A Phase 2, Randomized, Double Blind, Placebo Controlled Multicenter Study to Evaluate Safety and Efficacy of Transplantation of Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors (MSC-NTF) in Patients With ALS
Phase: PHASE2
Conditions: Amyotrophic Lateral Sclerosis (ALS)
Sponsor: Brainstorm-Cell Therapeutics

BrainStorm Cell Therapeutics  
Phase 2 Clinical Protocol BCT-001-US Amendment 1:  
23 Sept 2014 
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Clinical study protocol  
BCT-001-US  
 
 
A PHASE 2, RANDOMIZED, DOUBLE BLIND, 
PLACEBO CONTROLLED MULTICENTER STUDY 
TO EVALUATE SAFETY AND EFFICACY OF 
TRANSPLANTATION OF AUTOLOGOUS 
MESENCHYMAL STEM CELLS SECRETING 
NEUROTROPHIC FACTORS IN PATIENTS WITH 
AMYOTROPHIC LATERAL SCLEROSIS  
 
 
 
 
 
 
 
 
 
 
 
 
Brainstorm Cell Therapeutics Ltd. 
12 Bazel St., POB 10019, 
Kiryat Aryeh, Petach Tikva, 
Israel 49001 

BrainStorm Cell Therapeutics  
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Clinical study protocol [BCT-001-US] 
PROTOCOL TITLE 
A PHASE 2, RANDOMIZED, DOUBLE BLIND, PLACEBO 
CONTROLLED MULTICENTER STUDY TO EVALUATE SAFETY 
AND EFFICACY OF TRANSPLANTATION OF AUTOLOGOUS 
MESENCHYMAL STEM CELLS SECRETING NEUROTROPHIC 
FACTORS IN PATIENTS WITH AMYOTROPHIC LATERAL 
SCLEROSIS 
PROTOCOL 
NUMBER 
BCT-001-US 
STUDY DESIGN 
(PHASE) 
Phase 2 
PROTOCOL 
DATE/VERSION 
September 23, 2014/Amendment 1 
IND NUMBER 
IND 15878 
Investigational 
Product 
Autologous mesenchymal stem cells secreting neurotrophic factors 
(MSC-NTF, NurOwn™) 
INDICATION 
Amyotrophic Lateral Sclerosis (ALS) 
SPONSOR 
Brainstorm Cell Therapeutics Ltd. 
12 Bazel St., POB 10019, 
Kiryat Aryeh, Petach Tikva, 
Israel 49001 
PRINCIPAL 
INVESTIGATORS 
Robert H. Brown, 
MD, DPhil,  
 
Professor of Neurology, University of Massachusetts 
Medical School/Memorial Medical Center, 
Neurology Department Chair, University of 
Massachusetts/Memorial Medical Center 
Merit E. 
Cudkowicz, MD, 
MSc., 
Professor of Neurology, Harvard School of 
Medicine, Chief of Neurology, Massachusetts 
General Hospital 
Anthony 
Windebank, MD 
Professor of Neurology, Mayo Clinic College of 
Medicine 
MEDICAL MONITOR Kenneth J. Tack, MD 
PRC Clinical 
(810) 227-1386 
 
Good Clinical Practices 
This study will be conducted under Good Clinical Practices, in accordance with the Declaration of Helsinki, in 
compliance with the International Conference on Harmonization (ICH) guidelines. 
 
 
 

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CONFIDENTIAL 
This Clinical protocol contains confidential information of Brainstorm Cell Therapeutics Ltd. 
("Brainstorm").   The information in this document is confidential and may not be disclosed to 
others without the prior written authorization of Brainstorm, except to the extent necessary to 
obtain informed consent from persons receiving the investigational product or their legal 
guardians, or for discussions with local regulatory authorities, institutional review boards, 
ethics committees, or persons participating in the conduct of the study. 
 

Phase 2 Clinical Protocol BCT-001-US Amendment l:
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PROTOCOL APPROVAL
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Multicenter Study of
Transplantation of Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors
in Patients with Amyotrophic Lateral Sclerosis; BCT-001-US.
Approved by:
Name
Title/Company
Signature
Date
Yael Gothelf. Ph.D.
VP Regulatory Affairs
Brainstorm Cell Therppeutics
Anthony Fiorino,
MD. PhD
CEO, Brainstorm Cdll
Therapeutics
Dale W. Usner. Ph.D.
VP Biostatistics and Data
Management, SDC
Kenneth J. Tack, MD
Medical Monitor, PRC Clinical hr4rrf'74 "lscpfZott

BrainStorm Cell Therapeutics  
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PROTOCOL APPROVAL 
 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Multicenter Study of 
Transplantation of Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors 
in Patients with Amyotrophic Lateral Sclerosis; BCT-001-US. 
  
Approved by: 
 
Name 
Title/Company 
Signature 
Date 
Yael Gothelf, Ph.D. 
VP Regulatory Affairs 
Brainstorm Cell Therapeutics 
 
 
Anthony Fiorino, 
MD, PhD 
CEO, Brainstorm Cell 
Therapeutics 
 
 
Dale W. Usner, Ph.D. 
VP Biostatistics and Data 
Management, SDC 
 
 
Kenneth J. Tack, MD 
Medical Monitor, PRC Clinical  
 
 
 
 
 
 
 

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INVESTIGATOR’S AGREEMENT 
 
 
I have received and read the Clinical Protocol BCT-001-US, for BrainStorm Cell 
Therapeutics’ MSC-NTF cells.  I have read the protocol and agree to conduct the study 
as outlined.  I agree to maintain the confidentiality of all information received or 
developed in connection with this protocol. 
 
 
 
 
Printed Name of Investigator 
 
 
Signature of Investigator 
 
 
Date 
 
 

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STUDY SYNOPSIS 
 
Name of Sponsor 
Brainstorm Cell Therapeutics Ltd. 
12 Bazel St., POB 10019, 
Kiryat Aryeh, Petach Tikva, 
Israel 49001 
Investigational Product 
MSC-NTF cells 
Indication  
Amyotrophic Lateral Sclerosis (ALS) 
Title of Study 
A Phase 2 Randomized, Double-Blind, Placebo-Controlled Multicenter Study of 
Transplantation of Autologous Mesenchymal Stem Cells Secreting Neurotrophic 
Factors in Patients with Amyotrophic Lateral Sclerosis 
Protocol Date/Version 
September 23, 2014/Amendment 1 
OBJECTIVES 
Primary: 
To evaluate the safety of transplantation of expanded autologous MSC-NTF cells administered on a single 
occasion via combined intrathecal (IT) administration and 24 intramuscular (IM) injections given into the right 
biceps and triceps muscles in patients with ALS.   
Secondary:  
To compare the change in slopes from the pre-transplantation period to the post-transplantation period in ALSFRS-
R between the treatment and placebo groups through 24 weeks post-transplantation. 
To compare the change in slopes from the pre-transplantation period to the post-transplantation period in SVC 
between the treatment and placebo groups through 24 weeks post-transplantation. 
To compare the slope of the rate of decline in the ALSFRS-R at 24 weeks following transplantation relative to the 
12-16 week baseline period before transplantation in all patients (both treatment and placebo groups). 
To compare the slope of the rate of decline in SVC at 24 weeks following transplantation relative to the 12-16 
week baseline period before transplantation in all patients (both treatment and placebo groups). 
METHODOLOGY 
Study Design 
This is a Phase II randomized, double blind, placebo controlled multicenter study that will 
be conducted in 48 patients with early ALS (ALSFRS-R scores of ≥30) at up to 3 study 
sites.  After providing informed consent, each patient will undergo approximately 12-16 
week baseline period during which monthly ALSFRS-R scores and SVCs will be obtained. 
During this period of time their bone-marrow will be harvested and mesenchymal stromal 
cells will be isolated and expanded. Twelve to 16 weeks after screening, patients will 
undergo transplantation with their autologous MSC-NTF or matching placebo; product will 
be administered both intrathecally as well as intramuscularly as 24 IM injections given into 
the right biceps and triceps muscles, all at a single study visit.  Following treatment they will 
have up to six monthly visits at which the ALSFRS-R and SVC will be obtained, along with 
vital signs, laboratory tests and recording of concomitant medications and adverse events 
(AEs, see scheme below). 
 
Treatments 
Administration of MSC-NTF cells given intrathecally and via multiple intramuscular 
injections on a single occasion.    
- 12-16 wks
Screening
(V1)
- 3-5 wks
BMA
(V4)
0
Trans
plantation
(V5)
24-26 wks
End of Study
(V10)
BMA: Bone Marrow Aspiration                                                   ↓Monthly visits
~ 9-10 months

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Treatment 
Duration 
Each participant will be followed-up for three months pre-and six months post 
transplantation; thus, each participant’s study participation will last for approximately 9 
months.  The expected study duration (taking into account the limitations of the 
manufacturing site which is expected to be able to process approximately 2-4 patients per 
month), the entire study duration is expected to be approximately 12-16 months.  
Study Drug and 
Formulation 
Study drug will be supplied in: 
• Twenty four 1ml syringes, each containing 2 x106 MSC-NTF cells in 200 µl (10 x106 
cells/mL) or the same number of syringes containing placebo for IM administration.  
• One 5 ml syringe containing 4 ml of MSC-NTF cell suspension at a dose of 100-125 
x106 cells or a 5 ml syringe containing placebo for IT administration.  
Dose and Route of 
Administration  
Study drug is to be delivered by IM and IT administration.  
The MSC-NTF cell dose is:  
• 100-125 x106 cells by IT administration  
• 48 x106 cells by IM administration.  
• Participants randomized to placebo will receive both IT and the same number of IM 
injections. 
Concomitant and 
Excluded 
Therapy 
Study participants will be on a stable dose of riluzole for at least 30 days prior to screening 
or not taking riluzole at all, nor plan to begin riluzole during the study period.  
SUBJECT POPULATION 
Number of 
Subjects Planned  
48 total (3:1 randomization with 36 subjects in the active treatment arm and 12 in the 
placebo arm). 
Major Inclusion 
Criteria 
Age 18 to 75 years old. 
ALS symptom onset defined as first onset of weakness ≤ 24 months and ALSFRS-R ≥30 at 
the Screening Visit. 
Upright slow vital capacity (SVC) measure ≥65% of predicted for gender, height, and age at 
the Screening Visit. 
ASSESSMENTS 
Safety 
Tabulation of AEs, changes in physical and neurological examination findings, hematology, 
serum chemistry, urinalysis, vital signs and requirement of concomitant medications. 
Efficacy  
The change in slope from the pre-transplantation period to the post-transplantation period in 
ALSFRS-R scores and slow vital capacity (SVC) through Weeks 12 and 24 post-
transplantation for treatment compared to placebo.  
The change in slope from the pre-transplantation period to the post-transplantation period in 
ALSFRS-R scores and slow vital capacity (SVC) through Weeks 12 and 24 post-
transplantation for each treatment group. 
The change in slope from the pre-transplantation period to the post-transplantation period in 
hand held dynamometry (HHD) and EIM (optional) through Weeks 12 and 24 post-
transplantation for treatment compared to placebo. 
The change in slope from the pre-transplantation period to the post-transplantation period in 
hand held dynamometry (HHD) and EIM (optional) through Weeks 12 and 24 post-
transplantation for each treatment group. 
For the Schedule of Study Assessments, see Table 1 in Appendix 1. 

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STATISTICAL METHODS AND ANALYSIS 
Efficacy 
All efficacy analyses will use one-sided alpha = 0.10 tests and present one-sided 90% 
lower confidence limits and two-sided 95% confidence intervals around the difference 
between treatments as well as two-sided 95% confidence intervals around the point 
estimates within each treatment group. All summaries will be presented by treatment 
group.   
Secondary Objectives: The change in slope from pre-transplantation to post-transplantation 
in ALSFRS-R and in SVC (as a percent of normal for age and sex) will be estimated using 
the mixed linear statistical model. The fixed effect variables in the model will be: 
• 
Visit, expressed in days from the beginning of treatment (i.e. pre-treatment times 
will have negative values, post-treatment times positive values); 
• 
Treatment; 
• 
Two-way interactions between visit & post-treatment indicator, (0 for pre-
treatment visits, 1 for post-treatment visits) and visit & treatment;  
• 
Three-way interaction between visit & post-treatment visit indicator & treatment; 
• 
Site.   
The repeated measures within a subject over visit will also be accounted for in the model, 
wherein the covariance structure will be evaluated using Bayesian information criterion 
(BIC). Covariance structures to be evaluated are: unstructured, toeplitz, spatial power with 
day, and compound symmetry.  
The three-way interaction between visit & post-treatment visit indicator & treatment will 
be used to compare the change in slope in the treatment group to the change in slope in the 
placebo group. 
The post-pre slope estimate for the active treatment group will be used to test the change 
from pre-transplantation to post-transplantation within the active treatment group. 
Exploratory Objectives:  The analysis for EIM (optional) and HHD will employ the same 
modeling approach as described above for the secondary objectives.  The analysis for 
HHD will be based on a combined score reflecting muscles in the right arm.   
A further analysis of HHD will compare the score for the right arm to the score for the left 
arm.  The linear mixed model will include, in addition to the terms described above, an 
indicator for "right arm", interactions between that indicator and all other variables in the 
model, and a random effect term for the right arm indicator. 
Safety 
The proportion of subjects having each AE will be compared between treatment groups 
using Fisher’s exact tests.  
When evaluating changes in safety parameters, baseline will be defined as the last 
measurement prior to transplantation (i.e., prior to treatment). 
Physical examination, neurological examination, hematology, serum chemistry, vital signs, 
ECG and concomitant medications will be summarized using descriptive statistics (n, 
mean, standard deviation, median, minimum, and maximum) if the data is continuous and 
using counts and percentages if the data is discrete.  Shifts from baseline in categorization 
of results (e.g. normal/abnormal or low/normal/high) will also be summarized. 
 
 

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TABLE OF CONTENTS 
STUDY SYNOPSIS ............................................................................................................ 6 
ABBREVIATIONS ........................................................................................................... 12 
6. 
CLINICAL STUDY PROTOCOL ...................................................................... 14 
6.1. 
INTRODUCTION .................................................................................................. 14 
6.1.1. Background ............................................................................................................. 14 
6.1.2. Summary of Previous Clinical Experience with MSC-NTF cell transplantation ... 14 
6.1.3. Summary of Relevant Nonclinical Experience with MSC-NTF ............................ 17 
6.1.4. MSC-NTF Benefit and Risk Assessment ............................................................... 20 
6.2. 
STUDY OBJECTIVES .......................................................................................... 21 
6.2.1. Primary objective .................................................................................................... 21 
6.2.2. Secondary Objectives ............................................................................................. 22 
6.2.3. Exploratory Objectives ........................................................................................... 22 
6.3. 
INVESTIGATIONAL PLAN ................................................................................ 22 
6.3.1. Overall Study Design and Plan ............................................................................... 22 
6.3.2. Study Schematic ..................................................................................................... 23 
6.3.3. Treatment Plan ........................................................................................................ 24 
6.3.4. Blinding and Randomization .................................................................................. 25 
6.3.5. Duration of study .................................................................................................... 25 
6.3.6. Discussion of Dose ................................................................................................. 25 
6.3.7. Discussion of Study Design, Including Choice of Control Group ......................... 26 
6.4. 
SUBJECT POPULATION ..................................................................................... 26 
6.4.1. Inclusion Criteria .................................................................................................... 26 
6.4.2. Exclusion Criteria ................................................................................................... 27 
6.5. 
STUDY ASSESSMENTS ...................................................................................... 28 
6.5.1. Clinical Laboratory Safety Tests ............................................................................ 28 
6.5.2. Physical Examinations, Vital Signs, and Electrocardiograms ................................ 28 
6.5.3. Pre-transplantation Visits ....................................................................................... 29 
6.5.4. Post transplantation follow-up ................................................................................ 31 
6.5.5. STUDY DISCONTINUATION ............................................................................. 33 
6.5.6. Temporary Treatment Discontinuation .................................................................. 34 
6.5.7. Permanent Treatment Discontinuation ................................................................... 34 
6.5.8. Safety Follow-Up ................................................................................................... 34 
6.5.9. Lost to Follow-Up .................................................................................................. 35 
6.6. 
INVESTIGATIONAL PRODUCT INFORMATION ........................................... 35 
6.6.1. General Information ............................................................................................... 35 
6.6.2. MSC-NTF Product Characteristics ......................................................................... 35 
6.6.3. Treatment Compliance ........................................................................................... 36 
6.6.4. Test product, Dose and Administration .................................................................. 36 
6.7. 
PRIOR AND CONCOMITANT THERAPY ......................................................... 36 
6.7.1. Prior Therapy .......................................................................................................... 36 
6.7.2. Concomitant Therapy ............................................................................................. 37 
6.8. 
SAFETY REPORTING .......................................................................................... 37 
6.8.1. Adverse Events definitions and reporting .............................................................. 37 
6.8.2. Reporting Responsibilities and Procedures for AEs and SAEs .............................. 39 
6.8.3. Prospective assessment of the occurrence of suicidality ........................................ 41 

