Clinical trial NCT03117738
Conditions: Alzheimer Disease
Sponsor: Nature Cell Co. Ltd.
Start date: 2017-05-09; Completion date: 2019-08-31
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a randomized, double-blind, placebo-controlled, parallel-group comparison study in subjects with Alzheimer's Disease. Following first screening period, subjects will be randomly assigned into one of the following arms: AstroStem and placebo control in a 1:1 ratio. AstroStem or placebo control will be administered via I.V. at Week 0. This procedure will be repeated 9 times at 2-week interval. Subjects will be scheduled for two follow-up visits at Weeks 30 and 52 to evaluate primary and secondary outcome endpoints.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: AstroStem intervention 2: Placebo-Control
Intervention descriptions: intervention 1: Autologous adipose tissue derived mesenchymal stem cells (AdMSC) intervention 2: Saline with 30% auto-serum

Protocol documents:
ICF_002.pdf: 
Nature Cell / Protocol Number AST-ADP2-US01 
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CONSENT TO TAKE PART IN A CLINICAL RESEARCH STUDY 
AND 
AUTHORIZATION TO DISCLOSE HEALTH INFORMATION 
 
Sponsor / Study Title: 
  
Nature Cell / A Phase 1/2, Randomized, Double-Blind, Placebo- 
Controlled Study to Evaluate the Safety and Efficacy of AstroStem 
Autologous Adipose Tissue Derived Mesenchymal Stem Cells, in 
Patients with Alzheimer’s Disease 
 
Protocol Number: 
 
AST-ADP2-US01 
Principal Investigator: 
(Study Doctor) 
 
«PiFullName» 
 
Telephone: 
 
«IcfPhoneNumber» 
 
Additional Contact(s): 
(Study Staff) 
 
«AdditionalStaffMemberContacts» 
 
Address: 
«PiLocations» 
 
 
 
 
This form is for use in a research study that may involve subjects who may or may not have the capacity 
to consent to take part in the study.  Accordingly, when the subject cannot legally consent to take part, 
pronouns “you” and “your” should be read as referring to the subject rather than the person (legally 
authorized representative) who is signing this form for the subject. In cases where the subject’s 
representative gives consent, the subject should be informed about the study to the extent possible given 
his/her understanding. During the course of the study, if the subject regains the capacity to consent, 
informed consent should be completed and the subject offered the ability to leave the study if desired. 
 
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 and date it.  You cannot take part in this research study until you sign and date this form. 
 
INTRODUCTION TO THE RESEARCH STUDY 
 
You are being asked to take part in this research study because you have Alzheimer’s disease (AD). 
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. 
 
AstroStem 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. 
 


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PURPOSE OF THE RESEARCH STUDY 
 
The main purpose of this research study is to see if AstroStem is safe and effective for subjects with 
Alzheimer’s disease.  
 
INFORMATION ABOUT THE STUDY 
 
In this study, you will either receive the active study drug, AstroStem, or a placebo-control, a saline with 
30% auto serum. Auto serum is part of your blood that has been taken and will be injected back into you 
with the saline. Please ask the study doctor or study staff if you have any questions about this placebo 
control.  
 
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: AstroStem 
• 
Group B: Saline with 30% auto serum  
 
During the study, neither you nor the study doctor will know nor get to choose which study drug you are 
receiving (‘study drug’ refers to the investigation drug [AstroStem] and the placebo-control [saline with 
30% auto serum]). 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.  
 
If you decide to be in this study, you will have to take your regular AD medication (donepezil, 
galantamine, memantine, rivastigmine or their combinations) on a stable dose(s) until the last follow-up 
visit. Change of type or dose of AD medication will not be allowed. 
 
You will be in the study for about 14 months and make a total of 14 visits to the study site. 
 
60 people at 2 - 3 research sites will take part in this study, including up to 30 people at this study site. In 
order to identify 30 subjects needed, we may need to screen as many as 45 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 (Week -6) – First screening, baseline  
Visit 2 (Week -4) – Liposuction  
Visit 3 (Week 0) – 1st injection of AstroStem or Placebo 
Visit 4 (Week 2) – 2nd injection of AstroStem or Placebo 
Visit 5 (Week 4) – 3rd injection of AstroStem or Placebo 
Visit 6 (Week 6) – 4th injection of AstroStem or Placebo 
Visit 7 (Week 8) – 5th injection of AstroStem or Placebo 
Visit 8 (Week 10) – 6th injection of AstroStem or Placebo 
Visit 9 (Week 12) – 7th injection of AstroStem or Placebo 
Visit 10 (Week 14) – 8th injection of AstroStem or Placebo 
Visit 11 (Week 16) – 9th injection of AstroStem or Placebo 
Visit 12 (Week 18) – 10th injection of AstroStem or Placebo 
Visit 13 (Week 30) – 1st Follow-up 


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Visit 14 (Week 52)- Final follow-up 
 
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 AstroStem or placebo-control group. Then 
regardless of your assigned group you will undergo a liposuction procedure to harvest cells that will be 
used to manufacture the study drug, AstroStem.  
 
Then you will return to the clinic in about 4 weeks for the 1st injection of the final study drug product. 
This will either be the AstroStem injection or saline with 30% auto serum injection, depending on your 
assignment.  
 
This procedure will be repeated 9 times at Visits 4-12 with 2 week interval. 
 
If a subject has experienced infusion reaction, allergic reaction or anaphylaxis in associated with the study 
drug administration, the subject will be terminated early. 
  
Following the 10th injection, you will visit the site for 1st follow-up at Week 30, then you will be asked to 
come in at Week 52 for the final follow-up.  
 
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 at Visit 1. 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 at Visit 1. 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 at Visits 1, 3, 6, 9, 12, 13, and 14 or early termination visit.  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 at Visits 1, 3, 6, 9, 12, 13 and 14 or early termination visit. 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 at Visits 1, 3, 6, 9, 
12, 13 and 14 or early termination visit. 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 at Visits 1, 3, 12, 13 
and 14 or early termination visit. 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 at Visits 1, 3, 6, 9, 12, 13 and 14 or early termination visit. This is 
for investigational purpose. 


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• 
Chest X-ray: Take a chest x-ray image to verify if you have a suspected active lung disease. This 
will be performed at Visit 1. 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 at Visit 2. This is for investigational purpose.  
• 
Injection of Study Drug Product: Receive intravenous administration of either the study drug or 
the placebo-control. This will be performed at Visit 3 to 12. This is for investigational purpose.  
• 
MRI Scans: Take a MRI scan of your brain to detect microhemorrhages (small brain bleeds), a 
single area of superficial siderosis (deposits of iron), or evidence of a prior microhemorrhage 
from the study at Visit 1. Take serial brain MRI scans to evaluate potential occurrence of cerebral 
vasogenic edema (excess fluid in the brain) at Visits 9, 13 and 14 or early termination visit. 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 1, 3, 6, 9, 12, 13 and 14 or early termination visit. This is 
for investigational purpose.   
• 
Blood biomarkers: Take blood samples to measure biomarkers at Visits 3, 13 and 14 or early 
termination visit. This is for investigational purpose. A biomarker is something found in the 
blood, other body fluids, or tissues that can be used to measure the progress of disease or the 
effects of treatment. 
• 
Collect blood for auto-serum: Take blood samples to collect serum at Visits 2,  3, 5, 7, and 9. 
 
You will have approximately 10 - 16 teaspoons (50 - 80 ml) or 3 – 5 teaspoons (15 - 25 ml) of blood 
withdrawn from a vein seven times throughout the study. The total amount of blood withdrawn during the 
study will be approximately 85 teaspoons (about 1.7 cups). 
 
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 3 months or are in another 
research study now. 
• 
Tell the study doctor about any problems you have during the study. 
• 
Allow the study doctor to give you intravenous administrations of the study drug 10 times.  
• 
The study doctor or study staff will talk to you about any food or medicines that you should not 
take while in this study. 
 
 
 


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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. 
 
 
Risks of Study Drug Administration (Investigational Drug, AstroStem iv administration) 
 
In previous clinical trials, the risks and side effects possibly related to the study drug we are studying 
included: 
• 
Inflammation,  
• 
Pain,  
• 
Infection and/or allergic reaction at the site of injection, 
• 
Hematoma (bruise),  
• 
Cellulitis (skin infection),  
• 
Pulmonary embolism (arteries in the lungs become blocked by a blood clot), 
• 
Deep vein thrombosis (blood clot),  
• 
Rash,  
• 
Fever,  
• 
Edema (swelling),  
• 
High blood pressure, 
• 
Joint pain,  
• 
Non-functioning tumor promotion (tumors that do not secrete hormones),  
• 
Diabetic retinopathy growth (diabetes complication that affects eyes),  
• 
Worsening of atherosclerosis (hardening of the arteries), 
• 
Cold,  
• 
Urinary stone,  
• 
Chest discomfort,  
• 
Toothache,  
• 
Dry cough,  
• 
Backache,  
• 
Migraine, 
• 
Rhinopharyngitis (common cold),  
• 
Gastrointestinal disease,  
• 
Metabolic or nutritional disease,  
• 
Hypertriglyceridemia (high levels of triglycerides (fats) in the blood),  
• 
Nervous disease,  
• 
Headache,  
• 
Urinary system disease,  
• 
Breathing issues,  
• 
Chest and mediastinal (a part of the chest) disease, 
• 
Potential occurrence of cerebral vasogenic edema, 
• 
Suicidal ideation (thoughts) and behavior. 
 


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Risks of Placebo-Control Administration (Saline with 30% auto serum iv administration) 
 
In previous clinical trials, the risks and side effects possibly related to saline iv administration we are 
conducting included: 
• 
Pain, infection and/or allergic reaction at the site of injection, 
• 
Rash,  
• 
Fever,  
• 
Fluid retention (too much fluid in your body),  
• 
High blood pressure, 
• 
Fast heartbeat, 
• 
Joint pain,  
• 
Shortness of breath. 
 
Risks Associated with Procedures 
 
Risks of Breach of Confidentiality: 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.   
 
Risks of Blood Draw: 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).   
 
Risks of Liposuction: 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 doctor or study staff.   
 
Risks of Questionnaires: During tasks that involve memory, you may become bored, fatigued, or 
frustrated by their difficulty. There are no physical risks to these tests. Some of the questions you will be 
asked on the questionnaire are personal and may make you feel embarrassed. You may skip any questions 
you do not feel comfortable answering, but it is important for you to give your best effort. 
 
Risks of MRI scan: Some people should not participate in MRI studies. These include persons with 
shrapnel or certain metallic implants, such as prostheses (artificial body part), or aneurysm clips, or 
persons with electronic implants, such as cardiac pacemakers or implanted hearing devices. The magnetic 
field generated by the MRI machine can cause a displacement or malfunctioning of these devices. There 
are no other known risks to body tissues associated with the magnetic field strength used in this study. 
Some participants report some anxiety or claustrophobia in the MRI scanner since the head must be 
placed fully inside the scanner tube. If anxiety or claustrophobia occurs, please let us know and we will 
stop the scan and bring you out of the scanner. In addition, fatigue and physical discomfort are possible. 
The MRI scanner makes a great deal of noise when taking images. To minimize the level of noise, you 
will be fitted with disposable earplugs or headphones to wear during the procedure. These may be a bit 
uncomfortable to wear, and will not eliminate all sound, so that communication with you is still possible. 
 
Risks of X-ray: 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. 


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Risks of ECG: ECG risks include mild irritation, slight redness, or itching at the sites on your skin where 
the recording patches are placed. 
 
Risks of Blood Pressure Cuff:  The blood pressure monitoring device is non-invasive and the most 
common complaint is potential discomfort due to the blood pressure cuff inflating. If this occurs, you 
simply can take off the cuff. 
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 3 months.  
Therefore, it is recommended to avoid fathering a child for 3 months after the last dose of the study drug. 
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.   
 
 
 


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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. 
 
Prohibited Concomitant Medications 
 
The following medications are not to be taken by subjects enrolled in this study during the trial (up to 
Week 52, a final follow-up visit): 
• 
Any other investigational drug  
• 
Any therapy that may affect Alzheimer’s disease, in the judgment of the study doctor  
• 
Immunosuppressant 
• 
Cytotoxic drug (drug that damages cells, for example, a chemotherapy drug for cancer)  
• 
Corticosteroids or similar steroidal anti-inflammatory medication (for example, Prednisone) on a 
regular basis (exceptions allowed include: regular use of steroidal nasal sprays, topical steroids, 
and estrogen-replacement therapy) 
 
ALTERNATIVES TO BEING IN THE STUDY 
 
You do not need to take part in this research study.  Treatments for the symptoms of Alzheimer’s disease 
include medications like donepezil, galantamine, memantine, rivastigmine, donepezil with memantine.  
Your study doctor can discuss the alternatives and the risks and benefits of these alternatives with you.  
 
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 
symptoms of Alzheimer’s disease. If you take part in this study, other people with Alzheimer’s disease 
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 $1050 for being in this study. You will get $75 for each study visit you complete. 
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. 
 
STUDY STAFF PAYMENT 
 
Nature Cell Co., Ltd. is paying the study doctor and study staff for their work in this study. 
 
 
 


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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 Chesapeake 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. 
 
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. 


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A federal law, called the Genetic Information Nondiscrimination Act (GINA), generally makes it illegal for 
health insurance companies, group health plans and most employers to discriminate against you based on 
your genetic information. 
 
