot 
Yes, Limited 
A Little 
No, Not 
Limited At All 
3. Vigorous activities, such as running, lifting heavy 
objects, participating in strenuous sports 
1 
2 
3 
4. Moderate activities, such as moving a table, pushing a 
vacuum cleaner, bowling, or playing golf 
1 
2 
3 
5. Lifting or carrying groceries 
1 
2 
3 
6. Climbing several flights of stairs 
1 
2 
3 
7. Climbing one flight of stairs 
1 
2 
3 
8. Bending, kneeling or stooping 
1 
2 
3 
9. Walking more than a mile 
1 
2 
3 
10. Walking several blocks 
1 
2 
3 
11. Walking one block 
1 
2 
3 
12. Bathing or dressing yourself 
1 
2 
3 
 
During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities 
as a result of your physical health? (circle one number on each line) 
 
 
Yes 
No 
13. Cut down on the amount of time you spent on work or other activities 
1 
2 
14. Accomplished less than you would like 
1 
2 
15. Were limited in the kind of work or other activities 
1 
2 
16. Had difficulty performing the work or other activities (for example, it took extra effort) 
1 
2 
 
During the past 4 weeks, have you had any of the following problems with your work or other regular daily activities 
as a result of any emotional problems (such as feeling depressed or anxious)? (circle one number on each line) 
 
 
Yes 
No 
17. Cut down the amount of time you spent on work or other activities 
1 
2 

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CONFIDENTIAL 
Nature Cell Co., Ltd. 
18. Accomplished less than you would like 
1 
2 
19. Didn’t do work or other activities as carefully as usual 
1 
2 
 
20. During the past 4 weeks, to what extent has your physical health or emotional problems interfered with your 
normal social activities with family, friends, neighbors or groups? (circle one) 
Not at all (1)   Slightly (2)   Moderately (3)   Quite a bit (4)   Extremely (5) 
 
21. How much bodily pain have you had during the past 4 weeks? (circle one) 
None (1)   Very mild (2)   Mild (3)   Moderate (4)   Severe (5)   Very severe (6) 
 
22. During the past 4 weeks, how much did pain interfere with your normal work (including both work outside the 
home and housework)? 
Not at all (1)   A little bit (2)   Moderately (3)   Quite a bit (4)   Extremely (5) 
 
These questions are about how you feel and how things have been with you during the past 4 weeks. For each 
question, please give the one answer that comes closest to the way you have been feeling. How much of the time 
during the past 4 weeks… (circle one number on each line) 
 
 
All of 
the 
Time 
Most 
of the 
Time 
A Good 
Bit of the 
Time 
Some 
of the 
Time 
A Little 
of the 
Time 
None 
of the 
Time 
23. Did you feel full of pep? 
1 
2 
3 
4 
5 
6 
24. Have you been a very nervous person? 
1 
2 
3 
4 
5 
6 
25. Have you felt so down in the dumps that 
nothing could cheer you up? 
1 
2 
3 
4 
5 
6 
26. Have you felt calm and peaceful? 
1 
2 
3 
4 
5 
6 
27. Did you have a lot of energy? 
1 
2 
3 
4 
5 
6 
28. Have you felt downhearted and blue? 
1 
2 
3 
4 
5 
6 
29. Did you feel worn out? 
1 
2 
3 
4 
5 
6 
30. Have you been a happy person? 
1 
2 
3 
4 
5 
6 
31. Did you feel tired? 
1 
2 
3 
4 
5 
6 
 
32. During the past 4 weeks, how much of the time has your physical health or emotional problems interfered 
with your social activities (like visiting with friends, relatives, etc.)? (circle one) 
All of the time (1)  Most of the time (2)  Some of the time (3)  A little of the time (4)  None of the time (5) 
 
How TRUE or FALSE is each of the following statements for you? (circle one number on each line) 
 
 
Definitely 
True 
Mostly 
True 
Don’t 
Know 
Mostly 
False 
Definitely 
False 
33. I seem to get sick a little easier than other people 
1 
2 
3 
4 
5 
34. I am as healthy as anybody I know 
1 
2 
3 
4 
5 
35. I expect my health to get worse 
1 
2 
3 
4 
5 
36. My health is excellent 
1 
2 
3 
4 
5 
 
Thank you very much for completing all the questions in this questionnaire. 
 

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Nature Cell Co., Ltd. 
Scores (by Study Coordinator):  
 
Item Numbers 
Response 
Score 
 
Item Numbers 
Response 
Score 
1, 2, 20, 22, 34, 36 
1 
2 
3 
4 
5 
100 
75 
50 
25 
0 
 
32, 33, 35 
1 
2 
3 
4 
5 
0 
25 
50 
75 
100 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
1 
2 
3 
0 
50 
100 
 
13, 14, 15, 16, 17, 18, 19 
1 
2 
0 
100 
21, 23, 26, 27, 30 
1 
2 
3 
4 
5 
6 
100 
80 
60 
40 
20 
0 
 
24, 25, 28, 29, 31 
1 
2 
3 
4 
5 
6 
0 
20 
40 
60 
80 
100 
 
 
Items 
Score (Mean) 
Physical Functioning 
3, 4, 5, 6, 7, 8, 9, 10, 11, 12 
Total: _______ / 10 = ________ 
Role Limitation (Physical) 
13, 14, 15, 16 
Total: _______ / 4 = ________ 
Role Limitation (Emotional) 
17, 18, 19 
Total: _______ / 3 = ________ 
Energy/fatigue 
23, 27, 29, 31 
Total: _______ / 4 = ________ 
Emotional well-being 
24, 25, 26, 28, 30 
Total: _______ / 5 = ________ 
Social Functioning 
20, 32 
Total: _______ / 2 = ________ 
Pain 
21, 22 
Total: _______ / 2 = ________ 
General Health 
1, 2, 33, 34, 35, 36 
Total: _______ / 6 = ________ 
 
 
Signature: __________________________ Date: __________________ 
 
 

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CONFIDENTIAL 
Nature Cell Co., Ltd. 
Appendix 9. MRI Improvement Evaluation  
 
MRI Improvement Evaluation Form 
 
 
Protocol Number:  JS-OAP2-US01 
 
Site No. 
Subject No. 
Subject Initials 
 
 
 
 
 
  The time of Evaluation (from Baseline):  
 
 
From baseline at Month 6  
 
From baseline at Month 12 
 
 
 
  Principal Investigator's MRI Final Evaluation:  
 
▶ Please select one of 3 followings for MRI result at above checked time.       
 
 
 
ⓐ Improvement 
 
ⓑ No change 
 
ⓒ Progress 
 
            
 
  Evaluated by: 
 
Principal Investigator  
 
 
 
 
 
Name / Signature 
 
Date (DD-MMM-YYYY)