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6.8.4. STUDY DISCONTINUATION ............................................................................. 41 
6.8.5. Clinical Laboratory Safety Tests ............................................................................ 42 
6.8.6. Physical Examinations, Vital Signs, and Electrocardiograms ................................ 42 
6.9. 
ASSESSMENT OF ENDPOINTS ......................................................................... 42 
6.9.1. Primary Endpoint: .................................................................................................. 42 
6.9.2. Secondary Endpoints: ............................................................................................. 43 
6.9.3. Exploratory ............................................................................................................. 43 
6.9.4. Statistical Methods and Sample Size Determination .............................................. 44 
6.10. STUDY COMMITTEES AND COMMUNICATIONS ........................................ 47 
6.10.1. Data and Safety Monitoring Committee ................................................................. 47 
6.11. 
LABORATORY REQUIREMENTS ..................................................................... 47 
6.12. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ...................... 47 
6.12.1. Ethics ...................................................................................................................... 47 
6.12.2. Data Quality Assurance .......................................................................................... 48 
6.12.3. Investigational Product Accountability .................................................................. 49 
6.12.4. Compensation, Insurance, and Indemnity .............................................................. 49 
6.12.5. Data recording/Case Report Forms ........................................................................ 49 
6.12.6. Record maintenance and retention ......................................................................... 50 
6.12.7. Study Termination .................................................................................................. 51 
6.13. USE OF STUDY INFORMATION AND PUBLICATION .................................. 51 
6.14. REFERENCES ....................................................................................................... 52 
6.15. APPENDICES ........................................................................................................ 54 
6.15.1. Appendix 1: Listing of study activities .................................................................. 54 
6.15.2. Appendix 2: Muscle Strength using Hand Held Dynamometry ............................. 57 
6.15.3. Appendix 3: Procedure for IT transplantation of MSC-NTF cells ......................... 60 
6.15.4. Appendix 4: Procedure for IM transplantation of MSC-NTF cells ........................ 62 
 
 
 

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FIGURES 
Figure 1: 
MSC-NTF cells’ conditioned medium protects motorneuron cells from 
hypoxia. .......................................................................................................... 18 
Figure 2: 
Transplantation of MSC-NTF cells improved the symptoms and the survival 
in a mice model of ALS. ................................................................................. 19 
Figure 3: 
Clinical Study flowchart ................................................................................. 24 
Figure 4: 
Study groups flowchart ................................................................................... 24 
 
TABLES 
 
Table 1: 
Schedule of Activities: ................................................................................... 54 
Table 2: 
Detailed Schedule of Activities for Cell Transplantation Visit (V5): ............ 56 
 
 
 

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ABBREVIATIONS  
ADL  
Activities of Daily Living 
AE 
 
Adverse Event 
ALS 
 
Amyotrophic Lateral Sclerosis 
ALSFRS-R 
ALS Functional Rating Scale –Revised 
ALT 
 
Alanine aminotransferase (alanine transaminase) 
AST 
 
Aspartate aminotransferase (aspartate transaminase) 
BDNF  
Brain Derived Neurotrophic Factor 
CBC  
Complete Blood Count 
CRF 
 
Case Report Form 
CSF 
 
Cerebral Spinal Fluid 
C-SSRS 
Columbia Suicide Severity Rating Scale 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMEM 
Dulbecco Modified Eagle Medium 
DSMB  
Data and Safety Monitoring Board  
ECG  
Electrocardiogram 
EIM 
 
Electrical Impedance Myography 
FAS 
 
Full Analysis Set 
FVC  
Forced Vital Capacity 
GCP  
Good Clinical Practice 
GDNF  
Glial Derived Neurotrophic Factor 
HBSS  
Hank's Balanced Salt Solution 
HGF  
Hepatocyte Growth Factor 
HHD  
Hand Held Dynamometry 
IGF-1  
Insulin-like Growth Factor 1 
IM 
 
Intramuscular 
IRB 
 
Institutional Review Board 
IT 
 
Intrathecal 
LP 
 
Lumbar Puncture 
MedDRA 
Medical Dictionary for Regulatory Activities 
MN 
 
Motor Neuron 
MOH  
Israel Ministry of Health 
MSC  
Mesenchymal Stromal Cells 
MSC-NTF 
Mesenchymal Stromal Cells secreting Neurotrophic Factors 
NTF 
 
Neurotrophic Factors 
PP 
 
Per Protocol 
PT 
 
MedDRA Preferred Term 
SAE 
 
Serious Adverse Event 
SAP 
 
Statistical Analysis Plan 
SNI 
 
Sciatic Nerve Injury 

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SOA  
Schedule of Activities 
SOC  
MedDRA System Organ Class 
SOD  
Superoxide dismutase 1 
SVC  
Slow Vital Capacity 
TEAE  
Treatment-Emergent Adverse Event 
VEGF  
Vascular Endothelial Growth Factor 
 
 
 
 
 
 

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6. CLINICAL STUDY PROTOCOL  
6.1. INTRODUCTION 
6.1.1. Background 
Amyotrophic lateral sclerosis (ALS) is a fatal neurological disease. There is currently no 
available treatment to stop or reverse its progressive course. There remains an unmet 
medical need for safe and effective treatments for people with ALS.  
Based on putative pathophysiologic mechanisms, there are several therapies under 
investigation such as anti-glutamatergic agents, drugs targeting protein misfolding and 
accumulation, 
antioxidant 
therapy, 
immunomodulatory 
agents, 
and 
stem 
cell 
transplantation. 
Cyto-therapy may hold the key to circumventing multiple hurdles in the ALS 
pathophysiological cascade (Morren JA et al. 2012). Apart from the replacement of lost or 
damaged motor neurons, stem cell implantation therapy may benefit ALS patients by an 
independent effect of cytoprotection. Experimental data has shown that non-neuronal cell 
replacement can be a strategic therapy in promoting motor neuron survival and improved 
neuromuscular function (Corti S et al. 2010). 
Neurotrophic factors secreting mesenchymal stromal cells (MSC-NTF) cells are a novel 
cell-therapeutic approach which aims to effectively deliver NTF directly to the site of 
damage in ALS patients.   
The MSC-NTF cell therapy (NurOwn) is based on transplantation of autologous bone 
marrow derived mesenchymal stromal cells (MSC), which are enriched from the 
mononuclear fraction of the patients’ own bone marrow, propagated ex vivo and induced 
to secrete NTF such as Glial Derived Growth Factor (GDNF) and Brain Derived Growth 
Factor (BDNF), Vascular Endothelial Growth Factor (VEGF) and Hepatocyte growth 
factor (HGF). These cells are thus designated MSC-NTF cells.  
The autologous MSC-NTF cells are back-transplanted into the ALS patient into the sites 
of damage, the spinal cord and/or the muscles, where axon terminals will take up the 
neurotrophic factors secreted by the transplanted cells. In the muscles, the transplanted 
cells are close to the motor-end plates at the axon terminals, and in the spinal cord the cells 
are close to the cell bodies. Axon terminals take up the NTF and transport them 
retrogradely along the axons into the neuron cell bodies, thus aiming to prevent further 
degeneration of the neuronal cells.  
NTFs are potent survival factors for embryonic, neonatal, and adult neurons and are 
considered potential therapeutic candidates for ALS. Delivery of appropriate NTFs to the 
immediate environment of afflicted neurons in ALS patients is expected to improve their 
survival and thus slow down disease progression and alleviate symptoms.  
6.1.2. Summary of Previous Clinical Experience with MSC-NTF cell transplantation 
An open-label, two patient-group Phase 1/2 trial of MSC-NTF in 12 people with ALS, has 
been recently completed at the Hadassah Medical Center in Jerusalem, Israel 
(ClinicalTrials.gov Identifier: NCT01051882).  

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In this first study, six participants with early stage ALS disease received intramuscular 
(IM) injections of MSC-NTF, and six patients with more progressive disease received 
MSC-NTF by intrathecal (IT) administration. The six participants with early-stage ALS 
received an IM dose of ~1 x 106 MSC-NTF cells/site into 24 sites along the biceps and 
triceps muscles of the right arm for a total of ~24x106 cells/patient, and those with more 
advanced disease received an IT dose of 1x106 MSC-NTF cells per Kg of body weight for 
a total of ~60x106cells/patient (see table below).  
 
Patient 
group 
Number 
of 
patients 
Route of 
Administration 
# of 
injection 
sites 
Site of 
Administration 
Dose  
Early 
stage 
6 
Intramuscular 
(IM) 
24 
Biceps and triceps 
muscles  
1 x 106 
cells/site 
Advanced 
stage 
6 
Intrathecal (IT) 
1 
Cerebrospinal fluid 
(CSF)  
1 x 106 
cells/kg 
body 
weight 
The interim safety report for the first 12 patients in the Phase 1/2 clinical trial, submitted 
to the Israel Ministry of Health (MOH), indicated that MSC-NTF cells treatment, either by 
IM or IT administration was generally well tolerated for 6 months. No treatment-related 
adverse events (AE) were reported in the 12 patients treated by either route of 
administration.  
In this study a trend towards a decreased rate of decline on ALSFRS and FVC efficacy 
measures in the IT treated patients over 6 months post-transplant as compared to the three 
months pre-transplant follow-up was observed.   
A Phase 2a dose-escalating study is currently ongoing at the Hadassah Medical Center in 
Jerusalem, Israel.   
The Phase 2a study is designed to determine the safety and preliminary effects on outcome 
measures of MSC-NTF administered by combination treatment of intramuscular and 
intrathecal administration, in three cohorts of 4 early-stage ALS patients, receiving 
increasing doses of MSC-NTF cells. The first group of patients received a combination 
treatment of the current dose, the second group of patients received a 1.5 fold combination 
treatment of the current dose and the third group of patients received a 2 fold combination 
treatment of the current dose (see table below).  
Dose 
Low 
Medium 
High 
Number of patients 
4 
4 
4 
IM Dose (cells/site) 
1x 106 
1.5x 106 
2 x 106 
IT Dose (cells/kg body weight) 
1 x 106 
1.5 x 106 
2 x 106 
Total dose 
~ 94 x 106 
~ 141 x 106 
~ 188 x 106 
All participants will be followed for 3 months before and 6 months after transplantation. 
This study will provide important safety and dosing data as well as preliminary assessment 

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of the effects of MSC-NTF on ALS relevant outcome measures (ClinicalTrials.gov 
Identifier: NCT01777646). 
An interim safety summary report for the first 12 patients in the study was submitted to the 
Hadassah Medical Center Ethical Committee about two month after transplantation of the 
12th patient. One SAE (death due to cardiopulmonary arrest) was reported as non-
treatment related. The majority of the other AE observed were procedure related and not 
treatment related. 
Four compassionate use ALS patients have been treated with MSC-NTF cells with no 
apparent safety related concerns. 
The first compassionate use ALS patient was treated by IT transplantation of 1 x 106 
cells/kg body weight autologous MSC-NTF cells. During the 5 months follow up, no 
treatment-related adverse effects had been reported. 
The second compassionate use ALS patient received a combination of IT and IM 
injections of autologous MSC-NTF cells: 1 x 106 cells/kg body weight IT and 1x106 
cells/site in 24 sites, IM. No significant treatment-related adverse effects had been 
reported observed during the 9 months post-transplantation follow-up. The follow-up 
report for this patient is attached hereto. 
The third compassionate use patient (diagnosed with both ALS and myasthenia gravis) 
received a higher combination dose of IT and IM injections of autologous MSC-NTF 
cells, namely 1.5 x 106 cells/kg body weight IT and 1.5 x 106 cells/site in 24 sites IM for a 
total of 147 x 106 MSC-NTF cells. During the 2 months follow-up no significant side 
effects were observed. This compassionate use patient showed an improvement in the 
ALSFRS-R score, in muscle power (muscle chart) and in the respiratory parameters 
(FVC). 
This patient was subsequently re-treated 5 months after the first injection with a second 
dose of MSC-NTF cells. Two months after repeated MSC-NTF transplantation all 
neurological functions were found to have improved.  A case report for this patient 
entitled 'Rare Combination of Myasthenia and ALS, Responsive to NTF-MSC Stem Cell 
Therapy' was recently accepted for publication in 'Muscle and Nerve'.  
No formal assessment was performed for the repeated treatment of this compassionate 
treated patient, or for the fourth compassionate treated patient. Brainstorm Cell 
Therapeutics has not received any reports from the treating physicians of any adverse 
effects suspected to be due to the product in these four patients. 
In this proposed Phase 2 study, our goal is to evaluate the safety of MSC-NTF cells and 
their effect on several widely used, validated outcome measures in ALS.  The MSC-NTF 
cells will be administered by combined IM and IT routes of administration; the doses 
being proposed in this study represent the highest doses that were administered in the 
previous clinical studies; in those studies and in the compassionate use patients, these 
doses appeared to be generally well-tolerated by the 28 subjects to whom they were 
administered.  

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6.1.3. Summary of Relevant Nonclinical Experience with MSC-NTF 
6.1.3.1. 
The Role of Neurotrophic Factors in ALS 
Neurotrophic factors (NTF) are small, naturally occurring polypeptides that support the 
development and survival of neurons. NTF are reported to be potent survival factors for 
embryonic, neonatal, and adult neurons and studies in ALS animal models have shown a 
delay in disease onset and/or progression after administration of various neurotrophic 
factors. Therefore, NTF are considered potential therapeutic candidates for ALS as well as 
for other neurodegenerative diseases. 
Several studies in peripheral nerve injury have shown that NTFs play an important role in 
the development, maintenance and regeneration of the nervous system. BDNF was shown 
to prevent the loss of motor units and to contribute to the maintenance of muscle mass 
when administered to the hind limb muscles of mice after neonatal peripheral nerve injury 
(Mousavi K et al., 2004). In addition BDNF enhances branching and arborization of 
Corticospinal motor neurons (Ozdinler PH et al., 2006).  GDNF and Insulin Growth 
Factor 1 (IGF-1) are two of the most potent survival factors known for peripheral neurons. 
Several studies have shown that GDNF and IGF-1 can prevent neuronal degeneration in 
mice and rats after axotomy, as well as the programmed cell death of motor neurons 
during development (Henderson, CE, et al. 1994, Mohajeri H et al. 1999, Wang, LJ et al. 
2002, Acsadi G et al. 2002, Ozdinler PH et al. 2006, Suzuki M et al. 2008). 
The ability of growth factors to protect dying motor neurons has also been extensively 
studied in ALS models of disease.   
A variety of preclinical and clinical studies already suggest that local delivery of vascular 
endothelial growth factor (VEGF) has neurotrophic and neuroprotective effects for ALS. 
The VEGF family, which includes factors that are primarily associated with angiogenesis 
are now increasingly recognized to have neurotrophic effects.  
Reduced expression of a member of this family, VEGF-A, in mice results in 
neurodegeneration similar to that of ALS, while treatment of animal models of ALS with 
either VEGF-A gene therapy or VEGF-A protein has yielded positive therapeutic 
outcomes. These basic research ﬁndings raise the potential for a VEGF therapy to be 
translated to the clinic for the treatment of ALS (Reviewed Keifer et al 2013).  
Increased expression of VEGF by intramuscular viral injections prolongs their survival 
and enhances motor performance (Azzouz, M et al. 2004, Zheng, C et al. 2004). 
Intracerebroventricular administration of VEGF in a rat model of ALS enhanced motor 
neuron survival, whereas an intraperitoneal injection of VEGF led to the preservation of 
neuromuscular connections (Storkebaum, E, et al., 2005). Moreover, a recent study 
indicates that intramuscular administration of a VEGF zinc finger transcription factor 
activator, which can induce VEGF expression, improves motor functions in SOD1-G93A 
rats (Kliem, MA, et al., 2011).  
A recent study has shown that hMSC engineered to express GDNF and VEGF 
synergistically significantly prolonged survival and slowed the loss of motor function in a 
rat model of ALS (Krakora D. et al. 2013).  
Hepatocyte growth factor (HGF) was first identified and molecularly cloned as a potent 
mitogen for mature hepatocytes (Nakamura et al., 1984, 1989).  