This law generally will protect you in the following ways: 
 
• 
Health insurance companies and group health plans may not request your genetic information that 
the sponsor will get from this research. 
• 
Health insurance companies and group health plans may not use your genetic information when 
making decisions regarding your eligibility or premiums. 
• 
Employers with 15 or more employees may not use your genetic information that the sponsor will 
get from this research when making a decision to hire, promote, or fire you or when setting the 
terms of your employment. 
 
All health insurance companies and group health plans and all employers with 15 or more people must 
follow this law. 
 
Be aware that this Federal law does not protect you against genetic discrimination by companies that sell 
life insurance, disability insurance or long-term care insurance. 
 
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.   
 


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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 
Chesapeake IRB 
6940 Columbia Gateway Drive, Suite 110 
Columbia, MD 21046 
• 
or call toll free:        877-992-4724 
• 
or by email:              adviser@chesapeakeirb.com 
 
Please reference the following number when contacting the Study Subject Adviser: Pro00019946. 
 
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. 
 
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. 


Nature Cell / Protocol Number AST-ADP2-US01 
Page 12 of 15 
 
«PiFullName» 
Chesapeake IRB Approved Version 26 Jun 2017 
Revised «PIApprovalDate» 
 
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 
 
________________________________  
 
 
 
 
_/____/____ 
Signature of Legally Authorized Representative (if applicable) 
 
 
Date 
 
___________________________________ 
Printed Name of Legally Authorized Representative (if applicable) 
 
 
STATEMENT OF PERSON EXPLAINING CONSENT  
 
I have carefully explained to the subject or the subject’s legally authorized representative the nature and 
purpose of the above study.  There has been an opportunity for the subject or the subject’s legally authorized 
representative to ask questions about this research study.  I have been available to answer any questions 
that the subject or the subject’s legally authorized representative has about this study. 
 
 
___________________________________ 
 
____/____/____ 
Signature of Person Explaining Consent 
 
Date 
 
___________________________________ 
Printed Name of Person Explaining Consent 
 
 
 


Nature Cell / Protocol Number AST-ADP2-US01 
Page 13 of 15 
 
«PiFullName» 
Chesapeake IRB Approved Version 26 Jun 2017 
Revised «PIApprovalDate» 
 
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 Chesapeake 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 AST-ADP2-US01 
Page 14 of 15 
 
«PiFullName» 
Chesapeake IRB Approved Version 26 Jun 2017 
Revised «PIApprovalDate» 
 
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, 2067.  
 
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. 
 
 


Nature Cell / Protocol Number AST-ADP2-US01 
Page 15 of 15 
 
«PiFullName» 
Chesapeake IRB Approved Version 26 Jun 2017 
Revised «PIApprovalDate» 
 
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 
 
 
 
 
 
 
 
 
 
____/____/____ 
Signature of Legally Authorized Representative 
 
Date 
 
___________________________________  
 
 
 
Printed Name of Legally Authorized Representative 
 
 
 
 
 
 
STATEMENT OF PERSON EXPLAINING AUTHORIZATION 
 
I have carefully explained to the subject and legally authorized representative the 
nature and purpose of this form.  I have been available to answer any questions that 
the subject and legally authorized representative has about this form. 
 
 
 
 
____/____/____ 
Signature of Person Explaining Authorization 
 
Date 
 
___________________________________  
 
 
 
Printed Name of Person Explaining Authorization  
 

Prot_000.pdf: 
AST-ADP2-US01 
Version 6.0, Mar 4, 2019 
 
Page 1 of 124 
 
 
CONFIDENTIAL 
Nature Cell Co., Ltd. 
  
 
 
 
A Phase 1/2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate 
the Safety and Efficacy of AstroStem, Autologous Adipose Tissue Derived 
Mesenchymal Stem Cells, in Patients with Alzheimer’s Disease 
 
Protocol Number: AST-ADP2-US01  
 
IND Number: 17,201 
 
 
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  
 
 
Version 6.0 Date: 
Mar 4, 2019 
Version 5.0 Date: 
Dec 11, 2017 
Version 4.0 Date: 
May 22, 2017 
 
 
Original Version Date: 
October 21, 2016 
 
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). 
 
 


AST-ADP2-US01 
Version 6.0, Mar 4, 2019 
 
Page 2 of 124 
 
 
CONFIDENTIAL 
Nature Cell Co., Ltd. 
 
Protocol Signature Page 
 
I have carefully read the attached protocol (v 6.0) entitled “A Phase 1/2, Randomized, Placebo-Controlled 
Study to Evaluate the Safety and Efficacy of AstroStem, Autologous Adipose Tissue Derived Mesenchymal 
Stem Cells, in Patients with Alzheimer’s Disease” dated Mar 4, 2019 and agree to its terms including 
principles of disclosure and confidentiality. 
 
I agree to obtain the approval for this protocol from the Institutional Review Board 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) 
 


AST-ADP2-US01 
Version 6.0, Mar 4, 2019 
 
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CONFIDENTIAL 
Nature Cell Co., Ltd. 
Table of Contents 
 
Page 
PROTOCOL SYNOPSIS .............................................................................................................................. 6 
SCHEDULE OF ASSESSMENTS ............................................................................................................... 9 
GLOSSARY AND ABBREVIATIONS ..................................................................................................... 10 
1. 
PURPOSE OF STUDY ..................................................................................................................... 11 
2. 
INTRODUCTION ............................................................................................................................ 12 
3. 
INVESTIGATIONAL PLAN ........................................................................................................... 13 
3.1 
Study Design ........................................................................................................................ 13 
3.2 
Selection of Study Population .............................................................................................. 13 
3.2.1 
Inclusion Criteria ................................................................................................ 13 
3.2.2 
Exclusion Criteria............................................................................................... 13 
3.3 
Removal of Subjects from Study ......................................................................................... 15 
3.4 
Premature Termination of Study / Closure of Center........................................................... 16 
3.5 
Treatment ............................................................................................................................. 16 
3.5.1 
Treatment to be Administered ............................................................................ 16 
3.5.2 
Identity of Investigational Product ..................................................................... 16 
3.5.3 
End of Study ....................................................................................................... 17 
3.5.4 
Selection of Dose in Study ................................................................................. 17 
3.5.5 
Choice of Control/Comparator ........................................................................... 17 
3.5.6 
Randomization and Blinding .............................................................................. 17 
3.5.7 
Prior and Concomitant Treatments .................................................................... 17 
3.5.8 
Treatment Compliance ....................................................................................... 18 
3.6 
Study Endpoints and Variables ............................................................................................ 18 
3.6.1 
Study Endpoints ................................................................................................. 18 
3.6.2 
Efficacy Variables .............................................................................................. 18 
3.6.3 
Safety Variables ................................................................................................. 19 
4. 
STUDY PROCEDURES .................................................................................................................. 20 
4.1 
Screening Period .................................................................................................................. 20 
4.1.1 
Visit 1: Screening (Week -8) .............................................................................. 20 
4.1.2 
Visit 2 (Week -4) ................................................................................................ 20 
4.1.3 
Preparation of Final Drug Product at Lab .......................................................... 21 
4.2 
Treatment Period .................................................................................................................. 21 
4.2.1 
Visit 3: Baseline (Week 0) ................................................................................. 21 
4.2.2 
Visits 4, 8, 10 and 11 (Weeks 2, 10, 14 and 16) ................................................ 22 
4.2.3 
Visits 5 and 7 (Weeks 4 and 8) .......................................................................... 22 
4.2.4 
Visit 6 (Week 6) ................................................................................................. 23 
4.2.5 
Visit 9 (Week 12) ............................................................................................... 23 
4.2.6 
Visit 12 (Week 18) ............................................................................................. 24 


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4.3 
Follow-up Period .................................................................................................................. 24 
4.3.1 
Visit 13: 1st Follow-up Visit (Week 30) ............................................................ 24 
4.3.2 
Visit 14: Final Follow-up Visit (Week 52) ........................................................ 25 
4.4 
Early Termination Visit ........................................................................................................ 25 
4.5 
Data Quality ......................................................................................................................... 25 
4.6 
Documentation ..................................................................................................................... 26 
5. 
ETHICAL AND LEGAL ASPECTS ................................................................................................ 27 
5.1 
Institutional Review Board (IRB) ........................................................................................ 27 
5.2 
Ethical Conduct of the Study ............................................................................................... 27 
5.3 
Regulatory Authority Approvals/Authorizations ................................................................. 27 
5.4 
Subject Information Consent ................................................................................................ 27 
5.5 
Insurance .............................................................................................................................. 28 
5.6 
Confidentiality...................................................................................................................... 28 
6. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE ................................. 29 
6.1 
Statistical and Analytical Plans ............................................................................................ 29 
6.1.1 
Analytical Populations ....................................................................................... 29 
6.1.2 
Treatment Group Comparability ........................................................................ 29 
6.1.3 
Significance Level .............................................................................................. 29 
6.1.4 
Primary Efficacy Analyses ................................................................................. 29 
6.1.5 
Secondary Efficacy Analyses ............................................................................. 30 
6.1.6 
Exploratory Efficacy Analyses........................................................................... 30 
6.1.7 
Safety Analyses .................................................................................................. 30 
6.1.8 
Missing Data ...................................................................................................... 31 
6.2 
Determination of Sample Size ............................................................................................. 31 
7. 
SAFETY DATA COLLECTION, RECORDING, AND REPORTING .......................................... 32 
7.1 
Definitions ............................................................................................................................ 32 
7.1.1 
Adverse Events................................................................................................... 32 
7.1.2 
Serious Adverse Events ...................................................................................... 32 
7.2 
Reporting Procedures for All Adverse Events ..................................................................... 33 
7.2.1 
Relationship of Adverse Event to Study Drug ................................................... 34 
7.2.2 
Adverse Event Severity ...................................................................................... 34 
7.3 
Serious Adverse Event Reporting Procedures ..................................................................... 34 
7.4 
Procedures for Managing Microhemorrhages and Cerebral Vasogenic Edema .................. 35 
8. 
USE OF DATA AND PUBLICATION ............................................................................................ 36 
9. 
REFERENCES.................................................................................................................................. 37 
10. 
APPENDICES .................................................................................................................................. 39 
Appendix 1. Laboratory Parameters ................................................................................................. 40 
Appendix 2. ADAS-Cog (Alzheimer’s Disease Assessment Scale-cognitive subscale) .................. 41 
Appendix 3. MMSE (Mini-mental status examination) .................................................................... 64 
Appendix 4. CDR-SOB (Clinical Dementia Rating-Sum of Box) .................................................... 70 


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Nature Cell Co., Ltd. 
Appendix 5. NPI (Neuropsychiatric Inventory) ................................................................................ 81 
Appendix 6. GDS (Geriatric Depression Scale)................................................................................ 94 
Appendix 7. ADCS-ADL (Alzheimer’s Disease Cooperative Study- Activities of Daily Living .... 95 
Appendix 8. C-SSRS (Columbia-Suicide Severity Rating Scale) .................................................. 104 
Appendix 9. Instruction for Liposuction Procedure ........................................................................ 114 
Appendix 10. IP Administration Instruction for Clinical Sites ....................................................... 120 


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CONFIDENTIAL 
Nature Cell Co., Ltd. 
PROTOCOL SYNOPSIS 
Name of Sponsor/Company: 
Nature Cell Co., Ltd. 
5F, 10 Gukhoe-daero 76-gil, Yeongdeungpo-gu, Seoul 150-870, Korea  
Investigational Product: AstroStem 
Protocol Number 
AST-ADP2-US01 
Indication 
Alzheimer’s Disease (AD) 
Protocol Title 
A Phase 1/2, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Safety and 
Efficacy of AstroStem, Autologous Adipose Tissue Derived Mesenchymal Stem Cells, in 
Patients with Alzheimer’s Disease 
Study Phase 
Phase 1 and 2 
Planned Number 
of Subjects 
Total up to 22 subjects 
- Treatment group: AstroStem (2x108 cells/220 mL), N=11 
- Control group: Saline 220 ml, N=11  
 
Objectives 
To evaluate the safety and efficacy of AstroStem (autologous adipose tissue derived 
mesenchymal stem cells, AdMSCs) in patients with Alzheimer’s disease 
Study Design 
This is a randomized, double-blind, placebo-controlled, parallel-group comparison study in 
subjects with Alzheimer’s Disease. Following first screening period, subjects will be randomly 
assigned into one of the following treatment arms: AstroStem and placebo.  
 
At Week -4, 30 mL of abdominal adipose tissue will be taken by liposuction from subjects. 
The adipose tissue samples will be sent to Biostar Stem Cell Research Institute to isolate 
AdMSCs. The isolated AdMSCs or saline will be sent to the clinical sites with identical 
syringes to preserve double-blinding of the study.  
 
A total 2x108 AdMSCs in 220 mL of saline or the same volume of saline will be administered 
via I.V. at Week 0. This procedure will be repeated 9 times at 2-week interval. Subjects will 
be scheduled for two follow-up visits at Weeks 30 and 52 to evaluate primary and secondary 
outcome endpoints.   
Drug 
Administration 
A total 2x108 AdMSCs in 220 mL of saline or the same volume of saline will be administered 
via I.V. for 2-6 hours to patients in the treatment group and the placebo group, respectively. 
Study Visits 
Visit 1 (Week -8) – Screening  
Visit 2 (Week -4) – Liposuction  
Visit 3 (Week 0) – 1st injection of AstroStem or Placebo 
Visit 4 (Week 2) – 2nd injection of AstroStem or Placebo 
Visit 5 (Week 4) – 3rd  injection of AstroStem or Placebo 
Visit 6 (Week 6) – 4th  injection of AstroStem or Placebo 
Visit 7 (Week 8) – 5th  injection of AstroStem or Placebo 
Visit 8 (Week 10) – 6th  injection of AstroStem or Placebo 
Visit 9 (Week 12) – 7th  injection of AstroStem or Placebo 
Visit 10 (Week 14) – 8th  injection of AstroStem or Placebo 
Visit 11 (Week 16) – 9th  injection of AstroStem or Placebo 
Visit 12 (Week 18) – 10th  injection of AstroStem or Placebo 
Visit 13 (Week 30) – 1st follow-up 
Visit 14 (Week 52) – Final follow-up 
Study 
Hypothesis 
AstroStem treatment group has improvement on neurological/neurocognitive assessment from 
baseline at Week 30 compared to the placebo group. 


