Clinical trial NCT02674399
Conditions: Osteoarthritis, Knee
Sponsor: Nature Cell Co. Ltd.
Start date: 2016-02-16; Completion date: 2018-12-28
Enrollment: 28 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
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). After each subject completes 6-month visit (Visit 6) and the data management team confirms all data have no issue, the individual database will be locked and the blinding will be open for the statistical analysis.Only subjects who are assigned will be requested to visit the study center for 9-month and 12-month follow-up visits (Visits 7 and 8). To see long-term effects of JointStem, all subjects who complete Visit 6 will be requested to visit the study center at 24-month after the injection.

Detailed description:

Arms: arm 1: autologous adipose tissue derived mesenchymal stem cells (AdMSC) arm 2: hyaluronic acid
Interventions: intervention 1: JointStem intervention 2: Synvisc-One
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
ICF_002.pdf: 
Nature Cell / Protocol Number JS-OAP2-US01 
Page 1 of 14 
 
Timothy Davis, MD 
Advarra IRB Approved Version 30 May 2018 
 
CONSENT TO TAKE PART IN A CLINICAL RESEARCH STUDY 
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
Sponsor / Study Title: 
  
Nature Cell / 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 
Principal Investigator: 
(Study Doctor) 
 
Timothy Davis, MD 
 
Telephone: 
 
(310) 574-2777 ext.8006 
(310) 574-2777 ext.8007 (24 Hour) 
 
Address: 
Orthopedic Pain Specialists 
2428 Santa Monica Blvd. 
Suite 208 
Santa Monica, CA  90404 
 
Orthopedic Pain Specialists 
1301 20th Street 
Suite 470 
Santa Monica, CA  90404 
 
 
Please read this form carefully.  Take time to ask the study doctor or study staff as many questions about 
the study as you would like.  The study doctor or study staff can explain words or information that you do 
not understand.  Reading this form and talking to the study doctor or study staff may help you decide 
whether to take part or not.  If you decide to take part in this study, you must sign your name at the end of 
this form.  You cannot take part in this research study until you sign this form. 
 
INTRODUCTION TO THE RESEARCH STUDY 
 
You are being asked to take part in this research study because you have knee osteoarthritis (OA). Please 
take your time in making your decision as to whether or not you wish to participate. Ask your study 
doctor or the study staff to explain any words or information contained in this informed consent document 
that you do not understand. You may also discuss the study with your friends and family. 
 
JointStem is an investigational drug developed by Nature Cell (NC), who is the sponsor of this study. An 
“investigational drug” is a drug that has not been approved by the U.S. Food and Drug Administration 
(FDA). Drugs that do not have approval by the FDA cannot be sold or prescribed by your physician.  
 
Taking part in this study is entirely voluntary. 
 
PURPOSE OF THE RESEARCH STUDY 
 
The main purpose of this research study is to see if JointStem is safe and effective for adults with knee 
osteoarthritis (OA).  
 


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INFORMATION ABOUT THE STUDY 
 
In this study, you will either receive the active study drug, JointStem, or an active comparator, a 
hyaluronic acid injection. The active comparator that will be used will be an FDA-approved hyaluronic 
injection that is believed to be a safe and effective treatment for OA. Please ask the study doctor or study 
staff if you have any questions about this active comparator.  
 
At your third visit, you will be randomized into one of the study groups described below. To be 
‘randomized’ means that you are put into a group by chance. It is like flipping a coin. You will have an 
equal chance of being in one of the two groups: 
 
• 
Group A: JointStem 
• 
Group B: Hyaluronic Acid  
 
During the study, neither you nor the study doctor will know nor get to choose which drug you are 
receiving (‘drug’ refers to the investigation drug [JointStem] and the active comparator [hyaluronic acid]). 
This is done so that a fair evaluation of results can be made. This information is available to the 
researchers if needed in an emergency. However, one physician that will be dedicated to making the 
injection will know what you are receiving, and therefore will not be making any assessments.  
 
However, after each subject completes the 6-month visit (Visit 6) the blinding will be open. Then, only 
subjects who were assigned to the JointStem group will continue to Visits 7 and 8 (9- and 12-month) and 
subjects who were assigned to the positive control group will end their participation in the study period.  
 
After the 1-year study period, for long-term follow- up visit, all subjects who completed the 6-month visit 
will be asked to visit the study site after 2 years from injection. 
 
If you decide to be in this study, you will have to stop using your regular medication for the treatment of 
OA. You will have to stop using any pain medication for osteoarthritis (except for rescue medication of 
3.25 g of acetaminophen per day, which is the only pain medication allowed to treat the pain arising from 
the patient’s osteoarthritis) 3 days before screening and until the last treatment visit. Also, you will not be 
allowed to receive any other treatment (including an intra-articular injection) in the affected joint during 
the entire study. If you stop your regular medication to be in the study, your OA symptoms might come 
back or your health might get worse.  
 
You will be in the study for about 8 to 14 months and make a total of 6 to 8 visits to the study site, 
depending on which group you are randomized into. For long-term follow- up visit, you will visit to the 
study site after 2 years from injection. 
 
30 people at 1 to 2 research sites will take part in this study, including up to all 30 people at this study 
site. In order to identify 30 subjects needed, we may need to screen as many as 60 because some people 
will not qualify to be included in the study. 
 
WHAT WILL HAPPEN DURING THE STUDY 
 
You will have the following visits: 
Visit 1 – Screening (Week -7) 
Visit 2 – Randomization and Harvesting (Week -5)  
Visit 3 – Baseline (Drug Administration) 
Visit 4 – Month 1 
Visit 5 – Month 3 


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Visit 6 – Month 6  
Visit 7 – Month 9 
Visit 8 – Month 12 
Long-term Follow-up Visit - Month 24 (Month ±2)  
 
At your first study visit, the study doctor or study staff will talk to you about the study. Then, you will be 
asked to sign this form, which will give the study doctor and the study staff the permission to begin the 
screening procedure to see if you qualify to be in the study. If the study doctor says you can be in the 
study and you want to be in the study, you will come in after about 2 weeks for a second visit and be 
randomized into one of the two treatment groups.  
 
At your second visit, you will be randomized into either JointStem or active control group. Then, you will 
undergo a liposuction procedure to harvest cells that will be used to manufacture the study drug, 
JointStem. You will only receive the JointStem injection, if you are randomized into the JointStem group. 
 
Then you will return to the clinic in about 5 weeks for the injection of the final drug product. This will 
either be the JointStem injection or the hyaluronic acid injection, depending on your assignment.  
 
Following the one-time injection, you will visit the site for various tests and procedures at Month 1, 3 and 
6. After Month 6, you will be asked to come in at Month 9 and Month 12 to make sure that you have no 
health problems (JointStem group only).  
 
For long-term follow- up visit, you will visit to the study site at Month 24 if you completed the 6-month 
visit and accepted the long term follow up visit. 
 