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Hepatocyte growth factor (HGF) is also a potent in vitro and in vivo survival-promoting 
factor for neurons (Kadoyama K, et al. 2007). HGF was first identified and molecularly 
cloned as a potent mitogen for mature hepatocytes (Nakamura et al., 1984, 1989). 
Subsequent studies revealed that HGF exerts multiple biological effects (c-Met) 
(Funakoshi and Nakamura, 2003).  
Neurotrophic effects of HGF have been demonstrated in vivo on embryonic spinal motor 
neurons during development and on adult motor neurons after axotomy of the hypoglossal 
nerve (Novak KD et al. 2000). Overexpression of neuronal HGF has been shown to result 
in the attenuation of neuronal cell death and progression of disease in a familial ALS 
transgenic mouse model (Sun W et al. 2002). Introduction of the HGF gene into neurons 
of transgenic mice expressing human mutant Cu⁄Zn superoxide dismutase (G93A mice) 
attenuates motor neuron degeneration and increases the life span of these mice. (Sun W et 
al. 2002). 
6.1.3.2. 
In vitro protection of motorneurons by MSC-NTF cells 
In order to test whether MSC-NTF cells are capable of rescuing motoneurons, we 
examined the effects of conditioned media of the MSC-NTF cells on a motoneuron cell 
line (NSC-34, Cashman NR et al. 1992). We found that the conditioned medium protects 
from NO damage (induced by SIN-1), glutamate toxicity, H2O2 (Sadan O et al.2009, 
Yust-Katz S et al. 2012) and hypoxia (Fig. 1) suggesting that soluble factors secreted from 
MSC-NTF cells may protect motor neurons from the damage associated to the 
pathophysiology of ALS. 
 
Figure 1: 
MSC-NTF cells’ conditioned medium protects motorneuron cells from 
hypoxia. 
Motorneuron cells (NSC 34) were exposed for 48hrs to hypoxia (1% H2, 4% CO2 and 95%N2) in the 
presence of conditioned medium of MSC-NTF cells or of MSC. Cell viability was measured by Alamar Blue 
(O.D., 544-590 nm) and the ratio between hypoxia and control (with no Hypoxia) for each conditioned 
medium was calculated. MSC-NTF conditioned medium is shown to be significantly more protective as 
compared to MSC conditioned medium against hypoxic stress (p<0.001, n=20). 
0
5
10
15
20
25
30
35
%   Hypoxia/Control 
MSC
MSC-NTF
**

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6.1.3.3. 
MSC-NTF secreting cells improve motor function and increase survival of 
SOD1 mice 
Aiming to evaluate the effect of autologous transplantation of mouse MSC-NTF cells in a 
mouse model of ALS, we used mouse bone marrow derived mesenchymal stem cells that 
were induced to differentiate and secrete NTF.  MSCs isolated from mice and induced to 
differentiate into NTF secreting cells, demonstrated similar phenotype and characteristics 
as the human MSC and MSC-NTF cells respectively. The MSC-NTF cells (5x105) were 
transplanted into the cerebral ventricle and into the leg muscles (5x105) of Superoxide 
dismutase 1 (SOD1) transgenic mice. We found that, compared to control (saline) injected 
mice, the cell-transplanted mice performed better on rotarod, had delayed onset of the 
disease and an extended life span.  Additionally the life span of the MSC-NTF treated 
SOD1 mice increased by 18.8 days as compared to saline injected SOD1 mice (151.8 vs. 
133 days, p<0.007, Fig. 2). 
 
 
Figure 2: 
Transplantation of MSC-NTF cells improved the symptoms and the 
survival in a mice model of ALS.  
SOD1 transgenic mice were transplanted with MSC-NTF cells (106) into the cerebral ventricle and into the 
leg muscles. The motor function was evaluated by rotarod (left panel). The survival curve shows the death 
rate of the treated and the saline control mice (right panel). 
6.1.3.4. 
Therapeutic Effects of Differentiated Mesenchymal Stem Cells in a Rat Model 
of Sciatic Nerve Injury 
Motor neuron (MN) loss is the origin of several fatal, progressive neurodegenerative 
diseases including ALS (Boillée et al., 2006). It is characterized by a progressive loss of 
MNs from the spinal cord, brainstem, and cerebral cortex.  
Sciatic nerves are the longest and largest single nerves in the body. They begin in the 
lower spinal cord and run through the pelvis and down the lower limb. The sciatic nerves 
innervate the back of the thigh, leg and foot muscles. 
Since the sciatic nerve supplies movement to most of the lower limb, damaging this motor 
system, models lower limb paralysis and the deficits that occur in diseases like ALS. 
While the etiologies of ALS and lower limb paralyses differ, the clinical presentations 
have similarities, and both lack effective treatments.  
It has been shown that the retrograde death of motor neurons in the adult spinal cord after 
sciatic nerve avulsion is due to apoptosis (Martin LJ et al. 1999). Since retrograde 
 
MSC-NTF
MSC-NTF
Control
Control

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degeneration and neuronal apoptosis may participate in the mechanisms for motor neuron 
death in ALS it is suggested that this model can provide important information toward the 
understanding of motor neuron protection in ALS.   
The protective effect of autologous MSC-NTF cells was studied in the sciatic nerve injury 
model in rat as a model for motorneuron damage which is representative of the damage 
seen in ALS (Dadon-Nachum M et al 2011a).   
We examined whether MSC-NTF cells are capable of rescuing motor neurons in a 
unilateral Sprague-Dawley rat Sciatic Nerve Injury (SNI) model. The right hind limb 
sciatic nerve was crushed for 30 seconds in two points above the first branching of the 
nerve using a clamp. One day later, rats were transplanted with rat MSC-NTF cells or 
control into the site of the lesion. Four days after transplantation, in rats injected with the 
MSC-NTF cells, motor function measured by rotarod was found to be markedly preserved 
(73% vs. control in the MSC-NTF cells treated rats as compared to 41% in the control-
injected group, p<0.01).  
These finding indicate that intramuscular transplantation of autologous MSC-NTF cells 
rescued neuron damage in the sciatic nerve injury in rats and therefore support the notion 
that MSC-NTF can protect and increase restoration of motor-neurons, the cell population 
that suffers the most damage in ALS (Dadon-Nachum M et al 2011).  
6.1.4. MSC-NTF Benefit and Risk Assessment 
ALS is a fatal neurological disease. There is currently only one product approved for the 
treatment of ALS, namely, riluzole, which was demonstrated to increase time to 
tracheostomy or death in patients randomized to riluzole compared to those randomized to 
placebo.  No other products have been approved for the treatment of ALS since riluzole’s 
approval in 1995.  Thus, there remains a great unmet medical need for safe and more 
effective treatments for people with ALS.  
Most of the current investigational therapies in development for ALS, such as anti-
glutamatergic agents, drugs targeting protein misfolding and accumulation, antioxidant 
therapy and immunomodulatory agents, focus on one of multiple putative 
pathophysiologic mechanisms. 
Cyto-therapy may hold the key to circumventing multiple hurdles in the ALS 
pathophysiological cascade (Morren JA et al. 2012). Apart from the replacement of lost or 
damaged motor neurons, stem cell implantation therapy may benefit ALS patients by an 
independent effect of cytoprotection.  
Experimental data have shown that non-neuronal cell replacement can promote motor 
neuron survival and improved neuromuscular function (Corti S et al. 2010). 
Preclinical studies in several animal models of neurodegenerative diseases have shown 
benefits of MSC-NTF transplantation, which support the evidence that these cells may be 
effective treatment of ALS patients. 
Autologous MSC-NTF transplantation appears to be generally safe in the 28 ALS patients 
in whom the product has been administered in two open-label GCP compliant clinical 
trials as well as in five treatments in 4 patients with ALS in which the cells were 
administered on a “compassionate” basis treatment.  

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In the open-label studies we previously conducted, no serious treatment-related adverse 
events were reported in the 12 treated ALS patients who were administered the product via 
either IM or the IT route of administration or in the 12 patients that received a combined 
IT and IM administration of increasing doses of MSC-NTF cells (See section 6.1.2). 
The dose for the proposed Phase 2 study is the highest IM and IT combined administration 
dose, found to be well tolerated in the Phase 2a clinical study and in the 'compassionate 
use' treated patients. 
In our previous study a trend towards a decreased rate of decline on the ALSFRS-R and on 
FVC was observed in the IT treated patients over 6 months post-transplant as compared to 
the three months pre-transplant follow-up, suggesting that the product should be further 
evaluated in this indication.  
MSC are plastic-adherent cells isolated from the mononuclear fraction of the bone 
marrow. The bone marrow compartment is a convenient source for MSC.  
In summary, autologous transplantation of adult bone marrow-derived MSC offers 
practical advantages since:  
• Bone marrow cells can be easily and safely obtained by needle aspiration. 
Although the crude bone marrow contains only very low numbers of MSC (1:104-
105), they can be enriched and expanded ex-vivo from the bone marrow 
mononuclear cell fraction.  
• There is no need for immunosuppression since rejection is not expected when 
autologous MSC are administered. 
Potential risks of participation in this study are considered to be low, and include the 
following: 
• Risks associated with bone marrow harvesting and related conscious sedation 
• Risks of LP include post-LP headache and CSF leak that could potentially require 
treatment.  
• Risks of IM administration may include local skin irritation at the injection sites.   
• As this is an autologous treatment and there is variability between patients' cells' 
growth capabilities, there is also a possibility that patients' cells will not grow 
sufficiently and may not allow the required cell dose to be transplanted back.  
Therefore, the potential benefits of IT and IM injections of MSC-NTFs justify the 
small risks associated with the harvesting of Bone Marrow and administration of this 
autologous product. 
6.2. STUDY OBJECTIVES 
6.2.1. Primary objective 
To evaluate the safety of MSC-NTF transplantation via combined IT and IM injections in 
participants with ALS.  

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6.2.2. Secondary Objectives 
To compare the change in slopes from the pre-transplantation period to the post-
transplantation period in ALSFRS-R between the treatment and placebo groups through 
12 and 24 weeks post-transplantation. 
To compare the change in slopes from the pre-transplantation period to the post-
transplantation period in SVC between the treatment and placebo groups through 12 and 
24 weeks post-transplantation. 
To compare the slope of the rate of decline in the ALSFRS-R at 12 and 24 weeks 
following transplantation relative to the 12-16 week baseline period before transplantation 
in all patients (both treatment and placebo groups). 
To compare the slope of the rate of decline in SVC at 12 and 24 weeks following 
transplantation relative to the 12-16 week baseline period before transplantation in all 
patients (both treatment and placebo groups). 
6.2.3. Exploratory Objectives  
To compare the slopes of decline of hand-held dynamometry (HHD), and electrical 
impedance myography (EIM, for patients in whom this optional outcome measure is 
available) against placebo as well as during the 12-16 week pre-transplant monitoring 
period relative to the 24 week post-transplant follow-up period.  
Determine feasibility of succeeding in blinding patients and caregivers to the treatment, in 
anticipation of a requirement to include the placebo group in the Phase III efficacy study.  
To examine the CSF of ALS patients at baseline and two weeks after treatment for the 
presence of neurotrophic factors and possible ALS biomarkers. 
6.3. INVESTIGATIONAL PLAN 
6.3.1. Overall Study Design and Plan 
This is the third clinical study of autologous MSC-NTF cells conducted by BrainStorm 
Cell Therapeutics and the first study conducted under this IND in the U.S.  It is a Phase II 
randomized, double blind, placebo controlled multicenter study that will be conducted in 
48 patients with early ALS (ALSFRS-R scores of ≥30) at up to 3 US study sites.  After 
providing informed consent, each patient will undergo a 12-16 week baseline period 
during which monthly ALSFRS-R scores and SVCs will be obtained. During this period 
of time their bone-marrow will be harvested and deriving mesenchymal stromal cells will 
be expanded. Twelve to 16 weeks after screening, patients will undergo transplantation 
with their autologous MSC-NTF or matching placebo; product will be administered both 
intrathecally as well as intramuscularly as 24 IM injections given into the right biceps and 
triceps muscles, all at a single study visit.  Following treatment they will have monthly 
visits at which the ASLFRS-R and SVC will be obtained, along with vital signs, 
laboratory tests and recording of concomitant medications and AEs. 
All participants will undergo informed consent and sign a written informed consent 
document.  Participants will be informed that in case their autologous bone marrow fails to 
grow adequate numbers of MSC they will not receive the transplant.  All participants will 
be observed for a total of 12-16 weeks prior to undergoing a bone marrow aspiration 

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procedure to establish each individual’s rate of progression over a total of about 3 months 
to be compared to post-treatment measures. This pre-treatment period also includes about 
four weeks of the cell propagation (see Figure 3). 
The 48 participants will be randomized (3:1) into a treatment or into a placebo group 
which will occur at Visit 3.  Cells from the treatment group participants will be propagated 
in a cell culture facility over a period that can range from 24 to 38 days.  Participants in 
both the treatment and placebo groups will then undergo combined IT and intramuscular 
(IM) injections (Figure 1). Both groups will be monitored for 24 weeks post-treatment.  
Participants in each group will be monitored by evaluators blinded to the treatment group, 
using identical procedures during the pre-transplantation period and for an additional 24 
weeks post-treatment.  Participants will be followed by in-person visits and telephone 
visits at least monthly throughout the trial (see schedule of activities (SOA) in Tables 1 
and 2). 
The autologous production process is on a per-patient basis and begins upon fresh bone 
marrow aspirate arrival to the cleanroom facility and is completed once the cells are ready 
for transplantation. Because the production capacity of the cell manufacturing facility is 
limited, it will be the limiting factor for the rate of enrolment. Based on the production 
capacity limitations, patients are expected to be recruited at a rate of approximately 2-4 
patients/months throughout the trial.  
6.3.2. Study Schematic 
The study comprises a 12-16 week pre-treatment follow-up period and a 24 week post-
treatment follow-up period (Figure 1).  
Patient bone marrow will be aspirated about 9-11 weeks following the first screening visit. 
The MSC isolation and cell propagation process will last about 3-5 weeks and will be 
followed by MSC-NTF cells transplantation.   
At the transplantation visit (about 12-16 weeks after the screening visit), subjects will be 
admitted to an inpatient study unit for study procedures and will be followed for 44-72 
hours post transplantation.  
Following treatment patients will be followed at monthly visits for a total of 24 weeks.  
Each patient will thus be followed for a total of about 38 weeks (9-10 months) from the 
first screening visit (Figure 3).   
 
 
- 12-16 wks
Screening
(V1)
- 3-5 wks
BMA
(V4)
0
Trans
plantation
(V5)
24-26 wks
End of Study
(V10)
BMA: Bone Marrow Aspiration                                                   ↓Monthly visits
~ 9-10 months

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Figure 3: 
Clinical Study flowchart 
Clinical study flowchart outlining the pre- and post-transplant follow-up.  
6.3.3. Treatment Plan 
6.3.3.1. 
Bone Marrow aspiration procedure: 
Human bone marrow will be aspirated by a credentialed health care provider as per 
Medical Centre procedures bilaterally from multiple punctures of the iliac crest of the 
pelvic bone of patients into 20 mL syringes prefilled with approximately 1.5 mL of a 
Heparin-containing solution (Heparin Solution, USP, 100 units/mL) diluted 1:20 in HBSS.   
Vacutainer tubes (Green cap 6 ml REF 367886 BD or equivalent with Sponsor approval) 
containing Lithium Heparin Sodium for injection (95 IU units/tube) will be pre-labelled 
and the cap pre-cleaned with Ethanol. After replacing the aspiration needle with a new 
sterile 19 gauge needle, the bone marrow aspirated from each single puncture (2-3 ml), 
will be injected into a separate pre-labelled Vacutainer tube. Immediately after bone 
marrow is injected into the tube, the tube will be thoroughly mixed to avoid clotting of the 
bone marrow sample.  
A total of 50-70 ml of Bone Marrow will be aspirated from each patient. 
6.3.3.2. 
IT Transplant Procedure 
Participants will undergo a lumbar puncture (Spinal needle 20GA 3.50 IN (0.9 x 90 mm) 
followed by intrathecal injection of cells or placebo (Dulbecco modified Eagle Medium, 
DMEM). The detailed transplantation procedure is provided in Appendix 3. 
6.3.3.3. 
IM Transplant Procedure  
Participants will undergo a unilateral (right) IM transplantation of cells or of placebo 
solution (DMEM) into 24 sites in the biceps and triceps muscles of the upper arm (Figure 
4).  The detailed transplantation procedure is provided in Appendix 4. 
 