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CONFIDENTIAL 
Nature Cell Co., Ltd. 
Name of Sponsor/Company: 
Nature Cell Co., Ltd. 
5F, 10 Gukhoe-daero 76-gil, Yeongdeungpo-gu, Seoul 150-870, Korea  
Investigational Product: AstroStem 
Protocol Number 
AST-ADP2-US01 
Indication 
Alzheimer’s Disease (AD) 
Clinical 
Endpoints 
The primary endpoint used to determine the safety and efficacy of AstroStem is the 
following: 
• 
Number of subjects with treatment related adverse events as assessed by analysis of 
adverse events including symptoms, and abnormal findings on physical 
examination, vital signs, ECG, and standard laboratory examination results 
• 
Change of ADAS-Cog (Alzheimer’s Disease Assessment Scale-cognitive subscale) 
from baseline at Week 30 
 
The secondary endpoints used to determine the efficacy and safety of AstroStem are:  
• 
Change of MMSE (Mini-mental status examination) from baseline at Week 30 
• 
Changes of CDR-SOB (Clinical Dementia Rating-Sum of Boxes) from baseline at 
Week 30 
• 
Changes of NPI (Neuropsychiatric Inventory) from baseline at Week 30 
• 
Changes of GDS (Geriatric Depression Scale) from baseline at Week 30 
• 
Change of ADCS-ADL (Alzheimer’s Disease Cooperative Study Activities of Daily 
Living) from baseline at Week 30 
• 
Changes of C-SSRS (Columbia Suicide Severity Rating Scale) from baseline at 
Week 30 
• 
Change of MRI imaging results from baseline at Week 30 
• 
Biomarkers in blood: Amyloid beta 40, Amyloid beta 42, Amyloid precursor protein 
intracellular domain (AICD), soluble neuregulin-1 (sNRG-1)  
Inclusion/ 
Exclusion  
Criteria 
Inclusion Criteria  
1. Male or female subjects aged 50 and above at the time of signing the Informed Consent 
form 
2. Subjects who can understand and provide written informed consent (assent) 
3. Subjects who have diagnosis of probable mild-to-moderate Alzheimer disease according 
to NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders 
and Stroke; Alzheimer’s Disease and Related Disorders Association) criteria  
4. Subjects who have MMSE Score of 16 to 26 at screening 
5. Subjects who are taking FDA-approved AD medications (donepezil, galantamine, 
memantine, rivastigmine or their combinations) treatment on a stable dosage for at least 
3 months prior to screening.   
6. Subjects who have one (or more) identified adult caregiver (study partner) who is able to 
read, understand, and speak the designated language at the study site; either lives with the 
subject or sees the subject for ≥2 hours/day ≥4 days/week; and agrees to accompany the 
subject to each study visit and to participate in the subject’s clinical assessments. 
 
Exclusion Criteria   
1. Subjects who are females who are pregnant, nursing, or of childbearing potential while 
not practicing effective contraception 
2. Subjects who have signs of delirium  
3. Subjects who have had cortical stroke within the preceding 2 years 
4. Subjects who have a prolonged QTc interval; >450 msec in male or >470 msec in female 
at screening 


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CONFIDENTIAL 
Nature Cell Co., Ltd. 
Name of Sponsor/Company: 
Nature Cell Co., Ltd. 
5F, 10 Gukhoe-daero 76-gil, Yeongdeungpo-gu, Seoul 150-870, Korea  
Investigational Product: AstroStem 
Protocol Number 
AST-ADP2-US01 
Indication 
Alzheimer’s Disease (AD) 
5. Subjects who have diagnosis of severe white matter hyperintensity (WMH), which is 
defined as ≥ 25mm of the deep white matter and ≥ 10mm of the periventricular 
capping/banding in lengths 
6. Subjects who have diagnosis of dementia or cause of cognitive impairment other than 
Alzheimer’s disease 
7. Subjects who have a significant abnormal result in laboratory tests, in the opinion of the 
investigator 
8. Subjects who have participated in any investigational drug, stem cell therapy, or device 
trial within the previous 3 months at screening 
9. Subjects with any current psychiatric diagnosis other than AD if, in the judgment of the 
investigator, the psychiatric disorder or symptom is likely to confound interpretation of 
drug effect, affect cognitive assessments, or affect the subject´s ability to complete the 
study 
10.  Subjects who are known to have autosomal dominant mutation-associated presenile AD 
11. Subjects who show signs of AIDS (Acquired Immunodeficiency Syndrome), HBV 
(Hepatitis B Virus), HCV (Hepatitis C), VDRL (Venereal Disease Research Laboratory) 
12. Subjects who have any conditions that would contraindicate an MRI, such as the presence 
metallic objects in the eyes, skin, or heart 
13. Subjects who have > 4 cerebral microhemorrhages (regardless of their anatomical location 
or diagnostic characterization as "possible" or "definite"), a single area of superficial 
siderosis, or evidence of a prior microhemorrhage as assessed by MRI 
14. Subjects who have history of malignant cancer within the last 5 years (The following is a 
partial list of conditions that are permissible for study entry: non-metastatic basal and/or 
squamous cell carcinoma of the skin, in situ cervical, or non-progressive prostate cancer) 
15. Subjects who have suspected active lung disease based on chest X-ray  
16. Subjects who are hypersensitive to fetal bovine serum or penicillin 
17. Subjects who are currently using immunosuppressants, cytotoxic drug, corticosteroids or 
similar steroidal anti-inflammatory medication (e.g., Prednisone) on a regular basis 
(exceptions allowed include; regular use of steroidal nasal sprays, topical steroids, and 
estrogen-replacement therapy) 
18. Subjects for whom the investigator judges the liposuction can cause any problems 
19. Subjects who have history of local anesthetic allergy 
Statistical 
Analysis 
The primary variable, score change of ADAS-Cog from baseline at Week 30 will be analyzed 
using T-test or Kruskal-Wallis test depending on the violation of normality assumption. The 
secondary efficacy variables include the percentage of subjects who show improvement along 
with several change scores from baseline. The percentage of subjects who show improvement 
will be compared between groups using chi-square test or Fisher’s exact test. The change 
scores will be analyzed using T-test or Kruskal-Wallis tests, as appropriate. Safety variables 
will be summarized descriptively, by treatment group and visit. When the first 4 subjects 
complete Visit 4 at Week 2, one unblinded interim safety analysis of the subjects can be 
performed by an independent safety monitor to evaluate the safety of AstroStem without the 
suspension of subject enrollment. Change of vital signs and AEs will be evaluated. 


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Nature Cell Co., Ltd. 
SCHEDULE OF ASSESSMENTS  
Procedure 
Screen 
Treatment 
Follow-up 
Early 
Termination 
V1 
V2 V3 V4 V5 V6 V7 V8 V9 V10 V11 V12 V13 V14 
Tested Group 
-W8 -W4 W0 W2 W4 W6 W8 W10 W12 W14 W16 W18 W30 W52 
Informed Consent1 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medication history 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
V 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
Vital signs 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
Hematology, serum 
chemistry, and urinalysis 2 
V 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
Pregnancy test 3 
V 
 
V 
 
 
 
 
 
 
 
 
V 
V 
V 
V 
Electrocardiogram 
V 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
Chest X-ray 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liposuction  
 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for IP 
 
V 
V 
 
V 
 
V 
 
V 
 
 
 
 
 
 
ADAS-Cog 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
MMSE 
V 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
CDR-SOB 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
NPI 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
GDS 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
C-SSRS 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
ADCS-ADL 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
MRI Scan 
V 
 
 
 
 
 
 
 
V 
 
 
 
V 
V 
V 
Biomarker 4 
 
 
V 
 
 
 
 
 
 
 
 
 
V 
V 
V 
Drug administration 
 
 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
 
 
 
Concomitant medications 
 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
Adverse events 
 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
1 Informed Consent Form should be signed prior to any clinical trial related activities 
2 See Appendix 1 for the complete list of laboratory tests 
3 Serum pregnancy test is performed for all females of childbearing potential. 
4 Amyloid beta 40, Amyloid beta 42, Amyloid precursor protein intracellular domain (AICD), soluble neuregulin-1 
(sNRG-1) 
 
 
 
 
 
 


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Nature Cell Co., Ltd. 
GLOSSARY AND ABBREVIATIONS 
Aβ 
Amyloid beta 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale-cognitive subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study Activities of Daily Living 
AdMSC 
Adipose Tissue Derived Mesenchymal Stem Cell 
AE 
Adverse Event 
AICD 
Amyloid precursor protein Intracellular Domain 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT (SGPT) 
Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase) 
APP 
Amyloid Precursor Protein 
AST (SGOT) 
Aspartate Aminotransferase (Serum Glutamic Oxaloacetic Transaminase) 
BUN 
Blood Urea Nitrogen 
CDR-SOB 
Clinical Dementia Rating-Sum of Boxes 
CFR 
Code of Federal Regulations 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CREDOS 
Clinical Research Center for Dementia of South Korea 
ECG 
Electrocardiography 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
GDNF 
Glial cell-derived Neurotrophic Factor 
GDS 
Geriatric Depression Scale 
hASCs 
Human Adipose-derived Stem Cells 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
ICH 
International Conference of Harmonization 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MMSE 
Mini-mental status examination 
NINCDS-
ADRDA 
National Institute of Neurological and Communicative Disorders and Stroke; 
Alzheimer’s Disease and Related Disorders Association 
NPI 
Neuropsychiatric Inventory 
NT3 
Neurotrophin 3 
PP 
Per Protocol 
PT-INR 
Prothrombin Time - International Normalized Ratio 
RBC 
Red Blood Cell Count 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
sNRG-1 
Soluble Neuregulin-1 
VDRL 
Venereal Disease Research Laboratory 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell Count 
WMH 
White Matter Hyperintensity 
 
 


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1. 
PURPOSE OF STUDY 
 
The purpose of this study is to evaluate the safety and efficacy of AstroStem (autologous adipose 
tissue derived mesenchymal stem cells, AdMSCs) in patients with Alzheimer’s disease. 
 
 


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2. 
INTRODUCTION 
 
Alzheimer’s Disease (AD) is the most prevalent neurodegenerative disorder in The United States affecting 
approximately 5.4 million Americans [1]. AD is characterized by progressive loss in memory and as well 
as a decline in the ability to learn that is associated with neuronal death. Well known hallmarks of AD are 
neuritic plaques and neurofibrillary tangles [2, 3] and extensive inflammation [4]. Currently, no treatment 
has been developed to fully cure or prevent the progression of dementia that is associated with AD. 
 
In addition to neuritic plaques and neurofibrillary tangles, oxidative stress, mitochondrial dysfunction, 
hormone dysregulation, inflammation, mitotic dysfunction, calcium imbalance, and genetic risk factors are 
all involved in AD processes [5]. The disease is now recognized as multifactorial and consequently strongly 
demands more effective treatments.  
 
Therapeutic potentials of stem cells in several brain disorders are enticing researchers to apply stem cell 
based therapies [6–9]. Among stem cells, adipose tissue-derived mesenchymal stem cells (AMSCs), 
mesenchymal stem cells isolated from adipose tissue, are well known for their pluripotency and ability to 
differentiate into mesenchymal and non-mesenchymal lineages [10]. AMSCs are readily accessible and 
show high proliferation rates in vitro with lower senescence ratios than bone marrow derived mesenchymal 
stem cells [11]. Considering clinical applications, AMSCs are the most suitable source of stem cells due to 
the possibility of intravenous transplantation of autologous AMSCs with no immune rejections, ethical 
problems or tumorigenesis [12] and intravenous injection is the most convenient, simple and safest method 
of administration. 
 
The paracrine effects of stem cells, including the production of growth factors and anti-inflammatory 
cytokines and anti-apoptotic regulation, are strongly exerted and induce neural regeneration, remyelination 
and immunomodulation [13]. In a preclinical study, we demonstrated that intravenously injected stem cells 
could enter the brain through blood brain barrier and hASCs could have beneficial effects in a murine model 
of Alzheimer’s disease [14]. Compared to placebo group, memory impairments, the number of amyloid 
plaques, protein level of Amyloid beta (Aβ) and Amyloid Precursor Protein (APP) were reduced after 
intravenous injection of hASCs in Tg2567 mouse brain. Furthermore, analysis of Tg2576 mouse brain 
revealed that anti-inflammatory cytokine, IL-10 and neurotrophic factors including vascular endothelial 
growth factor (VEGF), Glial cell-derived neurotrophic factor (GDNF), and Neurotrophin 3 (NT3) were 
significantly increased after the injection of hASCs. These findings suggest that a convenient and safe 
intravenous injection of hASCs might be very useful for the treatment of AD.    
 
The clinical study of AstroStem aims to evaluate the safety and efficacy of AstroStem as a potential 
treatment for AD. Based on the preclinical results, AstroStem could be an effective treatment option with 
a mechanism of action that has not been explored for AD indication. 


