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
Phase: PHASE1
Conditions: Alzheimer Disease
Sponsor: Nature Cell Co. Ltd.

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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). 
 
 

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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) 
 

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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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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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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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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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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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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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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 
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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 
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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 3. MMSE (Mini-mental status examination)  
 
 

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Appendix 4. CDR-SOB (Clinical Dementia Rating-Sum of Box) 
 

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Appendix 5. NPI (Neuropsychiatric Inventory) 
 

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Appendix 6. GDS (Geriatric Depression Scale)  
 

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Appendix 7. ADCS-ADL (Alzheimer’s Disease Cooperative Study- Activities of Daily Living 
 

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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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