If you take part in this study, you will have the following tests and procedures: 
 
• 
Medical and Medication History: Ask you to answer questions about your health, your medical 
history, and the medications you take. This will be performed during the screening period. This is 
a part of the standard of care. 
• 
Demographic Questions: Ask you to give personal information, such as your date of birth, race, 
heights, and weight. This will be performed during the screening period. This is a part of the 
standard of care. 
• 
Physical Examination: You should ask the study doctor about what will happen during this exam. 
This will be performed during the screening period, Visits 3, 5, 6, 7 and 8 and early termination 
visit or final follow-up visit (if applicable). This is a part of the standard of care. 
• 
Vital Signs and Weight: Check your blood pressure by putting a band around your arm (this will 
squeeze your arm for about a minute), check your pulse, listen to you breathe in and out, and take 
your temperature. Get your weight measured. This will be performed at every visit. This is a part 
of the standard of care. 
• 
Hematology and Serum Chemistry: Take blood samples for laboratory tests. This will be 
performed during the screening period, Visits 3, 4, 5, 6, 7 and 8 and early termination visit or 
final follow-up visit (if applicable). This is for investigational purpose.  These tests will include 
HIV test for Screening.  Positive results will be reported to the appropriate regulatory agency. 
• 
Urinalysis: Take a urine sample to do laboratory tests. This will be performed during the 
screening period, Visits 3, 4, 5, 6, 7 and 8 and early termination visit or final follow-up visit (if 
applicable). This is for investigational purpose. 
• 
Pregnancy Testing (females only): Test your blood to see if you are pregnant. The study doctor or 
study staff will tell you if the pregnancy test results are positive. The results of the pregnancy test 
must be negative in order for you to be in the study. This will be performed during the screening 


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period, Visits 6, 8 and early termination visit or final follow-up visit (if applicable). This is a part 
of the standard of care. 
• 
Electrocardiogram: An electrocardiogram (ECG) measures the electrical activity of your heart. 
This will be performed during the screening period, Visits 3, 6, 8 and early termination visit or 
final follow-up visit (if applicable). This is for investigational purpose. 
• 
X-ray: Take an x-ray image of your knee for radiological classification of your knee 
osteoarthritis. This will be performed during the screening period. This is part of the standard of 
care.  
• 
Liposuction: Harvest adipose tissue (fat cells) from your abdomen from which to isolate the stem 
cells for the study treatment. This will be performed during Visit 2. This is for investigational 
purpose.  
• 
Injection of Drug Product: Receive a single intra-articular injection of either the study drug or the 
active comparator in the knee. This will be performed during Visit 3. This is for investigational 
purpose.  
• 
MRI Scan: Take an MRI scan of your knee to measure the damaged cartilage area. This will be 
performed during the screening period, Visits 6 and 8 and early termination visit or final follow-
up visit (if applicable). This is part of the standard of care.   
• 
Questionnaires: Ask you to fill out questionnaires about your health, quality of life and the study 
drug. This will be performed at Visits 3 through 8 and early termination visit or final follow-up 
visit (if applicable). This is for investigational purpose.   
 
For long term follow-up, records of treatments and medications since the last visit will be collected. 
 
You will have approximately 2 - 4 teaspoons (10 – 20 ml) of blood withdrawn from a vein eight times 
throughout the study. The total amount of blood withdrawn during the study will be approximately 18 
teaspoons. 
 
During this study, you may leave the study at any time. Leaving the study will not result in any penalty or 
loss of benefits to which you are entitled. If you decide to stop participating in the study we encourage 
you to talk to the study doctor or study staff first to learn about any potential health or safety 
consequences. To help you leave the study safely, the study doctor may ask you to participate in more 
tests. The study doctor also has the right to stop your participation in the study at any time. This could be 
because it is in your best medical interest, your condition worsens, new information becomes available, 
you have an unexpected reaction, you fail to follow instructions, or because the entire study has been 
stopped.  
 
You will be given any new information we become aware of that would affect your willingness to 
continue to participate in the study. 
 
YOUR ROLE IN THE STUDY 
 
Taking part in a research study can be an inconvenience to your daily life.  Please consider the study time 
commitments and responsibilities as a research subject when you are deciding to take part.  Your 
responsibilities as a study subject include the following: 
 
• 
Tell the truth about your medical history and current conditions. 
• 
Tell the study doctor if you have been in a research study in the last 30 days or are in another 
research study now. 
• 
Tell the study doctor about any problems you have during the study. 
• 
Allow the study doctor to make the one-time injection of the study drug into your knee.  


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• 
The study doctor or study staff will talk to you about any food or medicines that you should not 
take while in this study. 
 
RISKS OF THE STUDY 
 
Being in this study involves some risk to you. You should discuss the risk of being in this study with the 
study staff. 
 
Effects of Condition Being Studied (osteoarthritis) 
• 
Pain 
• 
Tenderness 
• 
Stiffness 
• 
Loss of flexibility 
• 
Grating sensation 
• 
Bone spurs 
• 
Crackles 
• 
Swelling 
• 
Joint deformity 
• 
Limping 
 
Risks of Study Drug (Investigational Drug – JointStem Injection) 
 
In previous clinical trials, the risks and side effects possibly related to the drug we are studying included: 
• 
Inflammation, pain, infection and/or allergic reaction at the site of injection 
• 
Hematoma, cellulitis, deep vein thrombosis, rash, fever, edema (swelling), non-functioning tumor 
promotion, diabetic retinopathy growth, and worsening of artherosclerosis (hardening of the 
arteries) 
• 
Cold, urinary stone, chest discomfort, toothache, dry cough, backache, hypertriglyceridemia 
(elevated triglyceride levels), migraine 
• 
Rhinopharyngitis (common cold), musculoskeletal/connective tissue disease, arthralgia (joint 
pain), lower back pain, gastrointestinal disease, metabolic or nutritional disease, 
hypertriglyceridemia (high levels of triglycerides in the blood), nervous disease, headache, 
urinary system disease, breathing issues, chest and mediastinal (a part of the chest) disease 
 
Risks of Study Drug (Active Comparator – Synvisc-One® Injection) 
 
Known risks/side effects for the active comparator include the following: 
• 
Pain 
• 
Swelling 
• 
Heat 
• 
Redness 
• 
Fluid build-up in/around knee 
• 
Hypersensitivity 
• 
Mild bruising 
• 
Temporary achy feeling 
• 
Temporary knee inflammation 
 
 
 


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Risks Associated with Procedures 
 
Taking part in this research study may involve providing information that you consider confidential or 
private. Efforts, such as coding research records, keeping research records secure and allowing only 
authorized people to have access to research records, will be made to keep your information safe. In 
addition, there is a slight risk of a breach of confidentiality. We will do our best to protect your 
confidential information.   
 
During blood drawing, you may experience discomfort, pain, bruising and/or bleeding where the needle is 
inserted. Occasionally some people become dizzy lightheaded or feel faint. Infection may occur on rare 
occasions.  Frequent donation of blood can result in low iron in your blood (iron deficient anemia).   
 