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3. 
INVESTIGATIONAL PLAN 
 
3.1 
Study Design 
 
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of 
AstroStem for the treatment of Alzheimer’s Disease. Three investigational centers in the United 
Statesmay be utilized so that a total of approximately 22 subjects will be randomized.  
 
3.2 
Selection of Study Population 
 
The study population will be males or females, aged 50 and above, who have who have diagnosis 
of probable Alzheimer disease according to NINCDS-ADRDA (National Institute of Neurological 
and Communicative Disorders and Stroke; Alzheimer’s Disease and Related Disorders 
Association) criteria with 16-26 MMSE score. 
 
3.2.1 Inclusion Criteria 
 
1) Subjects who are males or females of any race, aged 50 and above at the time of signing the 
Informed Consent Form 
 
2) Subjects who can understand and provide written informed consent (assent). 
 
3) Subjects who have diagnosis of probable mild-to-moderate Alzheimer disease according to 
NINCDS-ADRDA (National Institute of Neurological and Communicative Disorders and 
Stroke; Alzheimer’s Disease and Related Disorders Association) criteria 
 
4) Subjects who have MMSE Score of 16 to 26 
 
5) Subjects who are taking FDA-approved AD medications (donepezil, galantamine, memantine, 
rivastigmine or their combinations) treatment on a stable dosage for at least 3 months prior to 
screening.   
 
6) Subjects who have one (or more) identified adult caregiver (study partner) who is able to read, 
understand, and speak the designated language at the study site; either lives with the subject or 
sees the subject for ≥2 hours/day ≥4 days/week; and agrees to accompany the subject to each 
study visit and to participate in the subject’s clinical assessments. 
 
 
3.2.2 Exclusion Criteria 
 


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1) Subjects who are female who are pregnant, nursing, or childbearing potential while not 
practicing effective contraception 
 
2) Subjects who have signs of delirium  
 
3) Subjects who have had cortical stroke within the preceding 2 years 
 
4) Subjects who have a prolonged QTc interval; >450 msec in male or >470 msec in female at 
screening 
 
5) Subjects who have diagnosis of severe white matter hyperintensity (WMH), which is defined 
as ≥ 25mm of the deep white matter and ≥ 10mm of the periventricular capping/banding in 
lengths 
 
6) Subjects who have diagnosis of dementia or cause of cognitive impairment other than 
Alzheimer’s disease 
 
7) Subjects who have a significant abnormal result in laboratory tests, in the opinion of the 
investigator 
 
8) Subjects who have participated in any investigational drug, stem cell therapy, or device trial 
within the previous 3 months at screening 
 
9) Subjects with any current psychiatric diagnosis other than AD if, in the judgment of the 
investigator, the psychiatric disorder or symptom is likely to confound interpretation of drug 
effect, affect cognitive assessments, or affect the subject´s ability to complete the study 
 
10) Subjects who are known to have autosomal dominant mutation-associated presenile AD 
 
11) Subjects who show signs of AIDS (Acquired Immunodeficiency Syndrome), HBV (Hepatitis 
B Virus), HCV (Hepatitis C), VDRL (Venereal Disease Research Laboratory) 
 
12) Subjects who have any conditions that would contraindicate an MRI, such as the presence 
metallic objects in the eyes, skin, or heart 
 
13) Subjects who have > 4 cerebral microhemorrhages (regardless of their anatomical location or 
diagnostic characterization as "possible" or "definite"), a single area of superficial siderosis, or 
evidence of a prior microhemorrhage as assessed by MRI 
 
 


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14) Subjects who have history of malignant cancer within the last 5 years (The following is a partial 
list of conditions that are permissible for study entry: non-metastatic basal and/or squamous 
cell carcinoma of the skin, in situ cervical, or non-progressive prostate cancer) 
 
15) Subjects who have suspected active lung disease based on chest X-ray  
 
16) Subjects who are hypersensitive to fetal bovine serum or penicillin 
 
17) Subjects who are currently using immunosuppressants, cytotoxic drug, corticosteroids or 
similar steroidal anti-inflammatory medication (e.g., Prednisone) on a regular basis 
(exceptions allowed include; regular use of steroidal nasal sprays, topical steroids, and 
estrogen-replacement therapy) 
 
18) Subjects for whom the investigator judges the liposuction can cause any problems 
 
19) Subjects who have history of local anesthetic allergy 
 
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 
• 
Subjects enrolled in the current trial but taking any prohibited medication/therapy stated in 
the inclusion/exclusion criteria 
• 
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. 
 


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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 
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 
• 
Significant change of benefit-risk ratio for the subjects 
• 
Sponsor discontinues the investigation of AstroStem for the treatment of Alzheimer’s 
Disease 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 -4), 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 Visits 3 through 12, the 
randomized subject will receive a single intravenous injection per visit.  
 
3.5.2 Identity of Investigational Product 
 
AstroStem is in a 20 ml syringe including AdMSCs as 1x108 cells/10mL of saline with 30% auto-
serum and is stable at refrigerated condition (+2 to +8 °C) up to 1 week. A negative control syringe 
including saline with 30% auto-serum will be packed by the aluminum foil pack to be matched 
with AstroStem syringe in appearance to be indistinguishable. 
 


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3.5.3 End of Study 
 
The efficacy results will be analyzed when the last subject completes Visit 13 (Week 30 follow-
up) and this study is finished when the last subject completes Visit 14 (Week 52 follow-up).  
 
3.5.4 Selection of Dose in Study 
 
The dosage of AstroStem was chosen through pre-clinical study published in PLOS One [14]. 
 
3.5.5 Choice of Control/Comparator 
 
This study uses saline with 30% auto-serum as a control.  
 
3.5.6 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 AstroStem 
and 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.        
   
After the eligibility is confirmed, a subject will be assigned with one randomization code using the 
electronic data capture (EDC) system on Visit 2 (Week -4). A randomization code is assigned into 
one of two groups.   
 
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 
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 (up to Week 52, a final follow-up visit): 


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• 
Any investigational drug 
• 
Any therapy that may affect Alzheimer’s disease, in the judgment of the investigator  
• 
Immunosuppressant 
• 
Cytotoxic drug 
• 
Corticosteroids or similar steroidal anti-inflammatory medication (e.g., Prednisone) on a 
regular basis (exceptions allowed include; regular use of steroidal nasal sprays, topical 
steroids, and estrogen-replacement therapy) 
 
3.5.8 Treatment Compliance  
 
All subjects will return on Visits 4, 5, 6, 7, 8, 9, 10, 11 and 12 (Weeks 2, 4, 6, 8, 10, 12, 14, 16 and 
18) for subsequent injections and Visits 13 and 14 (Weeks 30 and 52) for follow-ups. 
 
3.6 
 Study Endpoints and Variables 
 
3.6.1 Study Endpoints 
 
Primary endpoints used to determine the safety and efficacy of AstroStem is the following: 
• Number of subjects with treatment related adverse events as assessed by analysis of adverse 
events including symptoms, and abnormal findings on physical examination, vital signs, 
ECG, and standard laboratory examination results 
• Change of ADAS-Cog (Alzheimer’s Disease Assessment Scale-cognitive subscale) from 
baseline at Week 30 
The secondary endpoints used to determine the efficacy and safety of AstroStem are the 
following: 
• Change of MMSE (Mini-mental status examination) from baseline at Week 30 
• Changes of CDR-SOB (Clinical Dementia Rating-Sum of Boxes) from baseline at Week 
30 
• Changes of NPI (Neuropsychiatric Inventory) from baseline at Week 30 
• Changes of GDS (Geriatric Depression Scale) from baseline at Week 30 
• Change of ADCS-ADL (Alzheimer’s Disease Cooperative Study Activities of Daily 
Living) from baseline at Week 30 
• Changes of C-SSRS (Columbia Suicide Severity Rating Scale) from baseline at Week 30 
• Change of MRI imaging results from baseline at Week 30 
• Biomarkers in blood: Amyloid beta 40, Amyloid beta 42, Amyloid precursor protein 
intracellular domain (AICD), soluble neuregulin-1 (sNRG-1) 
 
3.6.2 Efficacy Variables 
 
• 
ADAS-Cog at Visits 3, 6, 9, 12, 13 and 14 or Early Termination 


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• 
MMSE at Visits 1, 3, 6, 9, 12, 13 and 14 or Early Termination  
• 
CDR-Box at Visits 3, 6, 9, 12, 13 and 14 or Early Termination  
• 
NPI at Visits 3, 6, 9, 12, 13 and 14 or Early Termination  
• 
GDS at Visits 3, 6, 9, 12, 13 and 14 or Early Termination  
• 
ADCS-ADL at Visits 3, 6, 9, 12, 13 and 14 or Early Termination  
• 
Biomarkers in blood [Amyloid beta 40, Amyloid beta 42, Amyloid precursor protein 
intracellular domain (AICD), soluble neuregulin-1 (sNRG-1)] at Visits 3, 13 and 14 or 
Early Termination  
 
The rating scales used in this study are ADAS-Cog (Alzheimer’s Disease Assessment Scale-
cognitive subscale), MMSE (Mini-mental status examination), CDR-SOB (Clinical Dementia 
Rating-Sum of Box), NPI (Neuropsychiatric Inventory), GDS (Geriatric Depression Scale) and 
ADCS-ADL (Alzheimer’s Disease Cooperative Study Activities). All questionnaires that are 
subject-administered should be completed by the subjects alone or along with caregiver 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. 
 
3.6.3 Safety Variables 
 
• 
Hematology, blood chemistry and urinalysis at Visits 1, 3, 6, 9, 12, 13 and 14 or Early 
Termination.   See Section Appendix 1 for a complete list of laboratory tests to be done. 
• 
ECG evaluation at Visits 1, 3, 6, 9, 12, 13 and 14 or Early Termination  
• 
Complete physical examination at Visits 1, 3, 6, 9, 12, 13 and 14 or Early Termination  
• 
Vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight will be 
measured at all visits. 
• 
MRI Scan of the brain at Visit 1, 9, 13 and 14 or Early Termination. 
• 
C-SSRS at Visit 3, 6, 9, 12, 13, and 14 or Early Termination  
• 
Data regarding AEs and concomitant medications will be collected at all visits  
 


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4. 
STUDY PROCEDURES 
 
4.1 
Screening Period 
 
 
 
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. 
 
4.1.1 Visit 1: Screening (Week -8) 
 
The following screening assessments/procedures must be performed and the results documented 
within 2 weeks before Visit 2 unless otherwise indicated: 
• 
Administer informed consent   
• 
Review the inclusion and exclusion criteria (See Section 3.2) 
• 
Record demographic data (i.e., date of birth, race and height). 
• 
Record medical and medication history. 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Perform a complete physical examination. 
• 
Measure 12-lead ECG. 
• 
Collect blood and urine samples for hematology, serum chemistry, pregnancy test (only for 
women of childbearing potential) and urinalysis. 
• 
Complete MMSE assessment 
• 
Perform chest X-ray. 
• 
Perform MRI scan including fluid-attenuation inversion recovery (FLAIR) and T2*-
weighted gradient-recalled-echo (GRE) sequences.  
 
4.1.2 Visit 2 (Week -4) 
 
Visit 2 will occur approximately 4 weeks (± 1 week) after Visit 1. During this visit, the following 
assessments/procedures should be performed: 
• 
Confirm eligibility and perform randomization instructed in Section 3.5.6.  
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable. 
• 
In sterile conditions, collect blood and harvest approximately 30 mL of fat using the syringe 
liposuction technique with Tumescent (or super-wet) local anesthesia (Please see the detail 
procedures in Appendix 9).  
• 
Ship the packaging box containing the harvested syringes and serum tubes to the lab 
designated by the sponsor (pre-labeled). 
 


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4.1.3 Preparation of Final Drug Product at Lab  
 
The following procedures for the preparation of final drug product will be performed by well-
trained lab technicians at the lab designated by the sponsor. The official package containing the 
final drug product (syringes) will be shipped to the clinical site.   
 
 
 
 
 
4.2 
Treatment Period 
 
 
 
4.2.1 Visit 3: Baseline (Week 0) 
 
Visit 3 will occur approximately 4 weeks after Visit 2. During this visit, the following 
assessments/procedures should be performed: 


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• 
The following questionnaires will be completed: ADAS-Cog (see Appendix 2), MMSE 
(see Appendix 3), CDR-SOB (see Appendix 4). NPI (see Appendix 5), GDS (see Appendix 
6), ADCS-ADL (see Appendix 7) and C-SSRS (see Appendix 8). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Perform a complete physical examination. 
• 
Measure 12-lead ECG. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable. 
• 
Collect blood and urine samples for hematology, serum chemistry, pregnancy test (only for 
women of childbearing potential), biomarker analysis and urinalysis. 
• 
Collect blood for IP and ship the packaging box containing the serum tubes to the lab 
designated by the sponsor (Please follow the serum for IP handling instruction separately 
provided by the sponsor). 
• 
Administer the AstroStem in 220 mL of saline (two times of 10 ml AstroStem in 100 mL 
of saline) or the same volume of saline via I.V. for 2-6 hours to patients in the treatment 
group and the placebo group, respectively (Please see the detail procedures in Appendix 
10).  
 
4.2.2 Visits 4, 8, 10 and 11 (Weeks 2, 10, 14 and 16) 
 
Visits 4, 8, 10 and 11 will occur approximately 2 weeks (± 3 days) after the previous visit. During 
this visit, the following assessments/procedures should be performed: 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable.  
• 
Verify if subjects are eligible to have a repeated injection by confirming subjects has not 
experienced infusion reaction, allergic reaction or anaphylaxis in associated with the 
previous study drug administration. 
• 
Administer the AstroStem in 220 mL of saline or the same volume of saline via I.V. for 2-
6 hours to patients in the treatment group and the placebo group, respectively.  
 