Figure 4: 
Study groups flowchart 
Diagram delineating placebo and cells transplantation in the treatment and placebo groups.  
Transplantation
Placebo group
Treatment group
IT
IM 
(Right arm)
IT
IM
(Right Arm)
Bone Marrow Aspiration

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6.3.4. Blinding and Randomization 
Randomization will be used to avoid bias in the assignment of patients to treatment, to 
increase the likelihood that known and unknown subject attributes (e.g., demographics and 
baseline characteristics) are evenly balanced across treatment groups, and to enhance the 
validity of statistical comparisons. 
This is a double-blind study; the investigators, the subjects, and designated study monitors 
will be blinded to the treatment assignment throughout the subject’s participation in the 
trial. The exceptions to the blinding will be the Production team (unblinded personnel) at 
the cell culture facility at the site who distribute the MSC-NTF cells, and the unblinded 
statistician who will create the final randomization schedule but will not otherwise be 
involved in the trial.  
Randomization will be stratified by site.  Site-specific randomization lists will be provided 
to the Production manager prior to any subjects being randomized.  The Production 
manager will refer to the randomization list when assigning treatment to a subject, and 
will allocate the treatment corresponding to the subject’s randomization number.  
Randomization numbers will be assigned sequentially as subjects are randomized at each 
site.  Randomization will occur at Visit 3 (one week before Bone Marrow aspiration) after 
eligibility has been confirmed.  The subject’s randomization number will be recorded in 
the subject’s source documentation and CRFs, and the randomization number will be 
provided to the cell culture facility in preparation for the MSC isolation and cell 
propagation process. 
In the event that emergency unblinding is necessary, the treatment codes for all subjects, 
where the treatment code information for each subject will be separated to ensure that all 
treatment codes will not be unblinded unnecessarily, will be available from the Medical 
Monitor.  The randomization code may be broken only in the event of an emergency when 
it is essential to know which treatment the subject received in order to provide appropriate 
care. Whenever the code is broken for safety reasons, the date, time, and reason for 
unblinding must by documented by the investigator or any other person breaking the code, 
the Sponsor must be notified immediately.  
6.3.5. Duration of study 
Participants will be screened and undergo bone marrow aspiration after 9-10 weeks.  
Following aspiration, cells will be grown in culture for approximately 24-30 days (3-4 
weeks).  Participants in both the treatment and placebo groups will undergo combined IT 
and IM cell transplantation with either MSC-NTF cells or the placebo (DMEM).  
Following cell transplantation, participants will be monitored as inpatients for a period of 
at least 44 hours. Participants will be discharged after at least 44 hours and up to 72 hours 
unless a clinical adverse event(s) occur that require continued inpatient monitoring and/or 
treatment.  Each subject’s participation in the study will last for approximately 9 months. 
6.3.6. Discussion of Dose  
The combined IM and IT transplantation dose is the highest dose of MSC-NTF 
administered by combined intramuscular and intrathecal administration shown to have 
been safely administered in previous clinical trials in ALS patients (see section 6.1.2 
above).  

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6.3.7. Discussion of Study Design, Including Choice of Control Group 
The study is a randomized double blind placebo controlled study. The control group will 
be given placebo.  It is expected that 36 subjects given MSC-NTF and 12 subjects DMEM 
in the placebo arm will provide an adequate number of subjects to compare rates of 
adverse events between the treatment and control groups and allow us to explore the 
effects on the rates of decline on the ALSFRS-R and SVC between the treatment and 
placebo control groups as well as individual changes from baseline scores through Week 
24 following treatment. 
One of the study exploratory endpoints is aimed at determining feasibility of succeeding in 
performing successful IT administration of MSC-NTF cells and of blinding patients and 
caregivers to the treatment in anticipation of performing a larger Phase III efficacy study.  
ALS is a terminal disease, and life expectancy of patients is usually 3 to 5 years after 
diagnosis of ALS. Early stage ALS patients (≤24 months from ALS symptom onset and 
ALSFRS-R ≥30) were therefore chosen as the study population, to increase chances of 
participants of completing the full 9 months study and to obtain a patient population with a 
relatively homogenous rate of disease progression thus increasing the power for detecting 
a difference in the efficacy outcomes (either between treated and controls or change from 
baseline among treated vs. untreated subjects). Rates of decline on the ALSFRS-R in such 
patients are reported in the published scientific literature to range from -0.92 ± 0.08 
points/month (Castillo-Viguera et al 2010, NEALS data) to 2.35 (Sorenson EJ et al. 2008).   
Since ALS is a fatal, progressive, neurodegenerative disease characterized by motor-
neuron cell death in the brain and spinal cord, accompanied by rapid loss of muscle 
control and eventual complete paralysis and there is currently no available treatment to 
prevent its progressive course, a reduction in the slope of decline in the ALSFRS-R and/or 
in the SVC reflected as a change in disease progression (slope) compared to concurrent 
placebo controls will be considered to constitute a response that will be evaluated further 
in Phase III clinical studies.  
6.4. SUBJECT POPULATION 
This study will be conducted in subjects with a clinical diagnosis of ALS who meet the El 
Escorial criteria (Brooks, B.R., et al 2000) for possible, laboratory-supported probable, 
probable, or definite ALS. To be enrolled in this study, patients must meet all inclusion 
criteria in Section 6.4.1 below and must not have any of the exclusion criteria listed in 
Section 6.4.2. 
The subject population is chosen from the group of early-stage ALS participants with the 
aim of obtaining a homogeneous study population that will facilitate the interpretation of 
the study results and allow for identifying trends in efficacy outcomes.  
Due to the length of the study it is also aimed to include participants that will survive for 
the duration of the study. 
6.4.1. Inclusion Criteria 
Study subjects meeting all of the following criteria will be allowed to enroll in the study:  
1. Males and females ages 18 to 75 years old, inclusive. 

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2. ALS diagnosed as possible, laboratory-supported probable, probable, or definite as 
defined by revised El Escorial criteria. 
3. Disease onset, as defined by first reported occurrence of symptomatic weakness, 
spasticity, or bulbar symptoms, of more than 12 months and less than or equal to 
24 months.  
4. Current disease symptoms must include limb weakness. 
5. ALSFRS-R ≥30 at the Screening Visit. 
6. Upright slow vital capacity (SVC) measure ≥65% of predicted for gender, height, 
and age at the Screening Visit. 
7. Subjects must be taking a stable dose of riluzole for at least 30 days prior to 
enrolment or not be on riluzole, and not have been on it for at least 30 days prior to 
enrolment (riluzole-naïve subjects are permitted in the study). 
8. Capable of providing informed consent and willing and able to follow study 
procedures, including willingness to undergo lumbar puncture. 
9. Geographic accessibility to the study site and willingness and ability to comply 
with follow-up.  
10. Women of child-bearing potential must agree not to become pregnant for the 
duration of the study.  Women must be willing to consistently use two forms of 
contraceptive therapy throughout the course of the trial, and undergo a pregnancy 
test one week before bone marrow aspiration. Men must be willing to consistently 
use two forms of contraceptive if their partners are of child-bearing age. 
11. Citizen or permanent resident of the United States. 
6.4.2. Exclusion Criteria 
Study subjects meeting any of the following criteria during screening evaluations will be 
excluded from entry into the study: 
1. Prior stem cell therapy of any kind. 
2. Inability to lie flat for the duration of intrathecal cell transplantation and/or bone 
marrow biopsy, or inability to tolerate study procedures for any other reason. 
3. History of autoimmune disease (excluding thyroid disease) myelodysplastic or 
myeloproliferative disorder, leukemia or lymphoma, whole body irradiation, hip 
fracture, or severe scoliosis. 
4. Any unstable clinically significant medical condition other than ALS (e.g., within 
six months of baseline, had myocardial infarction, angina pectoris, and/or 
congestive heart failure), treatment with anticoagulants that, in the opinion of the 
investigator, would compromise the safety of patients.  
5. Any history of malignancy including any malignancy affecting the central nervous 
system and melanoma, within the previous 5 years, with the exception of localized 
skin cancers (with no evidence of metastasis, significant invasion, or re-occurrence 
within three years of baseline).  
6. Serum AST or ALT value >3.0 times the upper normal limit. 

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7. Serum creatinine value >2.0 times the upper normal limit. 
8. Positive test for Hepatitis B, Hepatitis C, HIV. 
9. Current use of immunosuppressant medication or use of such medication within 4 
weeks of Screening visit (Visit 1). 
10. Any history of acquired or inherited immune deficiency syndrome. 
11. Exposure to any other experimental agent (off-label use or investigational) or 
participation in a clinical trial within 30 days prior to Screening Visit (Visit 1). 
12. Use of non-invasive ventilation (NIV), diaphragm pacing system or invasive 
ventilation (tracheostomy). 
13. Any history of either substance abuse within the past year, or unstable psychiatric 
disease according to PI judgment.  
14. Placement or usage of feeding tube.  
15. Pregnant women or women currently breastfeeding. 
6.5. STUDY ASSESSMENTS 
The Schedule of Activities (SOA) provides a visual listing of study activities at each visit. 
Refer to Appendix 1 for table of SOA at each visit and the study manual for details of 
assessments, including the ALSFRS-R, SVC, HHD, EIM and C-SSRS. 
This is a multi-center study. The Sponsor will ensure that all Medical centers will be 
performing study assessment procedures in the same way by providing appropriate 
training to sites.  
6.5.1. Clinical Laboratory Safety Tests 
Clinical laboratory safety tests will be monitored throughout the trial at Visits 1, 3, 5, 7, 8, 
9 and 10 as listed in the Schedule of Activities (Tables 1 and 2).  
Tests include: 
Hematology: CBC (RBC with Indices, WBC with differential and platelet count, Hb, Ht). 
Blood Biochemistry: Na, K, Cl, HCO3, BUN, Cr, Gluc, Ca, Mg, Phos, total protein, 
triglycerides (TG), Total cholesterol, HDL, LDL, urea, creatinine, total bilirubin, 
AST(GOT), ALT(GPT), ALP, uric acid.  
Coagulation: PT, PTT. 
Urinalysis (dip-stick test) - Specific Gravity, pH, glucose, protein, ketones, blood. 
6.5.2. Physical Examinations, Vital Signs, and Electrocardiograms  
Participants will undergo physical examinations at all in-person visits except for the Bone 
Marrow aspiration visit (Visit 4), Vital Signs measurements (including blood pressure, 
pulse and respiration rate after sitting for at least 3 minutes) as well as body weight will be 
monitored at all in-person visits, and a 12-lead ECG will be obtained at visits 1, 5 and 10.  

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6.5.3. Pre-transplantation Visits 
6.5.3.1. 
Visit 1: Screening Visit  
Visit 1 is the screening Visit and precedes V2 by approximately 4-6 weeks. Subjects will 
undergo the following screening assessments: 
• Obtain Informed consent  
• Collect demographic data  
• Medical history 
• History of ALS symptoms and date of diagnosis  
• Review of concomitant medications  
• Physical examination including height and weight  
• El Escorial criteria  
• Neurological examination  
• Blood collection for hematology, coagulation, chemistry evaluations and a 
pregnancy test (Female participants) 
• Blood collection for HBV (surface and core antigen), HCV, HIV 1 and 2 and 
HTLV I and II, Treponema pallidum, and CMV tests  
• Urinalysis 
• Electrocardiogram (ECG)  
• Vital sign measurements   
• SVC pulmonary function test  
• ALSFRS-R questionnaire   
• Hand held dynamometry (HHD) 
• Electrical impedance myography (EIM) will be collected only at centers that opt to 
participate in EIM data collection.   
• Columbia Suicide Severity Rating Scale (C-SSRS) Baseline 
• Determine study eligibility  
6.5.3.2. 
Visit 2: Pre transplantation (Week 4-6) 
Visit 2 is the first visit of the pre transplantation follow-up period (Week 4-6). Participants 
will undergo the following assessments  
• Review of concomitant medications 
• Directed physical examination including weight 
• Vital sign measurements  
• Neurological examination 
• SVC pulmonary function test 
• Adverse events review 
• ALSFRS-R questionnaire 
• Hand held dynamometry (HHD) 
• Electrical impedance myography (EIM) will be collected only at centers that opt to 
participate in EIM data collection.    
• Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
• Confirm study eligibility  

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6.5.3.3. 
Visit 3: Pre transplantation Visit (Week 8-10) 
Visit 3 is the second visit of the pre-transplantation follow-up period (Week 8-10), about 1 
week before Bone Marrow aspiration. Participants will undergo the following 
assessments: 
• Review of concomitant medications 
• Directed physical examination including weight 
• Vital sign measurements  
• Neurological examination 
• Blood collection for hematology, coagulation and chemistry evaluations and a 
pregnancy test (Female participants) 
• Blood collection for HBV (surface and core antigen), HCV, HIV 1 and 2 and 
HTLV I and II, Treponema pallidum, and CMV tests.  
• Urinalysis 
• SVC pulmonary function test 
• Review of adverse events  
• ALSFRS-R questionnaire 
• Hand held dynamometry (HHD) 
• Electrical impedance myography (EIM) will be collected only at centers that opt to 
participate in EIM data collection.  
• Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
Following Visit 3, participants will be randomized into two arms at a 3:1 ratio: the 
treatment transplant arm (36) and the placebo transplant arm (12).  
Any participant discontinuing the study prior to transplantation of cells (or placebo) 
injections will be replaced with another participant to meet the target of 48 transplanted 
participants.  
Participants and medical team will be blinded to patient randomization.   
6.5.3.4. 
Visit 4: Bone Marrow Aspiration (Week 9-11)  
Once all safety test results are confirmed negative or normal, all participants will undergo: 
• Review of concomitant medications 
• Review of adverse events  
• Vital sign measurements  
After these assessments, all participants will undergo bone marrow aspiration (BMA) by a 
credentialed health care provider as per Medical Centre procedures from multiple 
punctures of the iliac crest of the patients' pelvic bone. 
6.5.3.5. 
Visit 5: Cell Transplantation (Days 0-2) 24-38 days from BMA 
At the transplantation visit, subjects will be admitted to an inpatient study unit for study 
procedures.  Pre-transplant activities will include: 
• Review of concomitant medications 
• Review of adverse events  
• Vital sign measurements  
• Directed physical examination including weight 
• Neurological examination 

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• SVC pulmonary function test 
• ALSFRS-R questionnaire 
• Hand held dynamometry (HHD) 
• Electrical impedance myography (EIM) will be collected only at centers that opt to 
participate in EIM data collection.    
• Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
Following pre-transplant procedures, subjects will undergo intrathecal injection of cells or 
placebo as well as 24 intramuscular injections of cells or placebo (transplantation) along 
the biceps and triceps muscle of the right arm (If the physician is unable to inject into the 
right arm, the cells may be injected into the left arm and the fact recorded on the CRF. See 
Appendix 4, describing the procedure for the IM injections).  CSF removed from the 
subject immediately prior to the intrathecal administration of cells will be retained for 
analysis. 
Concomitant medications and adverse events will be monitored throughout the study visit, 
as necessary.  In addition the following will be monitored: 
• Vital signs will be monitored at hours 1, 2, 3, 4, 6, 16, 22, 28, 40, and upon 
discharge at 44 hours or up to 72 hours post transplantation. Inpatient observation 
is up to 72 hours, with earlier discharge at investigator discretion. 
• Visual inspection of the injection sites will be performed at hours 1, 16 and 40. 
• Directed physical examinations will be performed at hours 16, and 40 post-
transplantation.   
• Hematology, coagulation chemistry evaluations and biochemistries as well as 
urinalysis will be checked at 16 hours.  
• Electrocardiogram (ECG) will be performed at 22 ± 4 hours post-transplantation   
Prior to discharge, activities will include: vital signs, review of medications and adverse 
events and questionnaire for assessment of blinding.  
6.5.4. Post transplantation follow-up 
6.5.4.1. 
Visit 6: Week 2 (± 5 days) Follow-Up 
At the week 2 post transplantation follow-up visit participants will undergo: 
• Review of concomitant medications 
• Review of adverse events  
• Vital sign measurements  
• Directed physical examination including weight 
• Neurological examination 
• ALSFRS-R questionnaire 
• SVC pulmonary function test 
• Hand held dynamometry (HHD) 
• Lumbar puncture and collection of 3 mL of CSF.  
• Electrical impedance myography (EIM) will be collected only at centers that opt to 
participate in EIM data collection.    
• Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit 