For the liposuction procedure, you may experience discomfort, pain, bruising and/or bleeding for the local 
anesthesia and the fat harvesting process. We will do our best to ensure that the surgical conditions are 
sterile and safe and that the physician performing the liposuction is qualified. For more information, 
please consult the study physician or staff.  
 
For the drug administration procedure, which involves an intra-articular (into the joint) injection of the 
investigational or the active comparator drug to the knee, one study physician dedicated to making the 
injection will make the injection, while hiding which treatment you are receiving (for example, by 
blindfolding). You may experience discomfort, pain, bruising and/or bleeding where the needle is inserted 
to make the injection of the study treatment. For the group receiving the investigational drug (JointStem), 
since the stem cells are made up of your own fat cells, no allergic reaction is anticipated. After 
administration of study drug, you are recommended to use crutches for 4-8 weeks to reduce weight 
bearing pressure on the knee. After the allotted time, a gradual increase of weight bearing is needed.  
 
Filling out the questionnaires could lead you to feel uncomfortable or upset.  Please tell the study doctor 
or study staff if you feel uncomfortable or upset while filling out a questionnaire. You have the right to 
refuse to answer any questions. 
 
There are very few risks known to be associated with MRI scans. The only risks relate to the presence of 
loose metalwork in the body (for example, surgical artery clips or foreign bodies) and patients with 
pacemakers.  During an MRI, you will have to lie still on your back in the MRI scanner in a tight space. 
This may make you anxious. The MRI scan does not cause any pain and does not expose you to x-ray 
radiation.  Sometimes a dye is used to help make the pictures clearer.  The dye is injected into your veins 
by an IV catheter (a small plastic tube inserted into a vein). The dye may cause you to get a metallic taste 
in your mouth and to feel warm. Rarely, it causes nausea and vomiting. The dye can also cause damage to 
the kidneys, which may lead to kidney failure. This is of particular concern if you have poor kidney 
function.  Rarely, the dye can cause a life-threatening allergic reaction. 
 
You may have a fill-in type x-ray.  The risk of radiation exposure from the x-ray is too small to be 
measured directly and is therefore difficult to compare to everyday risks. 
 
ECG risks include mild irritation, slight redness, or itching at the sites on your skin where the recording 
patches are placed. 
 
Prohibited Concomitant Medications 
 
The following medications are not to be taken by subjects enrolled in this study during the trial (up to 6-
month follow-up visit): 


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• 
Any pain medication for osteoarthritis except rescue medication (less than 3.25 grams of 
acetaminophen 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 an intra-articular injections) in the affected 
joint  
• 
Any other 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 
 
Allergic Reaction Risks 
 
As with taking any drug, there is a risk of allergic reaction.  If you have a very serious allergic reaction, 
you may be at risk of death.  Some symptoms of allergic reactions are:   
 
• 
Rash. 
• 
Wheezing and difficulty breathing.  
• 
Dizziness and fainting. 
• 
Swelling around the mouth, throat or eyes. 
• 
A fast pulse. 
• 
Sweating. 
 
Please seek treatment immediately and tell the study doctor and study staff if you have any of these 
symptoms, or any other side effects, during the study. 
 
Reproductive Risks 
 
Women Who Can Get Pregnant or Are Breastfeeding 
 
You may not take part in this study if you are breastfeeding, are pregnant, think that you may be pregnant, 
or are trying to get pregnant.  If you are pregnant or breastfeeding, there may be risks to you and the baby 
that are not known at this time.  Women who can get pregnant will be tested for pregnancy during the 
study. 
 
You must avoid getting pregnant in order to take part in this research study.  You should not have sexual 
intercourse or you should use 2 forms of birth control that is acceptable to you, the study doctor, and the 
sponsor.   
 
It is important for you to tell the study doctor at once if you get pregnant or think that you might be 
pregnant while you are in the research study.  If this happens, the study doctor will discuss with you what 
you should do.  If you get pregnant, you will be asked to stop taking part in the study. You may also be 
asked questions about your pregnancy and the baby.   
 
Men  
 
The effect of the study drug on male sperm is unknown.  In rare cases, drugs may damage sperm in ways 
that affect a child that is fathered.  Affected sperm may be present in the semen for about 2 months.  
Therefore, it is recommended to avoid fathering a child for 2 months after the last dose of the study drug. 


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You should not have sexual intercourse or you should use a method of birth control that is acceptable to 
you, the study doctor, and the sponsor.  If you think that you have gotten a woman pregnant, you must tell 
the study doctor at once.  If your partner gets pregnant during the study, you may be asked questions 
about the pregnancy and the baby.   
 
Unknown Risks 
 
You might have side effects or discomforts that are not listed in this form.  Some side effects may not be 
known yet.  New ones could happen to you.  Tell the study doctor or study staff right away if you have 
any problems. 
 
ALTERNATIVES TO BEING IN THE STUDY 
 
You do not need to take part in this research study.  Treatments for osteoarthritis include medications like 
Acetaminophen and Nonsteroidal anti-inflammatory drugs (NSAIDS).  Your study doctor can discuss the 
alternatives and the risks and benefits of these alternatives with you. Other common therapies include the 
following: 
 
• 
Physical therapy 
• 
Occupational therapy 
• 
Braces or shoe inserts 
• 
A chronic pain class 
• 
Cortisone shots 
• 
Lubrication injections 
• 
Realigning bones 
• 
Joint replacement  
 
POTENTIAL BENEFITS OF BEING IN THE STUDY 
 
You may or may not receive any direct benefit from being in the study.  It is possible that you may get 
better, stay the same, or get worse. The benefits of participating in this study may be improvement in your 
osteoarthritis, reduction in pain, and/or improvement in quality of life. If you take part in this study, other 
people with osteoarthritis may be helped. 
 
COSTS OF BEING IN THE STUDY 
 
The study drug and all tests, procedures and visits required by the study are provided at no cost to you.  
The sponsor, Nature Cell Co., Ltd., pays for them. However, costs for your regular medical care, which 
are not related to this study, will be your own responsibility.  
 
YOUR PAYMENT FOR BEING IN THE STUDY 
 
You may receive up to $500 for being in this study. You will get $50 for each study visit you complete. In 
addition, you will receive $50 for completing the Visit 1 MRI imaging on a separate visit. If you complete 
the study without missing any visits, at your last visit, you will receive an additional $50 for your 
complete participation. You will be paid at the end of each study visit.  If you do not finish the study, you 
will only be paid for the visits you completed. 
 
 
 


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STUDY STAFF PAYMENT 
 
Nature Cell Co., Ltd. is paying the study doctor and study staff for their work in this study. 
 
COMPENSATION FOR INJURY 
 
If you become ill or are hurt while you are in the study, get the medical care that you need right away. 
You should inform the healthcare professional treating you that you are participating in this study. 
 
Nature Cell shall reimburse for reasonable and necessary medical expenses (the “Covered Expenses”) 
incurred by study subjects for medical care, including hospitalization, in the treatment of adverse 
reactions arising from study drugs, devices, intervention, procedures and tests following their 
administration or use in accordance with the protocol, which expenses were not caused by negligence or 
misconduct of any person in the employment of study site or to your own failure to follow instructions. 
Nature Cell is not responsible for expenses that are due to pre-existing medical conditions or underlying 
disease.  
 