4.2.3 Visits 5 and 7 (Weeks 4 and 8) 
 
Visits 5 and 7 will occur approximately 2 weeks (± 3 days) after the previous visit. During this 
visit, the following assessments/procedures should be performed: 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable.  
• 
Collect blood for IP and ship the packaging box containing the serum tubes to the lab 
designated by the sponsor (Please follow the serum for IP handling instruction separately 
provided by the sponsor). 


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• 
Verify if subjects are eligible to have a repeated injection by confirming subjects has not 
experienced infusion reaction, allergic reaction or anaphylaxis in associated with the 
previous study drug administration. 
• 
Administer the AstroStem in 220 mL of saline or the same volume of saline via I.V. for 2-
6 hours to patients in the treatment group and the placebo group, respectively.  
 
4.2.4 Visit 6 (Week 6) 
 
Visit 6 will occur approximately 2 weeks (± 3 days) after Visit 5. During this visit, the following 
assessments/procedures should be performed: 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Perform a complete physical examination. 
• 
Measure 12-lead ECG. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable. 
• 
Verify if subjects are eligible to have a repeated injection by confirming subjects has not 
experienced infusion reaction, allergic reaction or anaphylaxis in associated with the 
previous study drug administration. 
• 
The following questionnaires will be completed: ADAS-Cog (see Appendix 2), MMSE 
(see Appendix 3), CDR-SOB (see Appendix 4). NPI (see Appendix 5), GDS (see Appendix 
6), ADCS-ADL (see Appendix 7) and C-SSRS (see Appendix 8). 
• 
Collect blood and urine samples for hematology, serum chemistry and urinalysis. 
• 
Administer the AstroStem in 220 mL of saline or the same volume of saline via I.V. for 2-
6 hours to patients in treatment group and placebo group, respectively.  
 
4.2.5 Visit 9 (Week 12) 
 
Visit 9 will occur approximately 2 weeks (± 3 days) after Visit 8. During this visit, the following 
assessments/procedures should be performed: 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Perform a complete physical examination. 
• 
Measure 12-lead ECG. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable. 
• 
Verify if subjects are eligible to have a repeated injection by confirming subjects has not 
experienced infusion reaction, allergic reaction or anaphylaxis in associated with the 
previous study drug administration. 
• 
The following questionnaires will be completed: ADAS-Cog (see Appendix 2), MMSE 
(see Appendix 3), CDR-SOB (see Appendix 4). NPI (see Appendix 5), GDS (see Appendix 
6), ADCS-ADL (see Appendix 7), and C-SSRS (see Appendix 8). 
• 
Perform MRI scan including FLAIR and T2- weighted gradient-echo sequences. 


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• 
Collect blood and urine samples for hematology, serum chemistry and urinalysis. 
• 
Collect blood for IP and ship the packaging box containing the serum tubes to the lab 
designated by the sponsor (Please follow the serum for IP handling instruction separately 
provided by the sponsor). 
• 
Administer the AstroStem in 220 mL of saline or the same volume of saline via I.V. for 2-
6 hours to patients in treatment group and placebo group, respectively.  
 
4.2.6 Visit 12 (Week 18) 
 
Visit 12 will occur approximately 2 weeks (± 3 days) after Visit 11. During this visit, the following 
assessments/procedures should be performed: 
• 
The following questionnaires will be completed: ADAS-Cog (see Appendix 2), MMSE 
(see Appendix 3), CDR-SOB (see Appendix 4). NPI (see Appendix 5), GDS (see Appendix 
6), ADCS-ADL (see Appendix 7) and C-SSRS (see Appendix 8). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Perform a complete physical examination. 
• 
Measure 12-lead ECG. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable. 
• 
Verify if subjects are eligible to have a repeated injection by confirming subjects has not 
experienced infusion reaction, allergic reaction or anaphylaxis in associated with the 
previous study drug administration. 
• 
Collect blood and urine samples for hematology, serum chemistry, pregnancy test (only for 
women of childbearing potential) and urinalysis. 
• 
Administer the AstroStem in 220 mL of saline or the same volume of saline via I.V. for 2-
6 hours to patients in treatment group and placebo group, respectively.  
 
4.3 
Follow-up Period 
 
 
 
4.3.1 Visit 13: 1st Follow-up Visit (Week 30) 
 
The first follow-up visit, Visit 13, will occur approximately 12 weeks (± 7 days) after Visit 12. 
During this visit, the following assessments/procedures should be performed: 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Perform a complete physical examination. 
• 
Measure 12-lead ECG. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable. 
• 
The following questionnaires will be completed: ADAS-Cog (see Appendix 2), MMSE 
(see Appendix 3), CDR-SOB (see Appendix 4). NPI (see Appendix 5), GDS (see Appendix 
6), ADCS-ADL (see Appendix 7) and C-SSRS (see Appendix 8). 


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• 
Collect blood and urine samples for hematology, serum chemistry, pregnancy test (only for 
women of childbearing potential), biomarker analysis and urinalysis. 
• 
Perform MRI scan including FLAIR and T2- weighted gradient-echo sequences.   
 
4.3.2 Visit 14: Final Follow-up Visit (Week 52) 
 
The final follow-up visit, Visit 14, will occur approximately 22 weeks (± 7 days) after Visit 13. 
During this visit, the following assessments/procedures should be performed: 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
a complete physical examination. 
• 
Measure 12-lead ECG. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable. 
• 
Perform The following questionnaires will be completed: ADAS-Cog (see Appendix 2), 
MMSE (see Appendix 3), CDR-SOB (see Appendix 4). NPI (see Appendix 5), GDS (see 
Appendix 6), ADCS-ADL (see Appendix 7), and C-SSRS (see Appendix 8). 
• 
Collect blood and urine samples for hematology, serum chemistry, pregnancy test (only for 
women of childbearing potential), biomarker analysis and urinalysis. 
• 
Perform MRI scan including FLAIR and T2- weighted gradient-echo sequences.   
 
4.4 
Early Termination Visit 
 
 
If a subject will drop-out the study before Visit 14 (Week 52), the clinical site will try to schedule 
an early termination visit. During this visit, the following assessments and procedures should be 
performed: 
• 
The following questionnaires will be completed: ADAS-Cog (see Appendix 2), MMSE 
(see Appendix 3), CDR-SOB (see Appendix 4). NPI (see Appendix 5), GDS (see Appendix 
6), ADCS-ADL (see Appendix 7) and C-SSRS (see Appendix 8). 
• 
Measure vital signs (sitting blood pressure, pulse, breathing, and temperature) and weight. 
• 
Perform a complete physical examination. 
• 
Measure 12-lead ECG. 
• 
Record any changes in concomitant medications. 
• 
Record any adverse events, if applicable. 
• 
Collect blood and urine samples for hematology, serum chemistry, pregnancy test (only for 
women of childbearing potential), biomarker analysis and urinalysis. 
• 
Perform MRI scan including FLAIR and T2- weighted gradient-echo sequences.   
 
4.5 
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 


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on-site review of the eCRF for completeness and clarity, consistency with source documents, and 
clarification of administrative matters. 
 
4.6 
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 
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 
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.  
 


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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 at least one intravenous 
injection and have post-injection efficacy measurements. This population will be evaluated for all 
efficacy variables. 
 
6.1.1.2 
Per-Protocol Population 
 
All subjects valid for ITT who complete Visit 13 (Week 30) 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 
 
A safety population will include subjects who received at least one intravenous injection and have 
post-injection safety measurements. This population 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 test will be performed using a 5% significance level. For the 
secondary efficacy endpoints, hypothesis tests will be performed individually at the 5% 
significance level. All hypothesis tests will be performed with two-sided alternative hypotheses. 
No adjustments on the significance level for multiple comparisons are planned, as this is a phase 
1/2 study. 
 
6.1.4 Primary Efficacy Analyses 
 


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The primary efficacy variable is the change from Baseline on the ADAS-Cog score at Week 30. 
The primary efficacy variable will be summarized with means, standard deviations, medians and 
ranges, overall and by group.  The change from Baseline ADAS-Cog score will be analyzed with 
Student’s t-test  or Kruskal-Wallis test depending on the violation of normality assumption.  
 
6.1.5 Secondary Efficacy Analyses 
 
The secondary efficacy analyses are described below.  They will be  summarized with means, 
standard deviations, medians and ranges for continuous variables and with counts and percentages 
for categorical variables. 
  
The percentage of subjects who show improvement will be compared between groups using chi-
square test or Fisher’s exact test, as appropriate.  Fisher’s exact test will be used if the expected 
frequency in any of the cells of the crosstabulation is less than 5.   
 
Change from baseline at Week 30 in MMSE, CDR-SOB, NPI, GDS and ADCS-ADL will be 
compared between groups using t-test or Kruskal-Wallis tests, as appropriate.  If the change is 
approximately normally distributed, t-test will be used.  If the change is markedly non-normally 
distributed, Kruskal-Wallis test will be used.  
 
6.1.6 Exploratory Efficacy Analyses 
 
Change from baseline scores at Visits 6, 9, 12, 13 and 14 or Early Termination for: ADAS-Cog, 
MMSE, CDR-Box, NPI, GDS, and ADCS-ADL will be  summarized with means, standard 
deviations, medians and ranges by treatment group and visit.  Biomarkers in blood [Amyloid beta 
40, Amyloid beta 42, Amyloid precursor protein intracellular domain (AICD), soluble neuregulin-
1 (sNRG-1)] will be summarized at all visits with means, standard deviations, medians and ranges 
for continuous variables and with counts and percentages for categorical variables. 
 
6.1.7 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. Change of MRI, C-SSRS, physical examinations, vital signs, 
ECG and standard laboratory results will be summarized with means, standard deviations, medians 
and ranges for continuous variables and with counts and percentages for categorical variables. 
Statistical tests are not planned for safety variables. 
 
6.1.7.1 Interim Safety Analyses 
 
When the first 4 subjects complete Visit 4 at Week 2, one unblinded interim safety analysis can be 
performed by an independent safety monitor contracted by the sponsor to evaluate the safety of 


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AstroStem without the suspension of subject enrollment. Change of vital signs and AEs will be 
evaluated.  
 
6.1.8 Missing Data 
 
No adjustments for missing data and no imputation methods are planned for this phase 1/2 study.  
 
6.2 
Determination of Sample Size 
 
There was no formal sample size calculation since this is a phase 1/2 study and is not a hypothesis-
driven study.  The number of enrolled subjects is predefined at n=22, for 11 subjects per group. 


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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 any AE or suspected adverse reaction that in the view of either 
the investigator or Sponsor, results in any of the following outcomes:  
 
• Death 
• A life-threatening AE: it is defined as an AE or suspected adverse reaction that in the view 
of the investigator or Sponsor, its occurrence places the patient or subject at immediate risk 
of death. It does not include an AE or suspected adverse reaction that, had it occurred in a 
more severe form, might have caused death.  
• Inpatient hospitalization or prolongation of existing hospitalization 
A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life function.  
• A congenital anomaly/birth defect 


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• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical intervention 
to prevent one of outcomes listed in the above definition 
 
Life threatening:  An adverse event or suspected adverse reaction is considered “life-threatening” 
if, in the view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse reaction that, 
had it occurred in a more severe form, might have caused death.  
 
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 24 hours OR 
• 
the admission is pre-planned (i.e., elective or scheduled surgery arranged prior to the start 
of the study) OR 
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: 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 subject 
identification, relationship to investigational product, start and stop dates, severity, action taken, 
and outcome. 
 


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7.2.1 Relationship of Adverse Event to Study Drug 
 
The following adverse event attributes must be assigned by the investigator:  adverse event 
diagnosis or syndrome(s) (if known, signs or symptoms if not known); event description (with 
detail appropriate to the event); dates of onset and resolution; severity; assessment of relatedness 
to study drug and action taken. The investigator may be asked to provide follow-up information, 
discharge summaries, and extracts from medical records or eCRFs. 
 
If applicable, the relationship of the adverse event to the study drug will be assessed by means of 
the question: “Is there a reasonable possibility that the event may have been caused by the study 
drug?”  The investigator should respond to this question with either Yes or No. 
 
7.2.2 Adverse Event Severity 
 
The severity of adverse events should be graded as follows: 
• 
Mild – Usually transient in nature and generally not interfering with normal activities 
• 
Moderate – Sufficiently discomforting to interfere with normal activities 
• 
Severe – Prevents normal activities 
 
Medically significant adverse events considered related to the study drug by the investigator or 
Sponsor will be followed until resolved or considered stable. 
 
It will be left to the investigator’s clinical judgment to determine whether an adverse event is 
related and of sufficient severity to require the subject’s removal from treatment or from the study. 
A subject may also voluntarily withdraw from treatment due to what he or she perceives as an 
intolerable adverse event. If either of these situations arises, the subject should be strongly 
encouraged to undergo an end-of-study assessment and be under medical supervision until 
symptoms cease or the condition becomes stable. 
 
7.3 
Serious Adverse Event Reporting Procedures 
 
Serious Adverse Events, 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 
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.  
 
Reporting of SAEs begins from the first administration of the study drug through within 30 days 
after the last dose of study drug.  Events assessed by the Investigator as related to study drug (or 


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having an unknown relationship at the time of reporting) should be reported within 24 hours 
regardless of the number of days since the last dose. 
 
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 30 days after 
administration of the last dose of study drug. Deaths assessed by the Investigator as related to study 
drug (or having an unknown relationship at the time of reporting) should be reported within 24 
hours regardless of the number of days since the last dose. 
 