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6.5.4.2. 
Visit 7: Week 4 (± 5 days) Follow-Up 
At the week 4 post transplantation follow-up visit participants will undergo: 
• Review of concomitant medications 
• Review of adverse events  
• Vital sign measurements  
• Directed physical examination including weight 
• Blood collection for haematology coagulation and chemistry evaluations  
• Urinalysis 
• Neurological examination 
• ALSFRS-R questionnaire 
• SVC pulmonary function test 
• Hand held dynamometry (HHD) 
• Electrical impedance myography (EIM) will be collected only at centers that opt to 
participate in EIM data collection.    
• Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
6.5.4.3. 
Visit 8: Week 8 (± 5 days) Follow-Up 
At the week 8 post transplantation follow-up visit participants will undergo: 
• Review of concomitant medications 
• Review of adverse events  
• Vital sign measurements  
• Directed physical examination including weight 
• Blood collection for haematology, coagulation and chemistry evaluations  
• Urinalysis 
• Neurological examination 
• ALSFRS-R questionnaire 
• SVC pulmonary function test 
• Hand held dynamometry (HHD) 
• Electrical impedance myography (EIM) will be collected only at centers that opt to 
participate in EIM data collection.    
• Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
6.5.4.4. 
Phone Call 1: Week 12 (± 5 days) Follow-Up 
Subjects will receive a phone call for this Week 12 follow-up.   
During the phone interaction, subjects will undergo: 
• Review of concomitant medications 
• Review of adverse events  
• ALSFRS-R questionnaire 
6.5.4.5. 
Visit 9: Week 16 (± 5 days) Follow-Up 
At the week 16 post transplantation follow-up visit participants will undergo: 
• Review of concomitant medications 
• Review of adverse events  
• Vital sign measurements  

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• Directed physical examination including weight 
• Neurological examination 
• Blood collection for haematology, coagulation and chemistry evaluations  
• Urinalysis 
• ALSFRS-R questionnaire 
• SVC pulmonary function test 
• Hand held dynamometry (HHD) 
• Electrical impedance myography (EIM) will be collected only at centers that opt to 
participate in EIM data collection.    
• Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
6.5.4.6. 
Phone Call 2: Week 20 (± 5 days) Follow-Up 
Subjects will receive a phone call for this Week 20 follow-up.   
During the phone interaction, subjects will undergo: 
• Review of concomitant medications 
• Review of adverse events  
• ALSFRS-R questionnaire 
6.5.4.7. 
Visit 10: Week 24 (± 5 days) Follow-Up 
At the week 24 post transplantation follow-up visit participants will undergo: 
• Review of concomitant medications 
• Review of adverse events  
• Vital sign measurements  
• Physical examination including weight 
• Neurological examination 
• Blood collection for haematology coagulation and chemistry evaluations  
• Urinalysis 
• Electrocardiogram (ECG)  
• ALSFRS-R questionnaire 
• SVC pulmonary function test 
• Hand held dynamometry (HHD) 
• Electrical impedance myography (EIM) will be collected only at centers that opt to 
participate in EIM data collection.    
• Columbia Suicide Severity Rating Scale (C-SSRS) Since Last Visit 
• Questionnaire for assessment of blinding 
6.5.5. STUDY DISCONTINUATION 
Subjects could choose to discontinue the study at any time, for any reason, specified or 
unspecified, and without prejudice. Participants could be discontinued from the study for 
any of the following reasons: 
• Participants whose MSC fail to proliferate and to produce a sufficient amount of 
cells for transplantation (see section 6.3.1)  
• At the participant's request 
• At the discretion of the Investigator, if deemed appropriate, for any reason 
• At the discretion of the Sponsor, if deemed appropriate, for any reason 

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In addition to the circumstances listed above for patients’ withdrawal from the study, 
Brainstorm Cell Therapeutics Ltd. and the Investigators reserve the right to terminate the 
study at any time. In any case of early termination (ET) of the study, Brainstorm Cell 
Therapeutics Ltd. and the Investigators will ensure that adequate consideration is given to 
the protection of each subject’s interest.  
An ET visit will be conducted only for subjects who discontinue the study after treatment, 
post visit 5. The ET visit will include all the procedures required at end of study visit 
(Visit 10).  
Any participant discontinuing the study prior to transplantation of cells (or placebo) 
injections will be replaced with another participant to meet the target of 48 transplanted 
participants. 
6.5.6. Temporary Treatment Discontinuation 
Since study treatment is only administered once during this trial, study treatment cannot be 
temporarily held for any serious adverse event or significant intercurrent illness. 
6.5.7. Permanent Treatment Discontinuation 
Permanent treatment discontinuation is defined as cessation of study drug administration. 
This may only occur if the subject does not receive all the intended doses of study 
treatment at the single treatment period (e.g., not all of the intended IM and/or IT doses 
are administered).  Safety follow-up (Section 6.5.8.) will still be performed.   
The primary reasons for permanent treatment discontinuation are listed in Section 6.8.4.  
Cross-references are provided to protocol sections with additional information.   
 
Reason 
Comment 
Adverse event or intercurrent illness 
Any intolerable adverse event that cannot be ameliorated by the 
use of adequate medical intervention or that in the opinion of the 
Investigator or Medical Monitor would lead to undue risk if study 
treatment were continued.  
Sponsor discontinuation of study 
The sponsor reserves the right to terminate the study anytime as 
described in Section 6.12.7. The sponsor will terminate this study 
following completion of the study objectives, or earlier if deemed 
necessary.  
Participant decision 
Participants may permanently discontinue study treatment 
anytime for any reason.  Following study drug discontinuation, 
patients 
should 
have 
protocol-required 
safety 
follow-up 
assessments unless the patient specifically declines further 
follow-up.   
6.5.8. Safety Follow-Up 
All patients who are treated or partially treated will have safety follow-up approximately 9 
months from enrolment in the study. Adverse events and serious adverse events will be 
followed up as described in Section 6.8. For patients who refuse further clinic study visits, 
telephone contact and/or home visits by study staff should be attempted and documented 
to review for adverse events.  

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6.5.9. Lost to Follow-Up 
Every reasonable effort will be made to contact any patient apparently lost to follow-up 
during the course of the study to complete study-related assessments and record 
outstanding data.   
Following unsuccessful telephone contact, an effort to contact the patient by mail using a 
method that provides proof of receipt will be attempted.  Alternate contacts will be used if 
the patient is not reachable (eg, primary care providers, referring physician, relatives).  
Such efforts should be documented in the patient’s source documents.   
If all efforts fail to establish contact, the patient will be considered lost to follow-up.   
6.6. INVESTIGATIONAL PRODUCT INFORMATION 
6.6.1. General Information 
The cell therapy is based on the autologous transplantation of adult bone marrow derived 
multipotent mesenchymal stromal cells (hMSC) which are induced ex-vivo to secrete 
neurotrophic factors (NTFs) such as Glial Cell Line Derived Neurotrophic Factor 
(GDNF), Brain-derived neurotrophic factor (BDNF), Vascular Endothelial Growth Factor 
and Hepatocyte Growth Factor (HGF) and are thus designated MSC-NTF cells. The MSC-
NTF cells are derived from hMSCs isolated from the patient’s own Bone Marrow, 
propagated in-vitro and induced to secrete NTFs using a medium based procedure.  
MSC-NTF cells are adult stem cells that are used for autologous “Self-transplantation”. 
There is no ethical or safety issues of involvement of embryonic cells. Since the cells are 
the patient's own cells there is no risk of rejection and no need for immunosuppressive 
agents, which can cause severe and/or long-term side effects.  
MSC-NTF cells delivery is easy and safe by standard procedures (IT and IM injections) 
and does not require surgical intervention. 
6.6.2. MSC-NTF Product Characteristics 
Participants’ bone marrow is aspirated and MSC are isolated from the total bone marrow 
mononuclear cell population, propagated in culture and induced to secrete NTFs. The 
MSC-NTF cells are then transplanted back into the patient as following:  
• 125 x106 cells by IT administration (however, if less than 125 x 106 cells are 
available, then the total available dose of cells should be administered, provided at 
least 100 x 106 cells are administered) 
• 48 x106 cells by IM administration.  
Patients randomized to placebo will receive both IT and the same number of IM injections 
The MSC-NTF cells' production process is carried out in the absence of antibiotics in the 
absence of phenol red and in the absence of animal derived components. The production 
process is cGMP compliant and is performed under full environmental control, in a class 
10,000 cleanroom (ISO 7). All cell manipulation procedures are performed in a class 100 
(ISO 5) laminar flow hood.  
The MSC-NTF cells are provided in a ready-to-use participant-personalized unique 
treatment package with the appropriate primary and secondary labels. The treatment 

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package consists of one 5 ml syringe for IT transplantation, and twenty four 1 ml syringes 
for IM transplantation. Each treatment package consists of ready-for-injection syringes 
containing freshly harvested autologous cultured MSC-NTF cells at the dose defined for 
the appropriate route of administration in the clinical study protocol. 
Syringes will be capped with a stopper (not a needle). The 5 ml syringe for IT 
transplantation will be packed in a pouch. The 1 ml syringes for IM transplantation will be 
placed in a 7-compartment tray that will be packed in a pouch.  
The treatment/placebo package is delivered to the clinical site in a shipping system 
container designed for maintaining a temperature of 2-8°C during shipment. The shipping 
system containing the syringes is shipped via ground transportation to the clinical site. 
Product should be administered to the patient within 5 hours from packaging. 
Placebo will be provided in the same number of syringes types and sizes as the cell-
containing syringes. 
All treatment as well as placebo syringes will be masked to preclude physician and 
patient's identification of their content. In addition the sponsor will make every effort to 
ensure blinding of the study by the attending physicians.  
The cell production process, including the in-process controls is described in full detail in 
the CMC section and in the Investigator's brochure (IB).  
6.6.3. Treatment Compliance 
It is expected that participants will be fully compliant during the pre-transplant follow-up 
period.  
Since patients are recruited at the early stage of the disease and ambulatory (Disease 
symptoms onset ≤ 24 months and ALSFRS-R ≥30 prior to Screening Visit) they are 
expected to be able to complete the full 6 months post treatment follow-up.  
To increase chances of post–treatment compliance, it will be attempted to recruit patients 
living in the vicinity of the medical centers and/or previously known to the Investigators.  
6.6.4. Test product, Dose and Administration 
Placebo or participants' autologous MSC-NTF cells will be used for a combination 
treatment of 125x 106 cells intrathecally, (however, if less than 125 x 106 cells are 
available, then the total available dose of cells should be administered, provided at least 
100 x 106 cells are administered), and 2x106 cells/site intramuscularly divided equally 
among 24 sites in the right biceps and triceps muscles unilaterally.  
6.7. PRIOR AND CONCOMITANT THERAPY 
6.7.1. Prior Therapy 
Participants who received prior cell therapy of any kind will be excluded from the study 
(See Section 6.4.2).  
Rilutek (riluzole) and Nuedexta (dextromethorphan hydrobromide and quinidine sulfate) 
are the only FDA-approved drugs for patients with ALS (Nuedexta is approved only to 

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treat pseudobulbar affect that occurs in some patients with ALS). Study participants must 
be on a stable dose of riluzole for at least 30 days prior to screening, or not on riluzole at 
all with no plans to begin therapy with riluzole for the duration of the study.  
6.7.2. Concomitant Therapy 
Concomitant medications given to the patient during the pre-transplant, in-patient post-
transplant and outpatient post-transplant periods will be recorded.   
Patients who were on a stable dose of riluzole for at least 30 days prior to screening will 
continue taking riluzole prior to study enrolment, unless requiring discontinuation for 
standard side-effects.  
6.8. SAFETY REPORTING 
For this study, AEs and SAEs will be collected from screening visit through the end of the 
study period and as detailed in Section 6.8.1. 
6.8.1. Adverse Events definitions and reporting 
Standard definitions for AEs are provided in this section for informational purposes. 
6.8.1.1. 
Adverse Event (21 CFR 312.32(a)) 
AE means any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. An AE 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. 
6.8.1.2. 
Serious Adverse Event (21 CFR 312.32(a)) 
An AE or suspected adverse reaction is considered “serious” (SAE) if, in the view of 
either the Investigator or Sponsor, it results in any of the following outcomes: 
• Death 
• Life-threatening (An AE 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 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 functions 
• A congenital anomaly/birth defect 
• Important medical events that may not result in death, be life-threatening, or require 
hospitalization may require medical or surgical intervention to prevent one of the 
outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse. 

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If it is not certain that an event meets the above definitions of an SAE, the site 
investigators will contact the Medical Monitor to discuss. 
6.8.1.3. 
Relatedness (Causality) 
Investigators will assess relatedness of adverse events to study drug using the following 
terms: 
• Definite: An AE that has a clear temporal association with investigational product 
administration (e.g., within 24 hours); provides a plausible pharmacologic 
explanation for the event;  
• Probable: There is a reasonable temporal association with administration of the 
investigational product; unlikely caused by other drugs or underlying conditions;  
• Possible:  There is a plausible temporal association with the investigational 
product, but other etiologies are possible and relatedness to the investigational 
product cannot definitely be ruled out. 
• Unlikely:   The temporal association with the investigational product is 
implausible (but not impossible). The event is likely related to other drugs or 
conditions. 
• Not Related: An AE with no temporal association with the investigational product 
but rather related to other etiologies such as concomitant medications or conditions 
or subject's known clinical state; subject has not received investigational product. 
 
6.8.1.4. 
Severity (Intensity) 
The severity of an adverse event will be graded on a scale: mild, moderate, severe, as 
defined below:  
• Mild:  Asymptomatic or mild symptoms, clinical or diagnostic observations only; 
intervention not indicated. 
• Moderate:  Minimal, local or non-invasive intervention indicated; interferes with 
age-appropriate activities of daily living. 
• Severe:  Disabling; unable to carry out age-appropriate activities of daily living. 
• Potentially Life-Threatening:  Medical or operative intervention indicated to 
prevent permanent impairment, persistent disability, or death 
6.8.1.5. 
Follow-Up of AEs  
After the initial recording of an AE, the Investigator should proactively follow the patient.  
Any non-serious AEs that are still on-going at the end of the study should be reviewed to 
determine if further follow-up is required.  The Investigator will document on the eCRF 
any/all on-going non-serious AEs that will not be followed further after the patient exits 
the study.  If in doubt, the Investigator should consult the study Medical Monitor.    
All SAEs should be followed until resolution, until the condition stabilizes, or until the 
patient is lost to follow-up, or otherwise explained.  Once the SAE is resolved, the 
corresponding AE eCRF page should be updated.  Additionally, any relevant laboratory 
test reports, consultation reports from other health care professionals, discharge 
summaries, or other information that has been gathered about the event should be 
transmitted to the Sponsor.  

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The Sponsor may request that the Investigator perform or arrange for the conduct of 
supplemental measurements and/or evaluations to elucidate as fully as possible the nature 
and/or causality of any AE.   
6.8.1.6. 
Outcome 
The following terms will be used during this study: 
• Fatal 
• Not Recovered/resolved 
• Recovering/resolving 
• Recovered/resolved 
• Recovered/resolved with sequelae 
• Unknown 
6.8.1.7. 
Clinically Significant Laboratory Abnormalities 
Any laboratory abnormalities deemed clinically significant by the Investigator should be 
reported on the AE CRF. A clinically significant abnormality is a confirmed abnormality 
(by repeat test) that is changed sufficiently from Screening so that in the judgment of the 
Investigator a change in management is warranted. This alteration may include: 
monitoring the laboratory test further, initiating other diagnostic tests or procedures, 
changing ongoing treatment, or administering new treatment. Whenever possible, the 
etiology of the abnormal finding (e.g., anemia) will be recorded on the CRF. Repeated 
additional tests and/or other evaluations required to establish the significance and etiology 
of an abnormal result should be obtained when clinically indicated. 
6.8.2. Reporting Responsibilities and Procedures for AEs and SAEs 
It is the responsibility of the Investigator or Sub-Investigator(s) to perform periodic 
assessment of all AEs/SAEs. 
A subject, who experiences an AE, whether serious or not serious, should receive 
appropriate treatment and medical supervision as clinically indicated. AEs/SAEs will be 
followed throughout the subject’s participation in the study, until resolution/stabilization 
or until a time that is mutually agreed upon between the Medical Monitor and the 
Investigator. 
The Investigator must report to the Sponsor all SAEs within 24 hours of learning about the 
event. The reporting mechanism for an SAE is by submitting all available information 
about the event via fax to the designated Safety Department contact. If the SAE has not 
resolved at the time the Investigator submits an initial SAE report, the Investigator must 
provide a follow-up report as soon as the event resolves (or upon receipt of significant 
information if the event is still ongoing). 
The following information and assessments will be recorded in the adverse event section 
of the SAE Reporting Form:  
• The date and time of onset of the event and when it ended using the 24 hour clock 
where midnight is 00:00 and noon is 12:00. 
• The signs, symptoms, or diagnosis of the event. 
• The adverse event severity using the criteria outlined above. 
• The relationship of the event to the investigational product as outlined above. 