You still have the right to make a claim through the legal system even if you sign this form, accept 
medical care, or accept payment for medical expenses. 
 
In no way does signing this consent form waive your legal rights nor does it relieve the investigators, 
Sponsor or involved institutions from their legal and professional responsibilities. 
 
To pay these medical expenses, the sponsor will need to know some information about you like your 
name, date of birth, and social security number or Medicare Health Insurance Claim Number. This is 
because the sponsor has to check to see if you receive Medicare and if you do, report the payment it 
makes to Medicare.  
 
PROTECTING THE PRIVACY OF YOUR HEALTH DATA 
 
Certain people and organizations will need to see, copy, and use your health data so that they can do their 
part in the study.  They are called ‘authorized users.’  Authorized users will be given access to and may 
make copies of your health data.  This health data may or may not include your name.  It may be traced 
back to you even if it does not include your name.   
 
To ensure that your information collected for this study will be kept private, your name will not be used 
whenever possible.  A code will be used instead of your name.  All of your study data will be kept in a 
secure location. 
 
Authorized users may include: 
 
• 
Representatives of Nature Cell Co., Ltd. 
• 
Representatives of KCRN Research LLC 
• 
Representatives of Advarra IRB (a Research Ethics Review Board that reviews this study). 
• 
The Food and Drug Administration (FDA) and other US governmental agencies. 
• 
Government agencies to whom certain diseases (like HIV, hepatitis, and STDs) must be reported. 
• 
Governmental agencies of other countries. 
• 
Labs working with the sponsor on this study. 
• 
Other authorized users. 
 


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Your health data needs to be shared for the research and other reasons.  Therefore, complete privacy of 
your health data cannot be promised.  However, sharing your health data will be guided by professional 
standards and the law. 
 
Information from this study may be presented at meetings or published in medical journals.  The 
information included at meetings or in journals will not include your name or information that can easily 
be traced back to you.   
  
For your safety, the study doctor should tell your regular health care provider that you are in this study.   
 
GETTING ANSWERS TO YOUR QUESTIONS OR CONCERNS ABOUT THE STUDY 
 
You can ask questions about this consent form or the study (before you decide to start the study, at any 
time during the study, or after completion of the study).  Questions may include: 
 
• 
Who to contact in the case of a research-related injury or illness; 
• 
Payment or compensation for being in the study, if any; 
• 
Your responsibilities as a study subject; 
• 
Eligibility to participate in the research; 
• 
The study doctor’s or study site’s decision to exclude you from participation; 
• 
Results of tests and/or procedures; 
• 
Other questions, concerns, or complaints. 
 
Contact the study doctor or study staff listed on the first page of this form with any questions, concerns 
or complaints.   
 
GETTING ANSWERS TO YOUR QUESTIONS ABOUT YOUR RIGHTS AS A RESEARCH 
SUBJECT 
 
This study has been reviewed by an Institutional Review Board (IRB). This Committee reviewed this 
study to help ensure that your rights and welfare are protected and that this study is carried out in an 
ethical manner. 
 
For questions about your rights as a research subject, contact:  
 
• 
By mail: 
Study Subject Adviser 
Advarra IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• 
or call toll free:        877-992-4724 
• 
or by email:              adviser@advarra.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00015668. 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by U.S. 
Law. This Web site will not include information that can identify you. At most, the Web site will include 
a summary of the results. You can search this Web site at any time. 
 
 


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BEING A STUDY VOLUNTEER 
 
Entering a research study is voluntary. 
 
• 
You may always say no.  You do not have to take part in the study. 
• 
If you start a study, you may stop at any time.  You do not need to give a reason. 
• 
If you do not want to be in a study or you stop the study at a later time, you will not be penalized 
or lose any benefits. 
• 
If you stop, you should tell the study staff and follow the instructions they may give you. 
 
Your part in the research may stop at any time for any reason, such as: 
 
• 
The sponsor or the study doctor decides to stop the study. 
• 
The sponsor or the study doctor decides to stop your part in the study for your safety. 
• 
You need additional medicine. 
• 
You do not follow the study rules. 
• 
You have a new injury or illness. 
• 
You decide to stop. 
 
You may be asked to stop the study even if you do not want to stop.  
 
NEW INFORMATION ABOUT THE STUDY 
 
You will be told about any new information found during the study that may affect whether you want to 
continue to take part.   
 
 
STATEMENT OF CONSENT  
 
I have read this form and its contents were explained to me.  I agree to be in this research study for the 
purposes listed above.  All of my questions were answered to my satisfaction.  I will receive a signed and 
dated copy of this form for my records.  I am not giving up any of my legal rights by signing this form.   
 
___________________________________ 
 
____/____/____ 
Signature of Research Subject 
 
Date 
 
___________________________________ 
Printed Name of Research Subject 
 
STATEMENT OF PERSON EXPLAINING CONSENT  
 
I have carefully explained to the subject the nature and purpose of the above study.  There has been an 
opportunity for the subject to ask questions about this research study.  I have been available to answer any 
questions that the subject has about this study. 
 
___________________________________ 
 
____/____/____ 
Signature of Person Explaining Consent 
 
Date 
 
___________________________________ 
Printed Name of Person Explaining Consent 


Nature Cell / Protocol Number JS-OAP2-US01 
Page 12 of 14 
 
Timothy Davis, MD 
Advarra IRB Approved Version 30 May 2018 
 
HIPAA Authorization Agreement 
Permission to Review, Use and Release Information about You  
 
If you decide to be in this study, the study doctor and research team will use and 
share health data about you to conduct the study.  Health data may include: 
 
• Your name. 
• Address. 
• Phone number. 
• Date of birth. 
• Medical history. 
• Information from your study visits, including all test results.   
 
Health data may come from your study records or from existing records kept by 
your doctor or other health care workers.   
 
For this study, the research team may share health data about you with authorized 
users.  Authorized users may include 
 
• Representatives of Nature Cell Co., Ltd. 
• Representatives of KCRN Research, LLC.  
• Representatives of Advarra IRB (a Research Ethics Review Board that 
reviews this study). 
• The Food and Drug Administration (FDA) and other US governmental 
agencies. 
• Government agencies to whom certain diseases (like HIV, hepatitis, and 
STDs) must be reported. 
• Governmental agencies of other countries. 
• Labs working with the sponsor on this study. 
• Other authorized users. 
 
The sponsor and those working for the sponsor may use the health data sent to 
them: 
 
• To see if the study drug works and is safe. 
• To compare the study drug to other drugs. 
• For other research activities related to the study drug. 
 


Nature Cell / Protocol Number JS-OAP2-US01 
Page 13 of 14 
 
Timothy Davis, MD 
Advarra IRB Approved Version 30 May 2018 
 
Once your health data has been shared with authorized users, it may no longer be 
protected by federal privacy law.   
 
Your permission to use and share health data about you will not end unless 
required by state law.  If state law applies, your permission to use and share health 
data about you will end on December 31, 2065.  
 