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. 
 
7.4 
Procedures for Managing Microhemorrhages and Cerebral Vasogenic Edema 
 
MRI scan will be performed at screening, Visit 9 (Week 12), Visit 13 (Week 30), Visit 14 (Week 
52), and/or Early Termination Visit. The protocols for MRI scans should include fluid-attenuation 
inversion recovery (FLAIR) and T2-weighted gradient-recalled-echo (GRE) sequences. Standards 
for the detection of cerebral microhemorrhage or superficial siderosis will include: 2D T2 GRE; 
field strength of 1.5 Tesla or greater; slice thickness of 5mm or less; Echo Time (TE) of 20 ms or 
greater.  Standard FLAIR sequences are generally appropriate for the detection of cerebral 
vasogenic edema. 
 
Subjects who are found to have new clinically asymptomatic microhemorrhages will be followed 
up closely, and a follow-up MRI will be done to evaluate the stability of those lesions. 
 
All Principal Investigators will be notified of the possible occurrence of cerebral vasogenic edema, 
its imaging manifestations, and the clinical signs and symptoms that may accompany this 
phenomenon. They will also be told of the measures to be taken if cerebral vasogenic edema 
occurs. Those measures will include more frequent serial MRI scans until the imaging 
abnormalities resolve, and consideration of treatment with high-dose dexamethasone if symptoms 
are severe. 
 
 
 


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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  
 
1. Alzheimer’s Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 
2016 April;12(4):459-509. 
 
2. Blurton-Jones M, Kitazawa M, Martinez-Coria H, Castello NA, Müller FJ, Loring JF, 
Yamasaki TR, Poon WW, Green KN, LaFerla FM. Neural stem cells improve cognition via 
BDNF in a transgenic model of Alzheimer disease. Proc Natl Acad Sci U S A. 2009 Aug 
11;106(32):13594-13599. 
 
3. Oddo S, Caccamo A, Kitazawa M, Tseng BP, LaFerla FM. Amyloid deposition precedes 
tangle formation in a triple transgenic model of Alzheimer's disease. Neurobiol Aging. 2003 
Dec;24(8):1063-70. 
 
4. Meda L, Cassatella MA, Szendrei GI, Otvos L Jr, Baron P, Villalba M, Ferrari D, Rossi F. 
Activation of microglial cells by beta-amyloid protein and interferon-gamma. Nature. 1995 
Apr 13;374(6523):647-650. 
 
5. Anand R., Gill K.D., Mahdi A.A. Therapeutics of Alzheimer’s disease: Past, present and 
future. Neuropharmacology. 2014;76:27–50. 
 
6. Ebert AD, Beres AJ, Barber AE, Svendsen CN. Human neural progenitor cells over-
expressing IGF-1 protect dopamine neurons and restore function in a rat model of Parkinson's 
disease. Exp Neurol. 2008 Jan;209(1):213-223. 
 
7. Lu P, Jones LL, Snyder EY, Tuszynski MH. Neural stem cells constitutively secrete 
neurotrophic factors and promote extensive host axonal growth after spinal cord injury. Exp 
Neurol. 2003 Jun;181(2):115-129. 
 
8. Park KI, Himes BT, Stieg PE, Tessler A, Fischer I, Snyder EY. Neural stem cells may be 
uniquely suited for combined gene therapy and cell replacement: Evidence from engraftment 
of Neurotrophin-3-expressing stem cells in hypoxic-ischemic brain injury. Exp Neurol. 2006 
May;199(1):179-190. 
 
9. Lee H.J., Lee J.K., Lee H., Carter J.E., Chang J.W., Oh W., Yang Y.S., Suh J.G., Lee B.H., 
Jin H.K., et al. Human umbilical cord blood-derived mesenchymal stem cells improve 
neuropathology and cognitive impairment in an Alzheimer’s disease mouse model through 
modulation of neuroinflammation. Neurobiol. Aging. 2012;33:588–602. 
 


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10. Anghileri E, Marconi S, Pignatelli A, Cifelli P, Galié M, Sbarbati A, Krampera M, Belluzzi 
O, Bonetti B. Neuronal differentiation potential of human adipose-derived mesenchymal stem 
cells. Stem Cells Dev. 2008 Oct;17(5):909-916. 
 
11. Huang T, He D, Kleiner G, Kuluz J. Neuron-like differentiation of adipose-derived stem cells 
from infant piglets in vitro. J Spinal Cord Med. 2007;30 Suppl 1:S35-40. 
 
12. Ra JC, Shin IS, Kim SH, Kang SK, Kang BC, Lee HY, Kim YJ, Jo JY, Yoon EJ, Choi HJ, 
Kwon E. Safety of intravenous infusion of human adipose tissue-derived mesenchymal stem 
cells in animals and humans. Stem Cells Dev. 2011 Aug;20(8):1297-1308. 
 
13. Urdzikova L.M., Ruzicka J., LaBagnara M., Karova K., Kubinova S., Jirakova K., Murali R., 
Sykova E., Jhanwar-Uniyal M., Jendelova P. Human mesenchymal stem cells modulate 
inflammatory cytokines after spinal cord injury in rat. Int. J. Mol. Sci. 2014;15:11275–11293. 
 
14. Kim S1, Chang KA, Kim Ja, Park HG, Ra JC, Kim HS, Suh YH. The preventive and 
therapeutic effects of intravenous human adipose-derived stem cells in Alzheimer's disease 
mice. Plos One 2012 Sep;7(9):e45757 
 
 
 


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10. 
APPENDICES  
 
Appendix 1. Laboratory Parameters 
 
Appendix 2. ADAS-Cog (Alzheimer’s Disease Assessment Scale-cognitive subscale) 
 
Appendix 3. MMSE (Mini-mental status examination) 
 
Appendix 4. CDR-SOB (Clinical Dementia Rating-Sum of Box)  
 
Appendix 5. NPI (Neuropsychiatric Inventory) 
 
Appendix 6. GDS (Geriatric Depression Scale) 
 
Appendix 7. ADCS-ADL (Alzheimer’s Disease Cooperative Study Activities of Daily Living) 
 
Appendix 8. C-SSRS (Columbia Suicide Severity Rating Scale) 
 
Appendix 9. Instruction for Liposuction Procedure 
 
Appendix 10. IP Administration Instruction for Clinical Sites 
 
 
 
 
 
 
 
 
 


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Appendix 1. Laboratory Parameters 
 
Blood and urine samples for complete laboratory evaluation (hematology, serum chemistry, 
biomarker analysis and urinalysis) at Visits 1, 3, 6, 9, 12, 13 and 14 or Early Termination.   
 
HEMATOLOGY 
CHEMISTRY 
URINALYSIS 
BIOMARKER*** 
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 ** 
HBV** 
HCV** 
VDRL** 
Color 
Appearance 
Specific gravity 
pH  
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Leukocyte esterase 
WBC 
RBC 
Epithelial cell 
Bacteria 
Hyaline casts 
 
Amyloid beta 40 
Amyloid beta 42 
Amyloid 
precursor protein 
intracellular 
domain (AICD) 
soluble 
neuregulin-1 
(sNRG-1) 
 
*  HCG (pregnancy test) only for all females of childbearing potential at Visits 1, 3, 12, 13 and 14 or Early 
Termination  
**  Visit 1 only 
*** Visits 3 and 13, 14 or Early Termination 
 
 
 


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Appendix 2. ADAS-Cog (Alzheimer’s Disease Assessment Scale-cognitive subscale)  


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Appendix 5. NPI (Neuropsychiatric Inventory) 
 


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Appendix 8. C-SSRS (Columbia-Suicide Severity Rating Scale) 
 
 


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Appendix 9. Instruction for Liposuction Procedure 
 


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Appendix 10. IP Administration Instruction for Clinical Sites 
 


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SAP_001.pdf: 
Page 1
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Statistical Analysis Plan  
Version 1.0 Final, 10Jul2019 
 
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Statistical Analysis Plan  
 
 
A Phase 1 / 2 , Randomized, Double-Blind, Placebo-Controlled 
Study to Evaluate the Safety and Efficacy of AstroStem, 
Autologous Adipose Tissue Derived Mesenchymal Stem Cells, in 
Patients with Alzheimer’s Disease 
 
 
 
IND Number: 17,201 
 
 
Nature Cell Co., Ltd. 
5F, 10 Gukhoe-daero 76-gil 
Yeongdeungpo-gu, Seoul     
150-870, Korea Protocol  
JS-OAP2-US01 Phase 2 
 
 
Statistical Analysis Plan Version 1.0: July 10, 2019  
 
Protocol Version 6.0: Mar 4, 2019  
 
Approval Date: 12 July 2019 
 
 
 
Confidential Notice 
This document contains confidential information of Nature Cell Co., Ltd. (NC). 
This document must not be disclosed to anyone other than the study staff and 
members of the scientific review board or independent review board. The 
information in this document cannot be used for any purpose other than the 
evaluation or conduct of the clinical investigation without the prior written 
consent of NC. If you have questions regarding how this document may be 
used or shared, contact the sponsor. For all study related questions, contact 
the US Representative, KCRN Research (KCRN). 


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Statistical Analysis Plan Approval 
 
 
Prepared by: 
 
 
 
_________________________________________ 
 
____________________ 
Eunsil Yim 
Date (DD MMM YYYY) 
Director, Biostatistics, KCRN Research 
 
 
Reviewed and Approved by: 
 
 
 
 
_________________________________________ 
 
____________________ 
Yeon Jang 
Date (DD MMM YYYY) 
Project Manager, KCRN Research 
 
 
 
 
_________________________________________ 
 
____________________ 
Christine Lee 
Date (DD MMM YYYY) 
Data Manager, KCRN Research 
 
 
Sponsor Review and Approval: 
 
 
 
 
_________________________________________ 
 
____________________ 
Jeong Chan Ra 
Date (DD MMM YYYY) 
CEO, Nature Cell 
 
 


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Table of Contents 
GLOSSARY AND ABBREVIATIONS .......................................................................................................... 4 
1. 
REVISION HISTORY ............................................................................................................................ 5 
2. 
STUDY OBJECTIVES........................................................................................................................... 5 
2.1. 
PRIMARY OBJECTIVE........................................................................................................................ 5 
2.2. 
SECONDARY OBJECTIVES .................................................................................................................. 5 
2.3. 
EXPLORATORY OBJECTIVES ............................................................................................................. 6 
3. 
STUDY DESIGN .................................................................................................................................... 7 
3.1. 
SUMMARY OF STUDY DESIGN ........................................................................................................... 7 
3.2. 
DETERMINATION OF SAMPLE SIZE .................................................................................................... 8 
3.3. 
METHOD OF ASSIGNMENT TO TREATMENT ........................................................................................ 8 
4. 
STATISTICAL METHODS .................................................................................................................... 8 
4.1. 
GENERAL CONSIDERATIONS ............................................................................................................. 8 
4.2. 
ADJUSTMENTS FOR COVARIATES ...................................................................................................... 9 
4.3. 
ANALYSIS POPULATIONS .................................................................................................................. 9 
4.3.1. 
Intent-to-Treat Population ..................................................................................................... 9 
4.3.2. 
Per-Protocol Population ........................................................................................................ 9 
4.3.3. 
Safety Population .................................................................................................................. 9 
4.4. 
BASELINE AND POSTBASELINE DEFINITION ...................................................................................... 10 
4.5. 
HANDLING OF DROPOUTS OR MISSING DATA................................................................................... 10 
4.6. 
TREATMENT GROUP COMPARABILITY ............................................................................................. 11 
4.6.1. 
Patient Disposition............................................................................................................... 11 
4.6.2. 
Protocol Deviations ............................................................................................................. 11 
4.6.3. 
Patient Characteristics ........................................................................................................ 11 
4.6.4. 
Prior and Concomitant Therapy .......................................................................................... 11 
4.6.5. 
Treatment Compliance ........................................................................................................ 12 
4.7. 
EFFICACY ANALYSES ..................................................................................................................... 12 
4.7.1. 
Primary Efficacy Analysis .................................................................................................... 12 
4.7.2. 
Secondary Efficacy Analyses .............................................................................................. 12 
4.7.3. 
Exploratory Efficacy Analyses ............................................................................................. 13 
4.8. 
SAFETY ANALYSES ........................................................................................................................ 13 
4.8.1. 
Adverse Events ................................................................................................................... 14 
4.8.2. 
Potential Hypersensitivity Events (Serious Adverse Events) .............................................. 14 
4.8.3. 
Clinical Laboratory Evaluation ............................................................................................. 16 
4.8.4. 
Suicide-Related Thoughts and Behaviors ........................................................................... 16 
4.8.5. 
Vital Signs ........................................................................................................................... 16 
4.8.6. 
Electrocardiogram ............................................................................................................... 17 
4.9. 
INTERIM ANALYSIS AND DATA MONITORING ..................................................................................... 17 
4.10. 
HANDLING OF DROPTOUTS OR MISSING DATA ............................................................................. 17 
4.11. 
SUBGROUP ANALYSIS ................................................................................................................ 17 
4.12. 
MULTIPLE COMPARISON/MULTIPLICITY ....................................................................................... 17 
5. 
CHANGES TO PROTOCOL-SPECIFIED ANALYSES ...................................................................... 17 
6. 
REFERENCES .................................................................................................................................... 17 
7. 
APPENDICES ..................................................................................................................................... 18 
7.1. 
APPENDIX 1. LABORATORY PARAMETERS ....................................................................................... 18 