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• The seriousness of the event according to definitions outlined above. 
• A description of any required therapy, medication, treatment, or diagnostic 
procedure. 
• Clinical data prior to the event, such as nutrition, concomitant medications, 
physical activity, etc. 
• Any additional data which might be relevant to the event.  
A written report is also required for all patients who died during the study. This report 
must document the events surrounding the patient’s death and the cause of death.  Attach a 
copy or summary of autopsy findings, if performed. 
All SAE reports and questions pertaining to an SAE should be directed to: 
1) Drug Safety: 
 
Katherine Smith, MD 
 
 
 
 
Office: (919) 262-5626  
 
 
 
 
Email: saereports@drugsafety.biz 
 
 
 
 
Fax: (919) 844-69482)  
2) Medical Monitor:  
Kenneth J. Tack, MD 
Office: (810) 227-1386 
Email: kjtack@comcast.net 
 
 
 
 
Cell: (810) 355-8218 
3) Sponsor:   
 
Tony Fiorino MD, Ph.D.  
Office: (201) 357-5382 
Email: tfiorino@brainstorm-cell.com 
 
Yael Gothelf Ph.D.  
Office: (646) 666-3188 Ext. 103 
Email: ygothelf@brainstorm-cell.com 
 
Brainstorm Cell Therapeutics Ltd. 
12 Bazel St. 
Kiryat Aryeh Petach Tikva  
49001 ISRAEL 
 
The Sponsor or designated CRO will report Investigational New Drug (IND) Safety 
Reports to the FDA and Investigators in accordance with the FDA regulations detailed in 
the Code of Federal Regulations (CFR) 21CFR312.32 and in accordance with Guidance 
for Industry and Investigators: Safety Reporting Requirements for INDs and BA/BE 
Studies, December 2012. The Investigator at each study site is responsible for reporting 
SAEs to his or her Institutional Review Board (IRB) in accordance with local IRB 
procedures. 
If new sites are added to the study, the Sponsor or designated CRO will notify all 
investigators at the sites involved in the study in writing of any severe/serious or 

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unexpected adverse events when this information is of global importance to subject safety 
and welfare. 
6.8.3. Prospective assessment of the occurrence of suicidality 
There is no evidence from animal or previous human studies to suggest that MSC-NTF 
cell transplantation will increase suicidal ideation or attempts; but, because these cells are 
delivered to the CSF and are active in the central nervous system, we plan to monitor 
suicidal ideation and behavior carefully throughout the trial.  
Suicidal ideation and behavior will be monitored using the Columbia Suicide Severity 
Rating Scale (C-SSRS; http://www.cssrs.columbia.edu), delivered at each in-person trial 
visit. All study staff delivering the C-SSRS will be fully trained in its appropriate use and 
only study staff prepared to appropriately respond to subjects exhibiting suicidal ideation 
or behavior will deliver the scale. The ‘Baseline’ questionnaire will be given at the 
Screening/Visit.  The ‘Since Last Visit’ questionnaire will be given at subsequent visits.  
6.8.4. STUDY DISCONTINUATION 
6.8.4.1. 
Study or Site Termination 
Conditions may arise during the study that could prompt the study to be halted or the study 
site to be terminated. Conditions that may prompt such considerations include, but are not 
limited to, the following: 
1. The discovery of unexpected, serious, or unacceptable risk to the subjects enrolled in 
the study. 
2. A decision on the part of the Data and Safety Monitoring Board (DSMB) to suspend 
or discontinue the study. 
3. A decision on the part of Sponsor to suspend, discontinue, or shorten the study. 
4. Study conduct at the study site may warrant termination under conditions that 
include the following: 
a) Failure of Investigator(s) to enrol eligible subjects into the study; 
b) Failure of Investigator(s) to comply with ICH-GCP guidelines, or FDA 
guidelines and regulations; 
c) Submission of false information from the research facility to the Sponsor, the 
Clinical Monitor, the FDA, or IRB; 
d) Insufficient adherence to protocol requirements; 
e) A conflict of interest of the Investigator, his/her institution, or site personnel 
that would negatively impact the integrity of the clinical trial; 
f) 
Institution or IRB under investigation for cause by a regulatory agency. 
6.8.4.2. 
Subject Withdrawal from Study 
Subjects may voluntarily withdraw from the study at any time during the course of the 
study. 
The Investigator will document on the appropriate CRF page the reason/circumstances for 
withdrawal. 

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Efforts will be made to follow all subjects who discontinue study for any reason. Such 
follow up will include all relevant evaluations for safety including clinical assessments 
and collection of laboratory study results as set out in this protocol. 
6.8.4.3. 
Study stopping rules 
Previous clinical studies with MSC-NTF cells did not result in any treatment-related 
SAEs. However, if in the course of this study, 2 or more subjects experience SAEs 
evaluated as possible, probable or definitely related to product administration, patient 
enrolment and dosing will be temporarily suspended pending DSMB review of the 
subjects with SAEs. 
6.8.5. Clinical Laboratory Safety Tests 
Clinical laboratory safety tests will be monitored throughout the trial at Visits 1, 3, 5, 7, 8, 
9 and 10 as listed in the Schedule of Activities (Tables 1 and 2).  
All samples to be tested will be shipped to a Central Laboratory. 
Tests include: 
Hematology: CBC (RBC with Indices, WBC with differential and platelet count, Hb, Ht) 
Coagulation: PT, PTT 
Blood Biochemistry: Na, K, Cl, HCO3, BUN, Cr, Gluc, Ca, Mg, Phos, total protein, 
triglycerides (TG), Total cholesterol, HDL, LDL, urea, creatinine, total bilirubin, 
AST(GOT), ALT(GPT), ALP, uric acid.  
Urinalysis (dip-stick test) - Specific Gravity, pH, glucose, protein, ketones, blood 
6.8.6. Physical Examinations, Vital Signs, and Electrocardiograms  
Participants will undergo physical examinations at all in-person visits except at the Bone 
Marrow Aspiration (BMA) visit (Visit 4), Vital Signs measurements (including blood 
pressure, pulse and respiration rate after sitting for at least 3 minutes) as well as body 
weight will be monitored at all in-person visits, and a 12-lead ECG will be obtained at 
visits 1, 5 and 10.  
6.9. ASSESSMENT OF ENDPOINTS 
6.9.1. Primary Endpoint:  
6.9.1.1. 
Safety 
The primary endpoint of the trial is the safety of MSC-NTF transplantation by IT and IM 
routes in participants with ALS 
Safety will be assessed based on the incidence of treatment-emergent adverse events 
(TEAEs) (including serious adverse events [SAEs]) including clinically relevant changes 
in vital signs, clinical laboratory assessments, physical and neurological examinations, and 
electrocardiogram (ECG) tests.  

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6.9.2. Secondary Endpoints: 
6.9.2.1. 
Revised ALS Functional Rating Scale (ALSFRS-R) 
The ALSFRS-R is a quickly administered (10 minutes) ordinal, validated rating scale 
(ratings 0-4) used to determine patients' assessment of their capability and independence in 
12 functional activities.  All 12 activities are relevant in ALS.  Initial validity was 
established by documenting that in ALS patients, change in ALSFRS-R scores correlated 
with change in strength over time, as measured by quantitative neuromuscular strength 
testing, and with quality of life measures, and predicted survival (Cedarbaum, J.M., et al. 
1999, Greenberg, S.A., et al 2005). The test-retest reliability is greater than 0.88 for all test 
items.  The advantages of the ALSFRS-R are that the categories are relevant to ALS, it is 
a sensitive and reliable tool for assessing activities of daily living function in patients with 
ALS, it is quickly administered, and is validated over the phone as well1.  
6.9.2.2. 
Slow Vital Capacity (SVC) 
SVC measure the maximum amount of air a patient can exhale in a single breath. SVC is 
used frequently in ALS clinic as part of a battery of tests used to assess diaphragmatic 
weakness and monitor disease progression. SVC will be measured with patient seated in 
upright position.  It can be measured quickly and effectively in the office setting. 
6.9.3. Exploratory 
6.9.3.1. 
Hand Held Dynamometry (HHD) 
HHD is a quantitative measure of muscle strength and has been validated against 
maximum voluntary isometric contraction (MVIC) (Greenberg, S.A., et al. 2002).  
Proximal arm and distal arm muscles will be examined bilaterally.  To normalize for 
varying strength of individual muscles, all values will be expressed as percent change 
from baseline; this value can be averaged to provide upper extremity, lower extremity, and 
total megascores.  An additional analysis will use mean and standard deviation for each 
muscle group established from the initial values for each subject in this trial, so that 
strength determinations can be converted to Z scores (the difference between the obtained 
score and the mean, divided by the standard deviation).  These Z scores can be combined 
in similar fashion to what was discussed above to produce megascores as well. 
Muscle strength measurements (elbow flexion, wrist extension, knee extension, and ankle 
dorsiflexion) will be performed using the Hand Held Dynamometer (HHD), as described 
in appendix 2 at Visits 1,2,3,5,6,7,8, 9 and 10. The tests take approximately 20 minutes to 
complete.  
                                                 
 
1 Kasarskis EJ, Dempsey-Hall L, Thompson MM, Luu LC, Mendiondo M, Kryscio R. Rating the severity of ALS by 
caregivers over the telephone using the ALSFRS-R. Amyotroph Lateral Scler Other Motor Neuron Disord. 2005 
Mar;6(1):50-4.; 
 
Mannino M, Cellura E, Grimaldi G, Volanti P, Piccoli F, La Bella V. Telephone follow-up for patients with amyotrophic 
lateral sclerosis. Eur J Neurol. 2007 Jan;14(1):79-84. 
 

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6.9.3.2. 
Electrical Impedance Myography (EIM, Optional) 
EIM measures the electrical impedance of individual muscles as a representation for 
muscle composition, which changes with disease progression.  Using a single probe that 
contains both stimulating and recording electrodes, measurements are taken twice over 
each muscle.  The probe is placed against a clean area of skin for less than 10 seconds per 
recording.  Four muscles will be tested in upper and lower extremities; elbow flexors, 
wrist extensors, knee extensors, and ankle dorsiflexors, for a total of 8 muscles tested per 
subject. The minute electrical signals produced by the stimulator are imperceptible; 
subjects only notice the pressure of the probe against their skin.  Sites will have the option 
of collecting the EIM outcome data. 
6.9.3.3. 
Analysis of Cerebrospinal Fluid 
Few studies have been performed that assess and quantify the presence of neurotrophic 
factors in the CSF.  Since MSC-NTF secrete several known neurotrophic factors, we 
intend to develop ELISA assays for neurotrophic factors and use these assays to assess the 
concentration of these factors after treatment.  We are also exploring the possible 
assessment of several putative ALS biomarkers in these CSF samples.  
6.9.4. Statistical Methods and Sample Size Determination 
Summaries for continuous variables will include the sample size, mean, standard 
deviation, median, minimum, and maximum. Minima and maxima will be reported with 
the same precision as the raw values; means, standard deviations, and medians will be 
presented to one additional decimal place than reported in the raw values. Summaries for 
discrete variables will include frequencies and percentages. All percentages will be 
rounded to one decimal place (i.e., XX.X%). Differences between treatment groups will be 
calculated as MSC-NTF cells – placebo and change from baseline will be calculated as 
post-treatment – pre-treatment (OR follow-up visit – baseline: e.g. Week 2 – baseline, 
Week 4 – baseline). The baseline visit will be defined as the last non-missing measure 
prior to initiation of investigational treatment. Additionally, for the pre-transplantation 
period and transplantation visits, change from screening (V1) summaries will be 
calculated as pre-transplantation period/transplantation visit – screening. 
All efficacy analyses will use one-sided alpha = 0.10 tests and present one-sided 90% 
lower confidence limits and two-sided 95% confidence intervals around the difference 
between treatments as well as two-sided 95% confidence intervals around the point 
estimates within each treatment group. All summaries will be presented by treatment 
group.   
A statistical analysis plan (SAP) will be prepared and finalized prior to database lock, 
unblinding and analysis of study results.  
6.9.4.1. 
Analysis Population 
The safety population includes all randomized subjects who receive study treatment 
(treatment or placebo) including those who do not complete the study. The safety 
population will be analyzed as treated and will be used for the safety analysis.  
The full analysis set (FAS) population includes all randomized subjects. The FAS will be 
analyzed as randomized. Analyses on the FAS population will be considered secondary. 

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The modified FAS (mFAS) population includes all FAS participants who receive study 
treatment. The mFAS will be analyzed as randomized. Analyses on the mFAS population 
will be considered primary. 
The per protocol (PP) data set will include all mFAS subjects who have no major protocol 
violations likely to seriously affect the primary outcome of the study as judged by a 
blinded evaluation performed by a group of study personnel including the medical 
monitor,  statistician, and clinical project manager prior to the unblinding of the study 
treatment. Analyses on the PP data set will group subjects according to the treatment 
actually received.  Analyses on the PP population will be considered secondary.  
Partially treated subjects will be included in the intention to treat analyses but won’t be 
included in the per protocol analyses.  
6.9.4.2. 
Safety analyses 
Primary Objective: The safety of MSC-NTF transplantation via combined IT and IM 
injection in participants with ALS is the primary objective of this study. Safety endpoints 
include AEs, changes in physical and neurological examination findings, hematology, 
serum chemistry, urinalysis, vital signs, and requirement of concomitant medications.  
All AEs will be coded to System Organ Class (SOC) and Preferred Term (PT) using the 
MedDRA®. The number of Treatment-Emergent Adverse Events (TEAEs) and the 
number of subjects with any TEAEs (along with percentages) will be tabulated by SOC 
and PT within each SOC by treatment group and over treatment groups. To count the 
number of subjects with any TEAEs, a subject who experiences multiple TEAEs within 
the same SOC will be counted only once for that SOC (whether or not the TEAEs are 
coded to the same PT). A subject who experiences multiple TEAEs coded to the same PT 
within the same SOC will be counted only once for that particular PT. In the summary, 
SOC will be listed in ascending alphabetical order; PTs will be listed in order of 
descending frequency for all subjects within each SOC.  
Separate summaries will be provided for the following categories of AEs:  
• TEAEs  
• TEAEs by severity 
• Treatment-related TEAEs 
• Serious TEAEs 
The proportion of subjects having each AE will be compared between treatment using 
Fisher’s exact tests.  
When evaluating changes in safety parameters, baseline will be defined as the last 
measurement prior to transplantation (i.e., prior to treatment). 
Physical examination, neurological examination, hematology, serum chemistry, vital signs 
and concomitant medications will be summarized using descriptive statistics (n, mean, 
standard deviation, median, minimum, and maximum) if the data is continuous and using 
counts and percentages if the data is discrete. Shifts from baseline in categorization of 
results (e.g. normal/abnormal or low/normal/high) will also be summarized. 