You may take back your permission to use and share health data about you at any 
time by writing to the study doctor.  If you do this, you will not be able to stay in 
this study.  No new health data that identifies you will be gathered after your 
written request is received.  However, health data about you that has already been 
gathered may still be used and given to others as described in this form.   
 
Your right to access your health data in the study records will be suspended during 
the study to keep from changing the study results.  When the study is over, you can 
access your study health data. 
 
If you decide not to sign this form, you will not be able to take part in the study. 
 
 
STATEMENT OF AUTHORIZATION 
 
I have read this form and its contents were explained.  My questions have been 
answered.  I voluntarily agree to allow study staff to collect, use and share my 
health data as specified in this form.  I will receive a signed and dated copy of this 
form for my records.  I am not giving up any of my legal rights by signing this 
form.   
 
 
 
 
____/____/____ 
Signature of Research Subject 
 
Date 
 
___________________________________  
 
 
 
Printed Name of Research Subject 
 
 
 
 
 
 


Nature Cell / Protocol Number JS-OAP2-US01 
Page 14 of 14 
 
Timothy Davis, MD 
Advarra IRB Approved Version 30 May 2018 
 
STATEMENT OF PERSON EXPLAINING AUTHORIZATION 
 
I have carefully explained to the subject the nature and purpose of this form.  I 
have been available to answer any questions that the subject has about this form. 
 
 
 
 
____/____/____ 
Signature of Person Explaining Authorization 
 
Date 
 
___________________________________  
 
 
 
Printed Name of Person Explaining Authorization  
 

Prot_000.pdf: 
JS-OAP2-US01 
Version 7.0, May 14, 2018 
 
Page 1 of 66 
 
 
CONFIDENTIAL 
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). 


JS-OAP2-US01 
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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 
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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 
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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 
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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: _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _  
 
 


JS-OAP2-US01 
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CONFIDENTIAL 
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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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CONFIDENTIAL 
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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: __________________ 


JS-OAP2-US01 
Version 7.0, May 14, 2018 
 
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CONFIDENTIAL 
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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 


JS-OAP2-US01 
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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. 
 


JS-OAP2-US01 
Version 7.0, May 14, 2018 
 
Page 65 of 66 
 
 
CONFIDENTIAL 
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: __________________ 
 
 


JS-OAP2-US01 
Version 7.0, May 14, 2018 
 
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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) 
 
 

SAP_001.pdf: 
Sponsor: Nature Cell Co., Ltd 
Statistical Analysis Plan V2.0 
Version: 2.0 
Confidential 
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Statistical Analysis Plan 
 
Protocol No.: JS-OAP2-US01, Version 6.0 
 
 
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    
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sponsor: Nature Cell Co., Ltd 
Protocol Version: JS-OAP2-US01, Version 6.0, April 07, 2017 
SAP Version No & Date: SAP_ JS-OAP2-US01, Version 2.0, April 05, 2018 
 
 
 


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Confidential 
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Signature Page 
 
 
Prepared by:  
 
 
 
 
 
Ami Yu  
STAT Manager, HERINGS 
 
Date (DD/MM/YYYY) 
 
 
 
Reviewed by: 
 
 
 
 
 
Byung-Ho Nam 
STAT Director, HERINGS 
 
Date (DD/MM/YYYY) 
 
 
 
 
 
Hugh Lee 
Project Director, KCRN Research 
 
Date (DD/MM/YYYY) 
 
 
 
Approval by: 
 
 
 
 
 
Title, Signature 
Sponsor 
 
Date (DD/MM/YYYY) 
 
  


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TABLE OF CONTENTS 
ABBREVIATIONS 
5 
1. 
INTRODUCTION 
6 
1.1 
STUDY OBJECTIVES 
6 
1.1.1 Primary Objective 
6 
1.2 
STUDY ENDPOINTS 
6 
1.2.1 Primary Efficacy Endpoints 
6 
1.2.2 Secondary Efficacy Endpoints 
6 
1.2.3 Safety Endpoints 
7 
1.3 
SUMMARY OF THE STUDY DESIGN 
7 
1.3.1 General Study Design and Plan 
7 
1.3.2 Randomization and Blinding 
9 
1.3.3 Sample Size and Statistical Power Considerations 
9 
1.3.4 Interim Analysis 
9 
2. 
STATISTICAL METHODS 
9 
2.1 
GENERAL CONSIDERATIONS 
9 
2.1.1 Reporting Precision 
10 
2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) 
10 
2.2.1 Intention-To-Treat Population (ITT) 
10 
2.2.2 Per-Protocol Population (PP) 
10 
2.2.3  Safety Population 
10 
2.3 
TIME WINDOWS FOR ANALYSIS 
10 
2.4 
HANDLING OF MISSING DATA 
11 
2.5 
ANALYSIS SOFTWARE 
11 
3. 
STUDY SUBJECTS 
11 
3.1 
DISPOSITION OF SUBJECTS 
11 
3.2 
PROTOCOL DEVIATIONS 
11 
4. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
11 
4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
11 
4.2 
MEDICAL HISTORY 
12 
5. 
STUDY DRUG AND EXPOSURE 
12 
5.1 
TREATMENT 
12 
5.2 
PRIOR AND CONCOMITANT THERAPY 
12 
6. 
EFFICACY ANALYSES 
12 
6.1 
PRIMARY EFFICACY ANALYSIS 
13 
6.2 
SECONDARY EFFICACY ANALYSIS 
14 
6.2.1 WOMAC Score 
14 
6.2.2 VAS Score 
15 


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6.2.3 MRI 
15 
6.2.4 Lysholm Knee Scoring Scale 
16 
6.2.5 KOOS 
16 
6.2.6 IKDC 
17 
6.2.7 RAND-36 Score 
17 
7. 
SAFETY ANALYSIS 
18 
7.1 
ADVERSE EVENTS 
18 
7.1.1 Deaths, Serious and Other Significant Adverse Events 
19 
7.2 
CLINICAL LABORATORY PARAMETERS 
20 
7.3 
VITAL SIGNS, PHYSICAL EXAMINATIONS FINDINGS, ECG 
20 
7.3.1 Vital Signs 
20 
7.3.2 Physical Examinations 
20 
7.3.3 ECG 
21 
8. 
INTERIM ANALYSES AND DATA AND SAFETY MONITORING BOARD 
(DSMB) 
21 
8.1 
INTERIM ANALYSES 
21 
8.2 
DSMB 
21 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
21 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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ABBREVIATIONS 
Abbreviation 
Term 
AdMSC 
Adipose Tissue Derived Mesenchymal Stem Cell 
AEs 
Adverse Events 
ALT 
Alanine Aminotransferase  
ANCOVA 
Analysis of Covariance 
AST 
Aspartate Aminotransferase  
ATC 
Anatomical Therapeutic Chemical  
BMI 
Body Mass Index 
BP 
Blood Pressure  
BUN 
Blood Urea Nitrogen 
DSMB 
Data and Safety Monitoring Board 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
IKDC 
International Knee Documentation Committee 
ITT 
Intention-to-Treat 
KOOS 
Knee Injury & Osteoarthritis Outcome Score 
LS Means 
Least square adjusted means 
LOCF 
Last-Observation-Carry-Forward  
MedDRA 
Medical Dictionary For Regulatory Activities 
MRI 
Magnetic Resonance Imaging 
PP 
Per Protocol 
PT 
Preferred Term 
PT-INR 
Prothrombin Time - International Normalized Ratio 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan  
SD 
Standard Deviation 
SI 
Système International 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event  
VAS 
Visual Analog Scale 
WHO 
World Health Organization 
WOMAC 
Western Ontario and McMaster Universities Arthritis Index 
 