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Glossary and Abbreviations 
 
Aβ 
Amyloid beta 
AD 
Alzheimer’s Disease 
ADAS-Cog 
Alzheimer’s Disease Assessment Scale-cognitive subscale 
ADCS-ADL 
Alzheimer’s Disease Cooperative Study Activities of Daily Living 
AdMSC 
Adipose Tissue Derived Mesenchymal Stem Cell 
AE 
Adverse Event 
AICD 
Amyloid precursor protein Intracellular Domain 
AIDS 
Acquired Immunodeficiency Syndrome 
ALT (SGPT) 
Alanine Aminotransferase (Serum Glutamic Pyruvic Transaminase) 
APP 
Amyloid Precursor Protein 
AST (SGOT) 
Aspartate Aminotransferase (Serum Glutamic Oxaloacetic Transaminase) 
BUN 
Blood Urea Nitrogen 
CDR-SOB 
Clinical Dementia Rating-Sum of Boxes 
CFR 
Code of Federal Regulations 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CREDOS 
Clinical Research Center for Dementia of South Korea 
ECG 
Electrocardiography 
eCRF 
Electronic Case Report Form 
GCP 
Good Clinical Practice 
GDNF 
Glial cell-derived Neurotrophic Factor 
GDS 
Geriatric Depression Scale 
hASCs 
Human Adipose-derived Stem Cells 
HBV 
Hepatitis B Virus 
HCV 
Hepatitis C Virus 
ICH 
International Conference of Harmonization 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
MCH 
Mean Corpuscular Hemoglobin 
MCHC 
Mean Corpuscular Hemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MMSE 
Mini-mental status examination 
NINCDS-
ADRDA 
National Institute of Neurological and Communicative Disorders and Stroke; 
Alzheimer’s Disease and Related Disorders Association 
NPI 
Neuropsychiatric Inventory 
NT3 
Neurotrophin 3 
PP 
Per Protocol 
PT-INR 
Prothrombin Time - International Normalized Ratio 
RBC 
Red Blood Cell Count 
SAE 
Serious Adverse Event 
SD 
Standard Deviation 
sNRG-1 
Soluble Neuregulin-1 
VDRL 
Venereal Disease Research Laboratory 
VEGF 
Vascular Endothelial Growth Factor 
WBC 
White Blood Cell Count 
WMH 
White Matter Hyperintensity 
 
 


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1. 
Revision History 
 
SAP Version 1 was created and approved prior to first patient visit and any unblinding of the 
study team.  
 
 
2. 
Study Objectives 
 
2.1. 
Primary Objective 
 
Table 1 shows the primary objectives and endpoints used to determine the safety and 
efficacy of AstroStem in patients with Alzheimer’s disease. 
 
Table 1. Primary Objectives and Endpoints 
 
Objectives 
Endpoints 
Primary Efficacy 
• To evaluate the efficacy of 
AstroStem in patients with 
Alzheimer’s disease 
 
Primary Safety 
• To evaluate the safety of 
AstroStem in patients with 
Alzheimer’s disease 
 
• Change of ADAS-Cog (Alzheimer’s Disease Assessment 
Scale-cognitive subscale) from baseline (Visit 3)  to Visit 
13 (Week 30) 
 
 
• Number of subjects with treatment related adverse 
events as assessed by analysis of adverse events 
including symptoms, and abnormal findings on physical 
examination, vital signs, ECG, and standard laboratory 
examination results 
 
2.2. 
Secondary Objectives 
 
Table 2 shows the secondary objectives and endpoints used to determine the safety and 
efficacy of AstroStem. 
 
Table 2. Secondary Objectives and Endpoints 
 
Objectives 
Endpoints 
Secondary Efficacy 
• To evaluate the efficacy of 
AstroStem in patients with 
Alzheimer’s disease 
 
 
 
• Change of MMSE (Mini-mental status examination) from 
baseline at Week 30 (Visit 13) 
• Changes of CDR-SOB (Clinical Dementia Rating-Sum of 
Boxes) from baseline at Week 30 


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Secondary Safety 
• To evaluate the safety of 
AstroStem in patients with 
Alzheimer’s disease 
• Changes of NPI (Neuropsychiatric Inventory) from 
baseline at Week 30 
• Changes of GDS (Geriatric Depression Scale) from 
baseline at Week 30 
• Change of ADCS-ADL (Alzheimer’s Disease Cooperative 
Study Activities of Daily Living) from baseline at Week 30 
 
 
• Changes of C-SSRS (Columbia Suicide Severity Rating 
Scale) from baseline at Week 30 
• Change of MRI imaging results from baseline at Week 30 
 
2.3. 
Exploratory Objectives 
 
Table 3 shows the exploratory objectives and endpoints used to determine the safety and 
efficacy of AstroStem. 
 
Table 3. Exploratory Objectives and Endpoints 
 
Objectives 
Endpoints 
Exploratory Efficacy 
• To evaluate the efficacy of 
AstroStem in patients with 
Alzheimer’s disease 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Exploratory  Safety 
• To evaluate the efficacy of 
AstroStem in patients with 
Alzheimer’s disease 
 
 
• Change of ADAS-Cog  from baseline at Visit 6, 9, 12 and 
14 or Early Termination 
• Change of MMSE from baseline at Visit 6, 9, 12 and 14 
or Early Termination 
• Changes of CDR-SOB  from baseline at Visit 6, 9, 12 and 
14 or Early Termination 
• Changes of NPI  from baseline at Visit 6, 9, 12 and 14 or 
Early Termination 
• Changes of GDS  from baseline at Visit 6, 9, 12 and 14 
or Early Termination 
• Change of ADCS-ADL  from baseline at Visit 6, 9, 12 and 
14 or Early Termination 
• Summary of Biomarkers in blood: Amyloid beta 40, 
Amyloid beta 42, Amyloid precursor protein intracellular 
domain (AICD), soluble neuregulin-1 (sNRG-1) at 
baseline,  Visit 13 and 14 or Early Termination  
 
 
• Changes of C-SSRS  from baseline at Visit 6, 9, 12 and 
14 or Early Termination 
• Change of MRI imaging results from baseline at Visit 9 
and 14 or Early Termination 


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3. 
Study Design 
 
3.1. 
Summary of Study Design 
 
This is a randomized, double-blind, placebo-controlled study to evaluate the efficacy and 
safety of AstroStem for the treatment of Alzheimer’s Disease. Three investigational 
centers in the United States may be utilized so that a total of approximately 22 subjects 
will be randomized. At Week -4, 30 mL of abdominal adipose tissue will be taken by 
liposuction from subjects. The adipose tissue samples will be sent to Biostar Stem Cell 
Research Institute to isolate AdMSCs. The isolated AdMSCs or saline will be sent to the 
clinical sites with identical syringes to preserve double-blinding of the study. A total 2x108 
AdMSCs in 220 mL of saline or the same volume of saline will be administered via I.V. at 
Week 0. This procedure will be repeated 9 times at 2-week interval. Subjects will be 
scheduled for two follow-up visits at Weeks 30 and 52 to evaluate primary and secondary 
outcome endpoints. The schedule of Assessments is illustrated in Table 4. 
 
Table 4. Schedule of Assessments 
 
Procedure 
Screen 
Treatment 
Follow-up 
Early 
Termination 
V1 
V2 
V3 V4 V5 V6 V7 
V8 
V9 
V10 V11 
V12 
V13 
V14 
Tested Group 
-W8 -W4 W0 W2 W4 W6 W8 W10 W12 W14 W16 W18 W30 W52 
Informed Consent1 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic information 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical/medication history 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
V 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
Vital signs 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
Hematology, serum 
chemistry, and urinalysis 2 
V 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
Pregnancy test 3 
V 
 
V 
 
 
 
 
 
 
 
 
V 
V 
V 
V 
Electrocardiogram 
V 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
Chest X-ray 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Liposuction  
 
V 
 
 
 
 
 
 
 
 
 
 
 
 
 
Serum for IP 
 
V 
V 
 
V 
 
V 
 
V 
 
 
 
 
 
 
ADAS-Cog 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
MMSE 
V 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
CDR-SOB 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
NPI 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
GDS 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
C-SSRS 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
ADCS-ADL 
 
 
V 
 
 
V 
 
 
V 
 
 
V 
V 
V 
V 
MRI Scan 
V 
 
 
 
 
 
 
 
V 
 
 
 
V 
V 
V 


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Biomarker 4 
 
 
V 
 
 
 
 
 
 
 
 
 
V 
V 
V 
Drug administration 
 
 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
 
 
 
Concomitant medications 
 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
Adverse events 
 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
V 
1 Informed Consent Form should be signed prior to any clinical trial related activities 
2 See Appendix 1 for the complete list of laboratory tests 
3 Serum pregnancy test is performed for all females of childbearing potential. 
4 Amyloid beta 40, Amyloid beta 42, Amyloid precursor protein intracellular domain (AICD), soluble 
neuregulin-1 (sNRG-1) 
 
3.2. 
Determination of Sample Size 
 
There was no formal sample size calculation since this is a phase 1/2 study and is not a 
hypothesis-driven study. The number of enrolled subjects is predefined approximately at 
n=22, about 11 subjects per group 
 
3.3. 
Method of Assignment to Treatment 
 
Patients who meet all criteria for enrollment will be randomized to double-blind treatment 
at visit 2. Assignment to treatment group will be determined by a computer-generated 
randomization code using the electronic data capture (EDC) system on Visit 2 (Week -4).  
 
Blinding of the drug contents from the subjects, investigators, and other study personnel 
at each clinical site is necessary. Because two syringes of AstroStem and 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.  
 
 
4. 
Statistical Methods 
 
4.1. 
General Considerations 
 
This document describes the statistical analyses planned prior to final treatment 
assignment unblinding of the aggregate database. Any change to the data analysis 
methods described in the protocol will require an amendment ONLY if it changes a 
principal feature of the protocol. Any other change to the data analysis methods described 
in the protocol and the justification for making the change will be described in the clinical 
study report (CSR). Additional exploratory analyses of the data will be conducted as 
deemed appropriate. 
 
All tests of treatment effects will be conducted at a two-sided alpha level of 0.05 unless 


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otherwise stated, and all confidence intervals (CI’s) will be given at a two-sided 95% level, 
unless otherwise stated. Statistical analysis will be performed using SAS software (SAS, 
Version 9.1.2 or higher). 
 
The following general terms will be used globally in the SAP: 
• Unless otherwise specified, the statistical analyses will be reported using summary 
tables and data listings.  
• Continuous variables will be summarized with n, mean, standard deviation, median, 
minimum, and maximum.  
• Categorical variables will be summarized by counts and by percentages of 
subjects in corresponding categories.  
• All summary tables will be presented by treatment.  
• Individual subject data obtained from the case report form (CRFs) and any derived 
data will be presented by subject in data listings. Data listings will be sorted by 
subject, and visit date and time, if applicable.  
 
4.2. 
Adjustments for Covariates 
 
There will be no adjustment for covariates.  
 
4.3. 
Analysis Populations 
 
4.3.1. 
Intent-to-Treat Population 
 
An intent-to-treat (ITT) population will include subjects who received at least one 
intravenous injection and have post-injection efficacy measurements. This population will 
be evaluated for all efficacy variables. 
 
4.3.2. 
Per-Protocol Population 
 
All subjects valid for ITT who complete Visit 13 (Week 30) 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. 
 
4.3.3. 
Safety Population 
 
A safety population will include subjects who received at least one intravenous injection 
and have post-injection safety measurements. This population will be evaluated for all 
safety variables.  
 


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4.4. 
Baseline and Postbaseline Definition 
 
Table 5 describes the rules for determining the patient population and baseline and 
postbaseline observations for study and type of analysis.  
 
Table 5. Patient Population with Baseline and Postbaseline Definitions by Type of 
Analysis 
 
 
Study Period/Analysis 
Patient Population 
Baseline Observation 
Postbaseline 
Observation(s) 
 Treatment Period  
Primary Efficacy analyses  
 
ITT Population with a 
baseline and at least 1 
postbaseline observation 
Visit 3 
Visit 13 
TEAEs 
Safety Population 
All Visits 1-3 
All Visits 3.01-14 
Serious Adverse Events, 
Discontinuations due to 
Adverse Events 
Safety Population 
N/A 
 
C-SSRS analyses 
Patients with a 
baseline and at 
least 1 postbaseline 
C-SSRS 
assessment 
All Prior History: Visits 
1-3 including  
All Visits 3.01-14 
Treatment-emergent abnormal 
laboratory values 
Safety Population with normal 
laboratory values at all 
nonmissing baseline visits 
(with respect to direction 
being analyzed) and who 
have at least 1 postbaseline 
observation 
Low: Minimum from 
Visits 1-3 
High: Maximum from 
Visits 1-3 
Abnormal: All Visits 1-3 
Low: Minimum from 
Visits 3.01-14  
High: Maximum 
from Visits 3.01-14  
Abnormal: All Visits 
3.01-14 
Treatment-emergent 
immunogenicity 
Safety Population 
Visit 3 
All Visits 3.01-14  
Treatment-emergent changes 
in temperature and weight 
Safety Population with a 
baseline and at least 1 
postbaseline observation 
Low: Minimum from 
Visits 1-3 
High: Maximum from 
Visits 1-3 
Low: Minimum from 
Visits 3.01-14  
High: Maximum 
from Visits 3.01-14  
Treatment-emergent changes 
in blood pressures, pulse, and 
ECGs 
Safety Population with a 
baseline and at least 1 
postbaseline observation 
Low: Last nonmissing 
from Visits 1-3 
High: Last nonmissing 
from Visits 1-3 
Low: Minimum from 
Visits 3.01-14  
High: Maximum 
from Visits 3.01-14  
Continuous safety analyses 
 
Safety Population with a 
baseline and at least 
1 postbaseline observation 
Last of Visits 1-3 
All scheduled visits 
3< Visits ≤14 
ECGs = electrocardiograms; eCRF = electronic case report form; ITT = intent-to-treat; N/A = not 
applicable; TEAEs = treatment-emergent adverse events 
 
Note: Visit 3.01 indicates the first unscheduled visit occurring after Visit 3 and prior to Visit 4.  
 