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6.9.4.3. 
Efficacy Analyses 
Secondary Objectives: The change in slope between the treatment and placebo group and 
from pre-transplantation to post-transplantation in ALSFRS-R and in SVC (as a percent of 
normal for age and sex) will be estimated using the mixed linear statistical model.   
The fixed effect variables in the model will be: 
• Visit, expressed in days from the beginning of treatment (i.e. pre-treatment times 
will have negative values, post-treatment times positive values).   
• Treatment 
• Two-way interactions between visit & post-treatment indicator, (0 for pre-
treatment visits, 1 for post-treatment visits) and visit & treatment 
• Three-way interaction between visit & post-treatment visit indicator & treatment 
• Site 
The repeated measures within a subject over visit will also be accounted for in the model, 
wherein, the covariance structure will be evaluated using Bayesian information criterion 
(BIC). Covariance structures to be evaluated are: unstructured, toeplitz, spatial power with 
day, and compound symmetry. 
The three-way interaction between visit & post-treatment visit indicator & treatment will 
be used to compare the change in slope in the treatment group to the change in slope in the 
placebo group. 
The post-pre slope estimate within each treatment group will be used to test the change 
from pre-transplantation to post-transplantation. 
Repeated measures covariance will be estimated by restricted maximum likelihood.  The 
Kenward and Roger method will be used to determine degrees of freedom and compute p-
values.  
Secondary objectives will be evaluated for the FAS, as well as the PP populations.  
Exploratory Objectives:  The analysis for EIM (optional) and HHD will employ the same 
modeling approach as described above for the secondary objectives.  The analysis for 
HHD will be based on a combined score reflecting muscles in the right arm.    
A further analysis of HHD will compare the score for the right arm to the score for the left 
arm.  The linear mixed model will include, in addition to the terms described above, an 
indicator for "right arm", interactions between that indicator and all other variables in the 
model, and a random effect term for the right arm indicator. Therefore, the fixed effect 
variables in the model will be: 
• Visit, expressed in days from the beginning of treatment (i.e. pre-treatment times 
will have negative values, post-treatment times positive values);   
• Treatment; 
• Right arm indicator; 
• Two-way interactions between visit & post-treatment indicator (0 for pre-treatment 
visits, 1 for post-treatment visits), visit & treatment, visit & right arm indicator, 
and treatment & right arm indicator; 
• Three-way interactions between visit & post-treatment visit indicator & treatment, 
visit & post-treatment indicator & right arm indicator, and visit & treatment & 
right arm indicator; 
• Four-way interaction between visit & post-treatment visit indicator & treatment & 
right arm indicator; 

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• Site. 
6.9.4.4. 
Determination of sample size  
No formal sample size calculation has been performed. The sample size chosen was not 
based on statistical considerations. The total of 36 treatment and 12 placebo subjects are 
expected to be a sufficient number to obtain adequate characterization of common TEAEs 
and to observe trends for treatment effects on the efficacy measures chosen for this study.  
6.10. STUDY COMMITTEES AND COMMUNICATIONS 
6.10.1. Data and Safety Monitoring Committee   
An independent, three member Data Safety and Monitoring Board (DSMB) will be 
assembled for this Phase 2 clinical trial.  The DSMB will consist of two expert 
neurologists (with ALS experience and no other involvement in this trial), with experience 
in safety trials and a statistician.  The DSMB will review initial safety data after 
approximately 12 patients have been treated and at periodic intervals thereafter. 
6.11. LABORATORY REQUIREMENTS 
A central laboratory will analyze the clinical laboratory safety samples (hematology, 
serum chemistry) as described in Section 6.8.5 for this study.  Laboratory samples will be 
sent to an independent laboratory for processing and analysis as specified by the Sponsor.   
6.12. INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS 
6.12.1. Ethics 
The Sponsor/Investigator will obtain, from the clinical sites Institutional Review Boards 
(IRB), prospective approval of the clinical  protocol and corresponding informed consent 
form(s); modifications to the clinical protocol and corresponding informed consent forms, 
and advertisements (i.e., directed at potential research subjects) for study recruitment. 
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s).  In such circumstances, 
the Sponsor/Investigator will promptly notify the clinical sites IRB of the deviation.  
The clinical sites IRB operate in compliance with FDA regulations at 21 CFR Parts 50 and 
21 CFR 56, and in conformance with applicable International Conference on 
Harmonization (ICH) Guidelines on Good Clinical Practice (CGP).  
In the event that the clinical sites IRB require, as a condition of approval, substantial 
changes to a clinical protocol submitted under an FDA-accepted IND application, or in the 
event of the Sponsor-Investigator’s decision to modify the previously accepted clinical 
protocol the Sponsor/Investigator will submit (i.e., in advance of implementing the 
change) a Protocol Amendment to the IND describing any change to the Phase 2 protocol 

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that significantly affects the safety of subjects, the scope of the investigation, or the 
scientific quality of the study.   
Examples of Phase 2 clinical protocol changes requiring the submission of a Protocol 
Amendment include: 
• Any significant change in the number of subjects under study. 
• Any significant change in the design of the protocol (such as the addition or 
deletion of a control group). 
• The addition of a new test or procedure that is intended to improve monitoring for, 
or reduce the risk of, a side effect or adverse event; or the dropping of a test 
intended to monitor the safety of the investigational drug. 
6.12.2. Data Quality Assurance 
6.12.2.1. Data Management 
Data from the study will be entered into CRFs in a validated database.  Data review, 
coding, and logic, range, cross-form, and consistency checks will be performed to ensure 
quality of the data.  Adverse events and medications will be coded using MedDRA and the 
World Health Organization Drug Dictionary (WHO-DD), respectively.   
6.12.2.2. Case Report Forms 
The study will use an electronic data capture system.  All case report forms will be 
designed and provided to the site by the Sponsor or designee.  All personnel accessing the 
electronic data capture system will be trained on the use of the system by the CRO 
responsible for data management.  All case report form books are to be filled out 
completely, reviewed, and signed by the Investigator or sub-investigators listed on the 
Form FDA 1572.   
6.12.2.3. Study Monitoring 
The Sponsor or designee will monitor this study in accordance with current GCP 
guidelines.  By signing this protocol, the Investigator grants permission to the Sponsor or 
designee and appropriate regulatory authorities to conduct onsite monitoring of all 
appropriate study documentation.  To ensure the accuracy of data collected on the case 
report forms, it is mandatory that Sponsor representatives (e.g. study monitor) have direct 
access to original source documents (e.g. paper or electronic patient records, patient 
charts, and laboratory reports) needed to verify the entries on case report forms.  During 
the review of these documents, the anonymity of the patient will be respected with strict 
adherence to professional standards of confidentiality.   
A study monitor will contact and visit the site regularly and will be allowed, on request at 
a mutually acceptable time, to inspect the various original medical records (paper or 
electronic) related to the study.  The study monitor will be responsible for inspecting the 
case report forms at regular intervals throughout the study, to verify the adherence to the 
protocol, and the completeness and correctness of all case report form entries.  The 
Investigator agrees to cooperate with the study monitor to ensure that any problems 
detected in the course of these monitoring visits are resolved.   

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6.12.2.4. Study Audits 
During the course of the study and after study completion, it is possible that one or more 
quality assurance audits will be undertaken by authorized Sponsor representatives.  The 
purpose of the audit is to ensure that the study is (or was) conducted and monitored in 
compliance with the protocol as well as recognized GCP guidelines and regulations.  If 
such audits are to occur, they will be arranged for a reasonable and agreed upon time.  By 
signing this protocol, the Investigator grants permission to the Sponsor or designee to 
conduct onsite audits of all appropriate facilities and study documentation.   
6.12.3. Investigational Product Accountability 
MSC-NTF cells are autologous cells prepared on a per-patient basis.  
At the end of the production process the patient's MSC-NTF cells are loaded in the 
syringes and immediately shipped to the medical center for transplantation. MSC-NTF 
cells have been shown to be stable in the syringes for over 5 hours at 2-8°C. 
Any syringes not administered to the patient will be immediately discarded as biohazard 
waste. 
The manufacturing facility will be responsible for maintaining production records.  The 
site will record the number of syringes administered to each patient. 
6.12.4. Compensation, Insurance, and Indemnity  
The subject will be appropriately treated or compensated, or both, for any health or other 
problems arising from participation in this study. In the event of a side effect or injury, 
appropriate medical care as determined by the Investigator or designated alternate will be 
provided.   
If bodily injury is sustained, resulting directly from the use of the study drug or by 
required study procedures, the Sponsor will reimburse for reasonable physician fees and 
medical expenses necessary for treatment of only the bodily injury that is not covered by 
the patient’s medical or hospital insurance, provided that the injury is not due to a 
negligent or wrongful act or omission by the study doctor and study staff.  No other 
compensation of any type will be provided by the Sponsor.  Financial compensation for 
lost wages, disability, or discomfort due to the study participation or procedures is not 
available.   
6.12.5. Data recording/Case Report Forms   
Case Report Forms (CRFs,) will be completed for each subject enrolled into the clinical 
study.  The Investigator will review, approve and sign/date each completed CRF; the 
Investigator’s signature serving as attestation of the Investigator’s responsibility for 
ensuring that all clinical and laboratory data entered on the CRF are complete, accurate 
and authentic.   
Source Data are the clinical findings and observations, laboratory and test data, and other 
information contained in Source Documents.  Source Documents are the original records 
(and certified copies of original records); including, but not limited to, hospital medical 
records, physician or office charts, physician or nursing notes, subject diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, x-

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rays, etc.  When applicable, information recorded on the CRF shall match the Source Data 
recorded on the Source Documents.   
Any clinical study data that will be recorded directly on the CRF, whereupon the CRF data 
is to be considered the Source Data will be identified.  
Subject names will not be supplied to the Sponsor. Only the subject number and subject 
initials will be recorded in the CRF.  Subject names appearing on any other document (eg, 
laboratory report) must be redacted on the copy of the document to be 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 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. Electronic systems will be used as the sole 
instrument for the recording and analysis of clinical and laboratory data related to the 
safety and/or effectiveness of the study drug(s).    
6.12.6. Record maintenance and retention  
The Sponsor/Investigator will maintain records in accordance with Good Clinical Practice 
guidelines; to include: 
• FDA correspondence related to the IND and clinical protocol, including copies of 
submitted Safety Reports and Annual Reports; 
• IRB correspondence (including approval notifications) related to the clinical 
protocol; including copies of adverse event reports and annual or interim reports; 
• Current and past versions of the IRB-approved clinical protocol and corresponding 
IRB-approved 
consent 
form(s) 
and, 
if 
applicable, 
subject 
recruitment 
advertisements; 
• Signed FDA Form 1572 Statements of Investigator (i.e., for the Sponsor-
Investigator) ; 
• Financial disclosure information (i.e., for the Sponsor-Investigator and for sub-
investigators who will be involved in the administration of the study drugs and/or 
the evaluation of research subjects [i.e., who will contribute significantly to the 
research study data]); 
• Curriculum vitae (i.e., for the Investigator and for sub-investigator(s)); 
• Certificates of required training; e.g., human subject protections, Good Clinical 
Practice, etc. (i.e., for the Sponsor-Investigator and for all sub-investigators who 
will be involved in the administration of the study drugs and/or the evaluation of 
research subjects [i.e., who will contribute significantly to the study data]); 
• Listing of printed names/signatures. (i.e., for the Sponsor-Investigator and for all 
sub-investigators who will be involved in the administration of the study drugs 
and/or the evaluation of research subjects [i.e., who will contribute significantly to 
the study data]); 
• Normal value(s)/range(s) for medical/laboratory/technical procedures or tests 
included in the clinical protocol; 
• Laboratory certification information;  
• Instructions for on-site preparation and handling of the investigational drug(s), 
study treatment(s), and other study-related materials (i.e., if not addressed in the 
clinical protocol); 
• Responsibility delegation log; 

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• Signed informed consent forms;  
• Completed Case Report Forms; signed and dated by Sponsor/Investigator; 
• Source Documents or certified copies of Source Documents;  
• Monitoring visit reports;  
• Copies of Sponsor-Investigator correspondence (including notifications of safety 
information) to sub-investigators; 
• Subject screening and enrolment logs; 
• Subject identification code list; 
• Investigational drug accountability records, including documentation of drug 
disposal; 
• Final clinical study report; 
• Decoding procedures for blinded trials; 
• Master randomization list; 
• Retained biological specimen log;  
• Interim data analysis report(s). 
The Investigator will retain the specified records and reports for up to 2 years after the 
marketing application is approved for the investigational drug; or, if a marketing 
application is not submitted or approved for the investigational drug, until 2 years after 
investigations under the IND have been discontinued and the FDA so notified. 
6.12.7. Study Termination 
The Sponsor will terminate this study following completion of the study objectives, or 
earlier if deemed necessary.   
The Sponsor reserves the right to terminate the study at any time.  When the Sponsor is 
aware of information on matters concerning the quality, efficacy, and safety of the study 
drug, as well as other important information that may affect proper conduct of the clinical 
study, the Sponsor may terminate the study and send a written notice of the termination 
along with the reasons to the Investigator.   
If an Investigator intends to terminate participation in the study, the Investigator must 
immediately inform the Sponsor and provide the reason for it.   
6.13. USE OF STUDY INFORMATION AND PUBLICATION 
All information obtained during the conduct of the study will be considered to be 
confidential. Written permission from the Sponsor is required before disclosing any 
information relative to this study. All publications (e.g., manuscripts, abstracts, and slide 
presentations) based on this study must be submitted to the Sponsor for corporate review 
and release at least 30 days before submission. 
 
 

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6.14. REFERENCES 
Acsadi, G, Anguelov, RA, Yang, H, Toth, G, Thomas, R, Jani, A et al.. Increased survival and function of 
SOD1 mice after glial cell-derived neurotrophic factor gene therapy. Hum Gene Ther 2002; 13: 1047–1059. 
Azzouz, M, Ralph, GS, Storkebaum, E, Walmsley, LE, Mitrophanous, KA, Kingsman,SM et al. VEGF 
delivery with retrogradely transported lentivector prolongs survival in a mouse ALS model. Nature 2004429: 
413–417. 
Boillée S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal 
neighbors. Neuron 2006; 52:39-59. 
Brooks, B.R., et al., El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis. 
Amyotroph Lateral Scler Other Motor Neuron Disord, 2000; 1:293-9. 
Cashman NR, Durham HD, Blusztajn JK, Oda K, Tabira T, Shaw IT, Dahrouge S, Antel JP. Neuroblastoma 
x spinal cord (NSC) hybrid cell lines resemble developing motor neurons. Dev Dyn. 1992; 194:209-21 
Castrillo-Viguera C, Grasso DL, Simpson E,  Clinical significance in the change of decline in ALSFRS-R. 
Amyotroph Lateral Scler. 2010; 11:178-80. 
Cedarbaum JM, , Malta E, Fuller C, Hilt D, Thurmond B, Nakanishi A. The ALSFRS-R: a revised ALS 
functional 
rating 
scale 
that 
incorporates 
assessments 
of 
respiratory 
function. 
BDNF ALS Study Group (Phase III). J Neurol Sci. 1999;;169:13-21. 
Corti S, Nizzardo M, Nardini M, et al. Systemic transplantation of c-kit+ cells exerts a therapeutic effect in a 
model of amyotrophic lateral sclerosis. Hum Mol Genet 2010; 19:3782-96. 
Dadon-Nachum M, Melamed E, Offen D. The "Dying-Back" Phenomenon of Motor Neurons in ALS. J Mol 
Neurosci. 2011; 43:470-7. 
Dadon-Nachum M, Sadan O, Srugo I, Melamed E, Offen D. Differentiated Mesenchymal Stem Cells for 
Sciatic Nerve Injury Stem Cell Rev. 2011a;7:664-71 
Funakoshi, H., Nakamura, T., 2003. Hepatocyte growth factor: from diagnosis to clinical applications. Clin. 
Chim. Acta 327, 1–23. 
Henderson, CE, Phillips, HS, Pollock, RA, Davies, AM, Lemeulle, C, Armanini, M et al. (1994). GDNF: a 
potent survival factor for motoneurons present in peripheral nerve and muscle. Science 266: 1062–1064. 
Kadoyama K, Funakoshi H, Ohya W, Nakamura T. Hepatocyte growth factor (HGF) attenuates gliosis and 
motoneuronal degeneration in the brainstem motor nuclei of a transgenic mouse model of ALS. Neurosci 
Res 2007; 59:446–56. 
Keifer OP, O'Connor DM, Boulis NM. Gene and protein therapies utilizing VEGF for ALS. Pharmacol 
Ther. 2013 Oct 29. doi:pii: S0163-7258(13)00214-3. 10.1016/j.pharmthera.2013.10.009. [Epub ahead of 
print] 
Kliem, MA, Heeke, BL, Franz, CK, Radovitskiy, I, Raore, B, Barrow, E et al. () Intramuscular 
administration of a VEGF zinc finger transcription factor activator (VEGFZFP-TF) improves functional 
outcomes in SOD1 rats. Amyotroph Lateral Scler 2011; 12:331–339.  
Krakora D, Mulcrone P, Meyer M, Lewis C,  Synergistic Effects of GDNF and VEGF on Lifespan and 
Disease Progression in a Familial ALS Rat Model. Mol Ther. 2013; 21:1602-10. 
Martin LJ, Kaiser A, Price AC. Motor neuron degeneration after sciatic nerve avulsion in adult rat evolves 
with oxidative stress and is apoptosis. J Neurobiol. 1999; 40:185-201. 
Mohajeri H, Figlewicz D and Bohn M. Intramuscular grafts of myoblasts genetically modified to secrete 
glial cell line-derived neurotrophic factor prevent motoneuron loss and disease progression in a mouse 
model of familial amyotrophic lateral sclerosis. Human Gene Therapy 1999; 10:1853–1866. 
Morren JA, Galvez-Jimenez N. Current and prospective disease-modifying therapies for amyotrophic lateral 
sclerosis. Expert Opin Investig Drugs. 2012; 21:297-320. 
Mousavi K, Parry DJ, and Jasmin BJ. BDNF rescues myosin heavy chain IIB muscle fibers after neonatal 
nerve injury. Am J Physiol. 2004; 287: C22-9 
Nakamura, T., Nawa, K., Ichihara, A.,. Partial purification and characterization of hepatocyte growth factor 
from serum of hepatectomized rats. Biochem. Biophys. Res. Commun. 1984; 122, 1450–1459. 
Nakamura, T., Nishizawa, T., Hagiya, M., Seki, T., Shimonishi, M., Sugimura, A., Tashiro, K., Shimizu, S.,. 
Molecular cloning and expression of human hepatocyte growth factor. Nature 1989; 342, 440–443. 