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1. 
INTRODUCTION 
 
The purpose of this statistical analysis plan (SAP) is to describe the procedures and the statistical 
methods that will be used to analyze and report results for Protocol JS-OAP2-US01. This SAP 
has been developed based on the study protocol (Version 5.0 dated on February 10, 2017) and 
electronic case report forms (eCRFs) and has been updated according to the amendment of study 
protocol (Version 6.0, June 26, 2017).  
 
1.1 
STUDY OBJECTIVES 
 
1.1.1 Primary Objective 
 
The primary objective of the study is to evaluate the efficacy and safety of autologous adipose 
tissue derived mesenchymal stem cells (AdMSC) for the treatment of osteoarthritis. 
 
1.2 
STUDY ENDPOINTS 
 
1.2.1 Primary Efficacy 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.  
 
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.  
 
1.2.2 Secondary Efficacy Endpoints 
 
The secondary efficacy endpoints are: 


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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 
 
1.2.3 Safety Endpoints 
 
Safety endpoints include: 
 Clinical laboratory tests  
 12-lead Electrocardiogram (ECG) 
 Physical examinations 
 Vital signs  
 Adverse events (AEs) and concomitant medications 
 
1.3 
SUMMARY OF THE STUDY DESIGN  
 
1.3.1 General Study Design and Plan 
 
This is a double-blind, randomized, controlled study to evaluate the efficacy and safety of 
JointStem for the treatment of 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: Hyaluronic Acid  
 
 
 
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 


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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). 
 
The Schedule of Assessments is presented by Table 1.  
 
Table 1 Schedule of Assessments 
 
Screen. Harv. Treat. 
1st Follow-up 
2nd Follow-Up 
Blinding 
N/A 
Double Blinding 
Open 7 
Visit 
1 
2 
3 
4 
5 
6 
ET 
7 
8 
Week / Month 
W-7 
W-5 
0 
M1 
M3 
M6 <M6 M9 
M12 or 
Final FU6 
Informed consent 
X 
 
 
 
 
 
 
 
 
Medical and Medication History 
X 
X 
 
 
 
 
 
 
 
Demographic information 
X 
 
 
 
 
 
 
 
 
Complete physical examination 
X 
 
X 
 
X 
X 
X4 
X 
X 
Vital signs and weight 
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 
MRI scan 3 
X 
 
 
 
 
X 
X5 
 
X 
WOMAC  
 
 
X 
X 
X 
X 
X4 
X 
X 
VAS  
X 
 
X 
X 
X 
X 
X4 
X 
X 
Lysholm  
 
 
X 
X 
X 
X 
X4 
X 
X 
KOOS 
 
 
X 
X 
X 
X 
X4 
X 
X 
IKDC  
 
 
X 
X 
X 
X 
X4 
X 
X 
Quality of Life (RAND-36)  
 
 
X 
 
X 
X 
X4 
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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1.3.2 Randomization and 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 data have no issue, the 
randomization codes 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 serious adverse event (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. 
 
1.3.3 Sample Size and Statistical Power Considerations 
 
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. 
 
1.3.4 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. No adjustment on the overall alpha-level will be made, as this 
is not a statistically powered study. The interim analysis is not covered by this SAP. 
 
 
2. 
STATISTICAL METHODS 
 
2.1 
GENERAL CONSIDERATIONS 
 
In general, continuous variables will be summarized by number of subjects, mean, SD, median, 
minimum, and maximum values. Categorical variables will be summarized by counts and 
percentage of subjects in each category. Source data for the summary tables and statistical 
analyses will be presented as subject data listings, which include data collected on the electronic 
case report forms (eCRFs) as well as any derived variables for all enrolled subjects. 
 


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2.1.1 Reporting Precision 
 
Summary statistics will be presented to the following degree of precision, unless otherwise 
specified: 
Statistics 
Degree of Precision 
Mean, Geometric mean, Median, 
Quartiles, Confidence limit boundaries 
One decimal place more than the raw data. 
Standard deviation, Standard error 
Two decimal places more than the raw data. 
Minimum, Maximum 
The same as the raw data. 
p-value 
Rounded to 4 decimal places and therefore presented 
as 0.xxxx; p-values smaller than 0.0001 as ‘<0.0001’; 
p-values greater than 0.9999 as ‘>0.9999’. 
Percentage 
One decimal place. A percentage of 100% will be 
reported as 100%. Percentages of zero will be 
reported as 0. 
 
For weight and height, one decimal place will be used for summary statistics. Fractional numeric 
values will be presented with a zero to the left of the decimal point (for example, 0.12 – 0.30). 
 
2.2 
DEFINITIONS OF ANALYSIS POPULATIONS (ANALYSIS SETS) 
 
2.2.1 Intention-To-Treat Population (ITT) 
 
An intention-to-treat (ITT) population will include subjects who received the intra-articular 
injection and have at least post-injection efficacy measurements.  
 
2.2.2 Per-Protocol Population (PP) 
 
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.  
 
2.2.3  Safety Population  
 
A Safety population will include any subject who was randomized and completed Visit 2 (Week -
5, at which time adipose tissue was be harvested).  
 
2.3 
TIME WINDOWS FOR ANALYSIS 
 
For by visit safety or efficacy summaries, only scheduled visits will be analyzed. 
 


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2.4 
HANDLING OF 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.  
 
2.5 
ANALYSIS SOFTWARE 
 
All summaries and statistical analyses will be generated using SAS® version 9.24 or later. 
 
 
3. 
STUDY SUBJECTS 
 
3.1 
DISPOSITION OF SUBJECTS 
 
Disposition will be summarized by treatment and total in all enrolled subjects. 
 
The disposition will include the following: 
 Subjects Randomized  
 Subjects in the ITT Population 
 Subjects in the PP Population 
 Subjects in the Safety Population 
 Subjects completed 6-month follow-up 
o If No, Reasons for withdrawal 
 Subjects completed 12-month follow-up 
o If No, Reasons for withdrawal 
 
A listing of dispositions will be provided for all enrolled subjects. 
 
3.2 
PROTOCOL DEVIATIONS 
 
The clinical team will identify deviations and the deviations will be recorded into the database.  
A subject data listing will be provided. 
 