 
4.5. 
Handling of Dropouts or Missing Data 
 


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No adjustments for missing data and no imputation methods are planned for this study. 
 
4.6. 
Treatment Group Comparability 
 
4.6.1. 
Patient Disposition 
 
Subject disposition information will be summarized for all subjects. Summaries will include: 
the number of subjects in each analysis population, the number of subjects completed 
the study, and the number of subjects discontinued study and its reason. All subjects 
randomized in the study will be included in the summary table. Patient allocation by 
investigator or site will be summarized. Patient allocation by investigator or site will also 
be listed as well. 
 
4.6.2. 
Protocol Deviations 
 
Listings of subjects with significant protocol deviations or violations will be provided. The 
following list of significant protocol violations will be determined from the clinical database 
and from the study clinical/medical group: 
• Lack of informed consent or late informed consent 
• Violations of inclusion/exclusion criteria 
• Significant violations of prohibited concomitant medication usage as determined 
by the clinical/medical group 
• Other significant protocol violations as determined by the clinical/medical group 
 
4.6.3. 
Patient Characteristics 
 
The following patient characteristics at baseline will be summarized by treatment group 
for all ITT patients: 
• Demographic (age, gender, ethnic origin, height, weight, BMI)  
• Medical history and Pre-existing condition  
 
Medical history and pre-existing conditions will be summarized by preferred term (PT) 
within system organ class (SOC).  Medical history is defined as illness(es) that ended 
prior to the signing of informed consent. Pre-existing conditions and AEs at baseline are 
those AEs occurring during the baseline/screening visits that is Visit 1, 2 and 3. 
 
4.6.4. 
Prior and Concomitant Therapy 
 
Verbatim terms on eCRFs will be mapped to Anatomical Therapeutic Chemical (ATC) 
class and Generic Drug Names using the World Health Organization (WHO) Drug 
Dictionary Enhanced (WHODDE) B2 format, March 1, 2015 release. 


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Prior medications are defined as medications started to take prior to the first injection. 
Concomitant medications are defined as medications started on or after the day of first 
injection of the study drug during the study.  
 
Prior and concomitant medications will be tabulated for the ITT population by WHODDE 
ATC level 2 classifications, preferred term, and treatment. If a subject reports the same 
preferred term multiple times, then the frequency of that preferred term will only be 
incremented by one. As with the preferred term, if a subject reports multiple medications 
within the same ATC level 2 classification, then the frequency of that ATC level 2 
classification will only be incremented by one. Percentages will be calculated using the 
total number of subjects in the safety population. Each summary will be ordered by 
descending order of incidence of preferred term within each ATC class. Prior and 
concomitant medications will be included in a data listing.  
 
4.6.5. 
Treatment Compliance 
 
Not applicable.  
 
4.7. 
Efficacy Analyses 
 
The primary efficacy hypothesis test will be performed using a 5% significance level. For 
the secondary efficacy endpoints, hypothesis tests will be performed individually at the 5% 
significance level. All hypothesis tests will be performed with two-sided alternative 
hypotheses. No adjustments on the significance level for multiple comparisons are 
planned, as this is a phase 1/2 study. All efficacy analyses will be based on the ITT 
population.  
 
4.7.1. 
Primary Efficacy Analysis 
 
The primary objective of this study is to test the hypothesis that AstroStem is superior to 
placebo in the improvement on neurological/neurocognitive assessment from baseline to 
week 30 in patients with Alzheimer’s Disease.  
 
The primary analysis will evaluate the efficacy of AstroStem compared with placebo on 
the overall mean change from baseline to week 30 in ADAS-Cog score. The primary 
efficacy variable will be summarized with means, standard deviations, medians and 
ranges, overall and by group. The change from Baseline ADAS-Cog score will be 
analyzed with Student’s t-test  or Kruskal-Wallis test depending on the violation of 
normality assumption.  
 
4.7.2. 
Secondary Efficacy Analyses 


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The secondary efficacy analyses will be summarized with means, standard deviations, 
medians and ranges for continuous variables including the changes from baseline at 
Week 30 in MMSE, CDR-SOB, NPI, GDS and ADCS-ADL. 
 
These changes score from baseline at week 30 will be analyzed with Student’s t-test  or 
Kruskal-Wallis test depending on the violation of normality assumption. . 
 
4.7.3. 
Exploratory Efficacy Analyses 
 
Change from baseline scores at Visits 6, 9, 12 and 14 or Early Termination for: ADAS-
Cog, MMSE, CDR-SOB, NPI, GDS, and ADCS-ADL will be summarized with means, 
standard deviations, medians and ranges by treatment group and visit. These changes 
score from baseline at Visits 6, 9, 12 and 14 or Early Termination will be analyzed with 
Student’s t-test or Kruskal-Wallis test depending on the violation of normality assumption.  
 
Biomarkers in blood [Amyloid beta 40, Amyloid beta 42, Amyloid precursor protein 
intracellular domain (AICD), soluble neuregulin-1 (sNRG-1)] will be summarized with 
means, standard deviations, medians and ranges for continuous variables and with 
counts and percentages for categorical variables. at baseline, Visit 13 and 14 or Early 
Termination  
 
4.8. 
Safety Analyses 
 
The safety and tolerability of treatment will be assessed by summarizing the following: 
• AEs 
• Treatment-emergent adverse events (TEAEs)  
o By PT 
o By SOC 
o By maximum severity  
o By considered to be related to investigational produce by investigator 
• Serious Adverse Events (SAEs) 
• AE leading to discontinuation 
• Suicide-Related Thoughts and Behaviors  
• Vital signs and weight 
• Laboratory measurements 
• Electrocardiograms (ECGs) 
 
All safety analyses will be based on the safety population. AE rates will be summarized 
by treatment group and overall, and will be broken down by severity, seriousness and 
relation to study drug. Change of MRI, C-SSRS, physical examinations, vital signs, ECG 


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and standard laboratory results will be summarized with means, standard deviations, 
medians and ranges for continuous variables and with counts and percentages for 
categorical variables. Statistical tests are not planned for safety.  
 
4.8.1. 
Adverse Events 
 
An AE is defined as any untoward medical occurrence in a subject who is administered a 
medicinal product and that does not necessarily have a causal relationship to the 
treatment. All AEs will be included in the data listings. Verbatim terms on case report 
forms will be mapped to preferred terms and system organ classes (SOC) using the 
Medical Dictionary for Regulatory Activities (MedDRA) (version 19.1). 
 
A Treatment Emergent Adverse Event (TEAE) is defined as an adverse event that occurs 
on or after the treatment dose. TEAE summary will be displayed by treatment. Unless 
otherwise specified, summaries that are displayed by SOC and preferred terms will be 
ordered alphabetically by SOC, and within each SOC, preferred terms will also be ordered 
alphabetically. Summaries of the following types will be presented: 
• Subject incidence of TEAEs by MedDRA SOC and preferred term. 
• Subject incidence of TEAEs by MedDRA SOC, preferred term, and severity. 
Severity will be recorded as deemed by investigator. At each level of subject 
summarization, a subject is classified according to the highest severity if the 
subject reported one or more events. 
• Subject incidence of study drug related TEAEs by MedDRA SOC and preferred 
term. 
• Subject incidence of TEAEs by descending incidence of preferred terms. 
• Subject incidence of serious TEAEs by MedDRA SOC and preferred term, if 
applicable. 
• Subject incidence of TEAE leading to early termination by MedDRA SOC and 
preferred term, if applicable. 
 
For each subject and for each adverse event, the duration of the event will be calculated 
as: 
Duration of AE = AE stop date - AE start date + 1 
 
The duration of AEs will be displayed in the data listing.  
 
4.8.2. 
Potential Hypersensitivity Events (Serious Adverse Events)   
 
A serious adverse event (SAE) is any AE or suspected adverse reaction that in the view 
of either the investigator or Sponsor, results in any of the following outcomes:  
• Death 


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• A life-threatening AE: it is defined as an AE or suspected adverse reaction that in 
the view of the investigator or Sponsor, its occurrence places the patient or subject 
at immediate risk of death. It does not include an AE or suspected adverse reaction 
that, had it occurred in a more severe form, might have caused death.  
• Inpatient hospitalization or prolongation of existing hospitalization 
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life function.  
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered serious when, based upon appropriate 
medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of outcomes listed in the above 
definition 
 
Life threatening:   
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the 
view of either the investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death. It does not include an adverse event or suspected adverse 
reaction that, had it occurred in a more severe form, might have caused death. 
 
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 24 hours OR 
• 
the admission is pre-planned (i.e., elective or scheduled surgery arranged prior to 
the start of the study) 
 
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:  
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.  
 


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4.8.3. 
Clinical Laboratory Evaluation  
 
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. 
 
Laboratory results (hematology, serum chemistry and urinalysis) will be presented in data 
listing. Abnormal values will be flagged as high or low relative to the local lab normal 
ranges, where applicable. Values that are deemed as abnormal, clinically significant  will 
also be flagged.  
 
Laboratory results will be summarized using descriptive statistics at baseline and post-
dose. Changes from baseline will also be summarized. Only non-missing assessments 
at baseline and post-dose will be analyzed.  
 
Any clinically significant lab abnormalities will be determined by the Principal Investigator 
and will be reported in the AE table summaries.  
 
4.8.4. 
Suicide-Related Thoughts and Behaviors 
 
Suicidal ideation, suicidal behavior, and self-injurious behavior without suicidal intent 
occurring during treatment, based on the C SSRS, will be summarized by treatment. In 
particular, for each of the following events, the number and percent of patients with the 
event will be enumerated by treatment: completed suicide, nonfatal suicide attempt, 
interrupted attempt, aborted attempt, preparatory acts or behavior, active suicidal ideation 
with specific plan and intent, active suicidal ideation with some intent to act without 
specific plan, active suicidal ideation with any methods (no plan) without intent to act, 
nonspecific active suicidal thoughts, wish to be dead, and self-injurious behavior without 
suicidal intent. 
 
In addition, the number and percent of patients who experienced at least one of various 
composite measures will be presented and compared. These include suicidal behavior 
(completed suicide, non-fatal suicidal attempts, interrupted attempts, aborted attempts, 
and preparatory acts or behavior), suicidal ideation (active suicidal ideation with specific 
plan and intent, active suicidal ideation with some intent to act without specific plan, active 
suicidal ideation with any methods [no plan] without intent to act, non-specific active 
suicidal thoughts, and wish to be dead), and suicidal ideation or behavior.  
 
4.8.5. 
Vital Signs 
 
Vital signs will be summarized using descriptive statistics at baseline and at each post-


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dose time point. Changes from baseline will also be summarized.  
 
4.8.6. 
Electrocardiogram  
ECG parameters (numeric) will be summarized using descriptive statistics at baseline and 
at each post-dose time point. Changes from baseline will also be summarized.  
 
4.9. 
Interim Analysis and Data Monitoring 
 
An unblinded interim safety analysis was done when there the first 4 subjects complete 
Visit 4 at Week 2 by an independent safety monitor.  Change of vital sign, concomitant 
medications and adverse events(AEs) were evaluated to monitor the safety of the 
AstroStem.  
 
Vital sign measured at Visit 3 and 4 were within normal ranges and no AEs were reported. 
In addition, all 4 subjects were found to be taking concomitant medications before and 
after administration of the treatment.  
 
4.10. Handling of Dropouts or Missing Data 
 
No imputations will be made for missing values.  
 
4.11. Subgroup Analysis 
 
There are no planned subgroup efficacy analyses.  
 
4.12. Multiple Comparison/Multiplicity  
 
No adjustments for multiplicity or multiple testing will be made.  
 
 
5. 
Changes to Protocol-Specified Analyses 
 
No changes to protocol-specified analyses are planned. 
 
 
6. 
References 
 
Alzheimer’s Association. 2016 Alzheimer's disease facts and figures. Alzheimers Dement. 
2016 April;12(4):459-509. 
 
 


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7. 
Appendices 
 
7.1. 
Appendix 1. Laboratory Parameters 
 
Blood and urine samples for complete laboratory evaluation (hematology, serum 
chemistry, biomarker analysis and urinalysis) at Visits 1, 3, 6, 9, 12, 13 and 14 or Early 
Termination.  
 
HEMATOLOGY 
CHEMISTRY 
URINALYSIS 
BIOMARKER*** 
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 ** 
HBV** 
HCV** 
VDRL** 
Color 
Appearance 
Specific gravity 
pH  
Protein 
Glucose 
Ketones 
Bilirubin 
Blood 
Leukocyte esterase 
WBC 
RBC 
Epithelial cell 
Bacteria 
Hyaline casts 
 
Amyloid beta 40 
Amyloid beta 42 
Amyloid 
precursor protein 
intracellular 
domain (AICD) 
soluble 
neuregulin-1 
(sNRG-1) 
 
*  
HCG (pregnancy test) only for all females of childbearing potential at Visits 1, 3, 12, 13 and 14 or 
Early Termination  
**  Visit 1 only 
*** Visits 3 and 13, 14 or Early Termination