 
4. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
 
4.1 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
 
Demographic data (age, gender, race, and ethnicity) and baseline characteristics (including 
height, weight and body mass index (BMI)) collected at study screening will be summarized 
using descriptive statistics by treatment group and total for the ITT population. 
 


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A subject data listing of demographics and baseline characteristics will be provided. 
 
4.2 
MEDICAL HISTORY 
 
Medical history will be coded with the Medical Dictionary for Regulatory Activities (MedDRA) 
Terminology version 18.1. The medical history conditions will be summarized by treatment 
group and total for the safety population using frequencies and percentages on the system organ 
class (SOC) and preferred term (PT). It also will be presented in the data listings. 
 
 
5. 
STUDY DRUG AND EXPOSURE 
 
5.1 
TREATMENT  
 
A subject data listing will be provided for study drug injection. 
 
5.2 
PRIOR AND CONCOMITANT THERAPY 
 
Prior medications are defined as medications that started prior to the intra-articular injection of 
study drug. Concomitant medications are defined as medications (other than the study drug) 
taken on or after the intra-articular injection of the study drug during the study. Medications 
started before the dose of study drug and continuing at the time of the intra-articular injection of 
study drug are considered both prior medication and concomitant medication. 
 
All investigator terms for medications recorded on the CRF will be coded using the World Health 
Organization (WHO) Anatomical Therapeutic Chemical (ATC) drug dictionary (Version Dec 
2015, WHODDE). The number (percentage) of subjects who took prior and concomitant 
medications will be summarized in the safety population, by ATC Classification, WHO Drug PT, 
treatment group and total. 
 
A subject data listing of prior and concomitant therapy will be provided. 
 
 
6. 
EFFICACY ANALYSES 
 
All efficacy analyses will be performed on the ITT and PP populations. 
 
The primary efficacy hypothesis tests will be performed using a 5% significance level (but, for 
the MRI improvement evaluation, it shall meet the effective judgment 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 
 PRIMARY EFFICACY ANALYSIS 
 
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. 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 effective judgment criteria. If null hypothesis is not 
dismissed at 5% significance level or it is lower than the effective judgment 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. The change is defined as 
WOMAC score at Month 6 minus WOMAC score at baseline. The number of patients, 
mean, standard deviation, minimum (min) and maximum (max) values for the observed 
values and change from baseline will be calculated and reported in summary table. In 
addition, p-value will also be provided. Shapiro-Wilks test will be used to test the 
normality of change of WOMAC score from baseline at Month 6. 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. The change is defined as VAS 
score at Month 6 minus VAS score at baseline. The number of patients, mean, standard 
deviation, minimum (min) and maximum (max) values for the observed values and 
change from baseline will be calculated and reported in summary table. In addition, p-


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value will also be provided. Shapiro-Wilks test will be used to test the normality of 
change of VAS score from baseline at Month 6. 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) 
 
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 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.  
 
6.2 
SECONDARY EFFICACY ANALYSIS 
 
6.2.1 WOMAC Score 
 
WOMAC score will be collected 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 Visit. Summary statistics of WOMAC score will be presented by visit and treatment group. 
The change from baseline will also be calculated and represented in summary table.  
 
 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) 


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      Change of WOMAC score from baseline at Months 9 and 12 will be analyzed using 
paired t-test (two-sided test, α=0.05) with the null hypothesis equal to zero. The number 
of patients, mean, standard deviation, minimum (min) and maximum (max) values for the 
baseline, months 9, months 12 and change from baseline will be calculated and reported 
in summary table. The p-value will also be provided. Shapiro-Wilks test will be used to 
test the normality of change of WOMAC score from baseline at Months 9 and 12. If 
change of WOMAC score from baseline at Months 9 and 12 doesn’t satisfy normal 
distribution, Wilcoxon signed rank test will be performed. 
 
6.2.2 VAS Score 
 
VAS score will be collected 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 Visit. 
Summary statistics of VAS score will be presented by visit and treatment group. The change 
from baseline will also be calculated and represented in summary table.  
 
 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. 
 
 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 (two-sided test, α=0.05) with the null hypothesis equal to zero. The number of 
patients, mean, standard deviation, minimum (min) and maximum (max) values for the 
baseline, months 9, months 12 and change from baseline will be calculated and reported 
in summary table. The p-value will also be provided. Shapiro-Wilks test will be used to 
test the normality of change of VAS score from baseline at Months 9 and 12.  If change 
of VAS score from baseline at Months 9 and 12 doesn’t satisfy normal distribution, 
Wilcoxon signed rank test will be performed. 
 
6.2.3 MRI 
 
 Comparison of MRI improvement evaluations between at Month 6 and at Months 9 and 
12 (JointStem group) 
MRI improvement evaluation at Month 12 compared to Month 6 will be analyzed using 
Bowker’s test. The frequency and percentage of subjects whose final PI evaluation is 


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‘Improvement’ “No change” or “progress” will be calculated at Month 6 and Months 12. 
The p-value of Bowker’s test will be provided.  
      
6.2.4 Lysholm Knee Scoring Scale 
 
Lysholm knee scoring scale will be collected 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 Visit. Summary statistics of lysholm knee scoring scale will be presented by visit and 
treatment group. The change from baseline will also be calculated and represented in summary 
table.  
 
 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. (two-sided test, α=0.05) with the null hypothesis equal to 
zero. The number of patients, mean, standard deviation, minimum (min) and maximum 
(max) values for the baseline, months 6, months 9, months 12 and change from baseline 
will be calculated and reported in summary table. The p-value will also be provided. 
Shapiro-Wilks test will be used to test the normality of change of Lysholm Knee Scoring 
Scale from baseline at Months 6, 9 and 12.  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. 
 
6.2.5 KOOS 
 
KOOS (Symptoms, Pain, ADL, Sport/Rec, QOL) will be collected 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 Visit. Summary statistics of KOOS will be presented 
by visit and treatment group. The change from baseline will also be calculated and represented in 
summary table.  
 
 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 


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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) 
Change of KOOS from baseline at Months 6, 9 and 12 will be analyzed using paired t-
test (two-sided test, α=0.05) with the null hypothesis equal to zero. The number of 
patients, mean, standard deviation, minimum (min) and maximum (max) values for the 
baseline, months 6, months 9, months 12 and change from baseline will be calculated and 
reported in summary table. The p-value will also be provided. Shapiro-Wilks test will be 
used to test the normality of change of KOOS from baseline at Months 6, 9 and 12.  If 
change of KOOS from baseline at Months 6, 9 and 12 doesn’t satisfy normal distribution, 
Wilcoxon signed rank test will be performed. 
 
6.2.6 IKDC 
 
IKDC will be collected 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 Visit. 
Summary statistics of IKDC will be presented by visit and treatment group. The change from 
baseline will also be calculated and represented in summary table.  
 
 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 
(two-sided test, α=0.05) with the null hypothesis equal to zero. The number of patients, 
mean, standard deviation, minimum (min) and maximum (max) values for the baseline, 
months 6, months 9, months 12 and change from baseline will be calculated and reported 
in summary table. The 95% CI and p-value will also be provided. Shapiro-Wilks test will 
be used to test the normality of change of IKDC from baseline at Months 6, 9 and 12. If 
change of IKDC from baseline at Months 6, 9 and 12 doesn’t satisfy normal distribution, 
Wilcoxon signed rank test will be performed. 
 
6.2.7 RAND-36 Score 
 


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RAND-36 Score (Physical Functioning, Role Limitation (Physical), Role Limitation (Emotional), 
energy/Fatigue, Emotional well-being, Social Functioning, Pain, General Health) 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 Visit. Summary statistics of RAND-36 Score will be 
presented by visit and treatment group. The change from baseline will also be calculated and 
represented in summary table.  
 
 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 (two-sided test, α=0.05) with the null hypothesis equal to zero. The number 
of patients, mean, standard deviation, minimum (min) and maximum (max) values for the 
baseline, months 6, months 9, months 12 and change from baseline will be calculated and 
reported in summary table. The 95% CI and p-value will also be provided. Shapiro-Wilks 
test will be used to test the normality of change of RAND-36 Score from baseline at 
Months 6, 9 and 12.  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. 
 
 
7. 
SAFETY ANALYSIS 
 
All safety analyses will be performed for safety population.  Statistical tests are not planned for 
safety variables. Safety assessments include: 
 AEs  
 Clinical laboratory tests  
 ECG 
 Physical examinations 
 Vital signs  
 
7.1 
ADVERSE EVENTS 
 
AEs will be coded by SOC and PT using the MedDRA (Version 18.1). The verbatim term will 
be included in the AE listing. 
 


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A treatment-emergent adverse event (TEAE) is defined as an AE that occur or worsen on or after 
the injection of study drug and before the end of the study. Only TEAEs will be included in 
summary tables. All AEs, treatment emergent or otherwise, will be presented in subject data 
listings. 
 
The TEAEs will be summarized as the number (percentage) of subjects with TEAEs within SOC 
and PT.  Subjects who report the same PT on multiple occasions will be counted once for the PT: 
under the highest severity (severe > moderate > mild) when summarized by severity and under 
the closest relationship to study drug when summarized by relationship. If a subject reports 
multiple PT for a SOC, the subject will be counted only once for that SOC.  
 
TEAEs will be summarized as below.  
 An overview table, including number of subjects with  
o TEAEs 
o serious AEs (SAEs) 
o study drug related TEAEs 
o TEAEs by severity  
o TEAEs leading to study discontinuation 
o TEAEs leading to death 
 TEAE by SOC and PT 
 TEAE by SOC, PT, and Severity 
 Study drug related TEAEs by SOC, PT 
 SAEs by SOC and PT 
 TEAEs leading to study discontinuation by SOC and PT 
 
All AE tables will be sorted by SOC and PT in decreasing frequency of the number and 
percentage of subjects summarized by treatment group and total.   
 
Missing date will be imputed followed table describes how missing date information will be 
handled: 
 
Partial Missing Start 
or Stop Date 
Imputed Start Date 
Imputed Stop Date 
Missing month and day, 
and the year is present 
January 1 of that year or first dose date if the 
year is the same as the year of first dose date 
December 31 of that 
year 
Missing day, but year 
and month are present 
 
First day of that month or first dose date if the 
year and month are the same as the year and 
month of first dose date 
Last day of that 
month 
Missing month, but year 
and day are present 
Missing month imputed as January 
Missing month 
imputed as December 
 
7.1.1 Deaths, Serious and Other Significant Adverse Events  


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The listings of serious AEs, AE leading to study discontinuation, and subjects who died during 
the study will be provided.  
 
7.2 
CLINICAL LABORATORY PARAMETERS 
 
Laboratory assessments (hematology, blood chemistry and urinalysis) are collected 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: 
 Chemistry: Total Bilirubin, Alkaline Phosphatase, Aspartate Aminotransferase (AST) 
(SGPT), Alanine Aminotransferase (ALT) (SGOT), Blood Urea Nitrogen (BUN), 
Creatinine, Glucose, Albumin, Total protein, Sodium, Potassium, Chloride, Bicarbonate, 
Calcium, HCG, HIV. 
 Hematology: Hemoglobin, Hematocrit, RBC, WBC, MCV, MCH, MCHC, Neutrophils 
(absolute), Lymphocytes (absolute), Monocytes (absolute), Eosinophils (absolute), 
Basophils (absolute), Platelets, PT-INR. 
 Urinalysis: Specific gravity, Color, Appearance, pH, Protein, Glucose, Ketones, Bilirubin, 
Blood, Leukocyte esterase, WBC, RBC, Epithelial cell, Bacteria, Hyaline casts. 
 
All laboratory parameters will be presented in Système International (SI) units. Quantitative 
results (including actual value and change from baseline) will be summarized using descriptive 
statistics by baseline and post-baseline visit for each laboratory test group above. Laboratory test 
results were evaluated as normal, abnormal (not clinically significant) or abnormal (clinically 
significant). The number and percentage of subjects of each category will be summarized by 
time point, treatment and total for each parameter.  
 
All laboratory data will be included in the listings. A pregnancy listing will be provided 
separately.  
 
7.3 
VITAL SIGNS, PHYSICAL EXAMINATIONS FINDINGS, ECG 
 
7.3.1 Vital Signs 
 
Vital signs include sitting blood pressure (BP), pulse, temperature, breathing rate and weight. All 
vital signs will be presented in Système International (SI) units. Quantitative results (including 
actual value and change from baseline to each post-baseline visit) will be summarized using 
descriptive statistics by time point, treatment and total for each parameter.  
 
Listings of vital signs with abnormal flags will be provided.  
 
7.3.2 Physical Examinations 
 


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Physical examination data will be summarized separately using descriptive statistics by time 
point, treatment and total, for each component. Listings for physical will be provided.  
 
7.3.3 ECG 
 
The 12-lead ECG parameters including value and changes from baseline will be summarized 
using descriptive statistics by time point, treatment and total.   
 
Subject listing will be provided. SI units will be used for both summarization and data listings. 
The critically significant abnormalities will also be flagged in data listings. 
 
 
8. 
INTERIM ANALYSES AND DATA AND SAFETY MONITORING BOARD 
(DSMB)  
 
8.1 
INTERIM ANALYSES 
 
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. No adjustment on the overall alpha-level will be made, as this 
is not a statistically powered study. The interim analysis is not covered by this SAP.  
 
8.2 
DSMB 
 
No DSMB is planned. 
 
 
9. 
SUMMARY OF MAJOR CHANGES IN THE PLANNED ANALYSES 
 
There is no major change in the planned analyses based on the study protocol (Version 6.0, Apr 7, 
2017).  
 
 
 
 
 
 
 
 
 


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Page 22 of  22 
 
DOCUMENT REVISON HISTORY 
 
DATE 
VERSION 
AUTHOR/ UPDATED BY 
COMMENTS 
March 15, 2017 
1.0 
Hugh Lee 
Initial version finalized  
April 5, 2018 
2.0 
Byung-Ho Nam 
Updated per protocol v6.0