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NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 Published: May 28, 2009 
(v4.03: June 14, 2010) U.S. Department of Health and Human Services National Institutes of Health 
National Cancer Institute 
Novak KD, Prevette D, Wang S, Gould TW, Oppenheim RW. Hepatocyte growth factor ⁄ scatter factor is a 
neurotrophic survival factor for lumbar but not for other somatic motoneurons in the chick embryo. J 
Neurosci. 2000; 20:326–37. 
Ozdinler PH, and Macklis JD. IGF-I specifically enhances axon outgrowth of corticospinal motor neurons. 
Nat Neurosci. 2006; 9: 1371-81 
Sadan O, Bahat-Stromza M, Barhum Y, Levy YS, Pisnevsky A, Peretz H, Bar Ilan A, Bulvik S, Shemesh N, 
Krepel D, Cohen Y, Melamed E, Offen D: Protective effects of neurotrophic factors secreting cells in a 
6OHDA rat model of Parkinson disease. Stem Cells and Development 2009; 18:1-13. 
Sorenson EJ, Windbank AJ, Mandrekar JN, Bamlet WR, Appel SH, Armon C, Barkhaus PE, Bosch P, 
Boylan K, David WS, Feldman E, Glass J, Gutmann L, Katz J, King W, Luciano CA, McCluskey LF, Nash 
S, Newman DS, Pascuzzi RM, Pioro E, Sams LJ, Scelsa S, Simpson EP, Subramony SH, Tiryaki E, 
Thornton CA. Subcutaneous IGF-1 is not beneficial in 2-year ALS trial. Neurology. 2008;71:1770-5. 
Storkebaum, E, Lambrechts, D, Dewerchin, M, Moreno-Murciano, MP, Appelmans, S, Oh, H et al. . 
Treatment of motoneuron degeneration by intracerebroventricular delivery of VEGF in a rat model of ALS. 
Nat Neurosci 2005; 8: 85–92. 
Sun W, Funakoshi H, Nakamura T. Overexpression of HGF retards disease progression and prolongs life 
span in a transgenic mouse model of ALS. J Neurosci 2002; 22:6537– 48 
Suzuki M, McHugh J, Tork C, Shelley B, Hayes A, Bellantuono I, Aebischer P, Svendsen CN: Direct 
Muscle Delivery of GDNF With Human Mesenchymal Stem Cells Improves Motor Neuron Survival and 
Function in a Rat Model of Familial ALS. Molecular Therapy 2008, 16:2002-2010 
Suzuki, M, McHugh, J, Tork, C, Shelley, B, Klein, SM, Aebischer, P et al.. GDNF secreting human neural 
progenitor cells protect dying motor neurons, but not their projection to muscle, in a rat model of familial 
ALS. PLoS ONE 2007; 2: e689. 
Wang, LJ, Lu, YY, Muramatsu, S, Ikeguchi, K, Fujimoto, K, Okada, T et al. . Neuroprotective effects of 
glial cell line-derived neurotrophic factor mediated by an adeno-associated virus vector in a transgenic 
animal model of amyotrophic lateral sclerosis. J Neurosci 2002; 22: 6920–6928. 
Yust-Katz S, Fisher-Shoval Y, Barhum Y, Ben-Zur T, Barzilay R, Lev N, Hod M, Melamed E, Offen D. 
Placental mesenchymal stromal cells induced into neurotrophic factor-producing cells protect neuronal cells 
from hypoxia and oxidative stress. Cytotherapy. 2012; 14:45-55.  
Zheng, C, Nennesmo, I, Fadeel, B and Henter, JI . Vascular endothelial growth factor prolongs survival in a 
transgenic mouse model of ALS. Ann Neurol 2004; 56: 564–567. 
 
 
 

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6.15. APPENDICES  
6.15.1. Appendix 1: Listing of study activities  
6.15.1.1. Scheduled monitoring events 
Table 1: 
Schedule of Activities: 
Study Period 
Screening 
Pre-transplantation period 
Cells/Placebo 
Transplantation 
Visit 
Post-transplantation follow-up 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Phone 
Call 1 
V9 
Phone 
Call 2 
V10 
EOS 
Procedure  
Screening 
Enrolment 
  
BMA 
Transplantation 
Time 
Schedule 
Precedes 
V2 by 4-6 
wks 
Wk 4-6 
Wk 
8-10 
Wk 9-
11 
D0-2 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
Informed 
consent 
x 
  
  
  
  
  
  
  
  
  
  
  
Eligibility 
criteria 
x 
x 
  
  
  
  
  
  
  
  
  
Demographic 
data 
x 
  
  
  
  
  
  
  
  
  
  
  
Height 
x 
  
  
  
  
  
  
  
  
  
  
  
Body weight 
x 
 x 
x 
x 
x 
x 
x 
x 
  
x 
  
x 
Physical 
examination 
x 
x  
 x  
  
x 
x 
x 
x 
  
x 
  
x 
12 lead ECG 
x 
  
 x  
 
  
  
 
  
 x  
Vital signs1 
x 
x 
x 
x 
x 
x 
x 
x 
  
x 
  
x 
Medical 
History 
x 
  
  
  
  
  
  
  
  
  
  
  
ALS Medical 
History 
x 
  
  
  
  
  
  
  
  
  
  
  
El Escorial 
Criteria 
x 
  
  
  
  
  
  
  
  
  
  
  
ALSFRS-R 
x 
 x 
 x 
x 
x 
x 
x 
x 
x 
x 
x 
Neurological 
Examination   
x 
 x 
x 
  
x 
x 
 x 
x 
  
x 
  
x 
EIM 
(Optional) 
x 
x 
x 
  
x 
x 
x 
x 
  
x 
  
x 
Slow Vital 
Capacity 
(SVC) 
x 
x  
x  
  
x 
x 
x 
x 
  
x 
  
x 
Muscle 
strength 
evaluation 
(MVIC - 
HHD) 
x 
x  
x  
  
x 
x 
x 
x 
  
x 
  
x 
Concomitant 
medication 
review 
x 
x  
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
HIV 1 and 2  
x 
  
x 
  
  
  
  
  
  
  
  
  

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Study Period 
Screening 
Pre-transplantation period 
Cells/Placebo 
Transplantation 
Visit 
Post-transplantation follow-up 
Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
Phone 
Call 1 
V9 
Phone 
Call 2 
V10 
EOS 
Procedure  
Screening 
Enrolment 
  
BMA 
Transplantation 
Time 
Schedule 
Precedes 
V2 by 4-6 
wks 
Wk 4-6 
Wk 
8-10 
Wk 9-
11 
D0-2 
Wk 
2 
Wk 
4 
Wk 
8 
Wk 
12 
Wk 
16 
Wk 
20 
Wk 
24 
HBV 
x 
  
x 
  
  
  
  
  
  
  
  
  
HCV 
x 
  
x 
  
  
  
  
  
  
  
  
  
HTLV I and 
II 
x 
  
x 
  
  
  
  
  
  
  
  
  
Treponema 
pallidum 
x 
 
x 
 
 
 
 
 
 
 
 
 
CMV 
x 
 
x 
 
 
 
 
 
 
 
 
 
Pregnancy 
test  
 x 
  
x 
  
  
  
  
  
  
  
  
  
Hematology2  
x 
  
x 
  
x 
  
x 
x 
  
x 
  
x 
Blood 
biochemistry 3 
x 
  
x 
  
x 
  
x 
x 
  
x 
  
x 
Coagulation 
tests 4 
x 
  
x 
  
x 
  
x 
x 
  
x 
  
x 
Urinalysis 5 
x 
  
 x 
  
x 
  
x 
x 
  
x 
  
x 
Bone marrow 
aspiration  
  
  
  
x 
  
  
  
  
  
  
  
  
Cell 
Transplant IM 
/ IT 
  
  
  
  
x 
  
  
  
  
  
  
  
CSF 
collection 
 
 
 
 
x 
x 
 
 
 
 
 
 
Visual 
inspection of 
injection site 
  
  
  
  
x 
  
  
  
  
  
  
  
Adverse 
events review 
 x 
 x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prospective 
assessment of 
the 
occurrence of 
suicidality  
x 
x 
x 
x 
x 
x 
x 
x 
x 
Assessment 
of blinding 
(Patient and 
Investigator) 
 
 
 
 
x 
 
 
 
 
 
 
x 
 
BMA- Bone Marrow aspiration 

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Table 2: 
Detailed Schedule of Activities for Cell Transplantation Visit (V5): 
Estimated Time 
08:00-16:00 
16:00 
17:00 
18:00 
19:00 
20:00 
22:00 
8:00 
14:00 
20:00 
8:00 
12:00 
Time\ Procedure 
Up to 8 hours 
before transplant  
Hr  
0 
Hr  
1 
Hr 
 2 
Hr  
3 
Hr  
4 
Hr  
6 
Hr  
16 
Hr  
22 
Hr  
28 
Hr  
40 
Hr  
44-72 
Admit to Inpatient 
Ward 
x 
  
  
  
  
  
  
  
  
  
 
Body weight 
x 
  
  
  
  
  
  
  
  
  
 
Physical Examination 
x 
  
  
  
  
  
x1 
  
  
x1 
 
Vital signs2 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
12 lead ECG 
 
 
 
 
 
 
 
 
x8 
 
 
 
ALSFRS-R 
x 
  
  
  
  
  
  
  
  
  
 
Neurological 
Examination  
x 
 
  
  
  
  
  
  
  
  
  
 
EIM (Optional) 
x 
 
  
  
  
  
  
  
  
  
  
 
Slow Vital Capacity 
(SVC) 
x 
 
  
  
  
  
  
  
  
  
  
 
Muscle strength 
evaluation (MVIC - 
HHD) 
x 
 
  
  
  
  
  
  
  
  
  
 
Concomitant 
medication review3 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Hematology4  
 
 
  
  
  
  
  
x 
  
  
 
Blood biochemistry5 
 
 
  
  
  
  
  
x 
  
  
 
Urinalysis6 
 
 
  
  
  
  
  
x 
  
  
 
 
Coagulation7 
 
 
 
 
 
 
 
x 
 
 
 
 
Cell Transplant IM / 
IT 1 
 
x 
  
  
  
  
  
  
  
  
 
Retention of CSF 
sample 
 
x 
 
 
 
 
 
 
 
 
 
 
Visual inspection of 
injection site 
 
 
 x 
  
  
  
  
x1 
  
  
x1 
 
Adverse events 
review 3 
x 
 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Prospective 
assessment of the 
occurrence of 
suicidality 
x 
 
 
 
 
 
 
 
 
 
 
 
Assessment of 
blinding (Patient and 
Investigator) 
 
 
 
 
 
 
 
 
 
 
 
x8 
Discharge from 
Inpatient Setting 
 
  
  
  
  
  
  
  
  
  
  
x 
 
1 Time Window: +/- 1 hour 
 
 
 
 
 
 
 
 
 
 
 
2 HR, BP, RR, Body temperature - Time Window: +/- 30 minutes  
 
3 Ongoing data collection throughout visit as necessary  
 
 
4 Hematology: CBC (RBC with Indices, WBC with differential and platelet count, Hb, Ht) - Time Window: +/- 2 hours 
 

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5 Blood Biochemistry: Na, K, Cl, HCO3, BUN, Cr, Gluc, Ca, Mg, Phos, total protein, triglycerides (TG), Total cholesterol, HDL, LDL, urea,  
 
creatinine, total bilirubin, AST(GOT), ALT(GPT), ALP, uric acid - Time Window: +/- 2 hours 
 
 
 
 
6 Urinalysis (dip-stick test) - Specific Gravity, pH, glucose, protein, ketones, blood 
7 Coagulation: PT, PTT 
8 Can be done prior to discharge 
6.15.2. Appendix 2: Muscle Strength using Hand Held Dynamometry  
Muscle strength tests will be assessed at visits 1, 2, 3, 5, 6, 7, 8, 9 and 10 
The evaluators will use the MIRCOFET 2 HHD for all subjects in this study.  The 
dynamometer will be zeroed prior to each muscle test by pressing the reset button. All 
subjects will be seated upright in a hardback chair with armrests for testing. If the subject 
cannot transfer to a chair then the subject can be tested in their wheelchair. 
Each muscle will be tested twice and both of the values recorded. However, up to three 
trials can be performed if the variability between the first two trials is greater than 15 % or 
if the evaluator thinks that one of the first two trials was not valid.  The numbers will be 
recorded on the forms provided by the coordination center.    
The testing pad for the HHD should be changed to fit the contour of the subject’s body. 
The finger test pad must be used for testing the first dorsal interosseous. The HHD should 
always be flat against the body part being tested and the force directed opposite to the 
direction of movement.   Prior to testing the subject with the HHD, the evaluator must 
ensure that the subject is able to actively move into the test position. 
The subject should rest between trials and then return to the starting position. The subject 
should be encouraged to push against the HHD with all of his/ her strength.  Subject must 
hold maximal contraction for at least two seconds.  Evaluator should match subject’s 
resistance for at least two seconds before increasing their force to break the contraction.  
Encouragement needs to be consistent with all subjects.    
Shoes and orthotics should be removed prior to testing the legs.  Stabilization of the 
subject is very important and should follow the instructions provided for each muscle 
group.  The subjects cannot hold on to the armrest during testing.  Subjects can be 
supported with pillows or by another person if they have trunk instability. Subjects can use 
BIPAP if needed during the testing.  
6.15.2.1. Shoulder Flexion 
The subject is seated in a hard back chair with the shoulder flexed at 45 degrees to the 
angle of the trunk. The forearm is in a neutral position and the elbow extended.  The 
subject’s feet are on the floor. The resistance with the hand held dynamometer is placed 1 
inch just proximal to the elbow crease. The evaluator stabilizes at the top of the shoulder, 
avoiding contact with the anterior deltoid muscle. Evaluator should match the subject’s 
resistance for at least two seconds before increasing their force to break the contraction.   
The number is recorded, the dynamometer is reset to zero, and the test repeated.  
6.15.2.2. Elbow Flexion 
The subject is seated in a hard back chair with their arm by their side, not resting on the 
armrest.  The elbow is flexed to 90 degrees. The subject’s feet are on the floor. The 
forearm is supinated. The hand held dynamometer is placed 1 inch proximal to the wrist. 

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The evaluator stabilizes at the posterior lateral elbow. Evaluator should match the 
subject’s resistance for at least two seconds before increasing their force to break the 
contraction.   The number is recorded, the dynamometer is reset to zero, and the test 
repeated. 
6.15.2.3. Elbow Extension 
The subject is seated in a hard back chair arm at the side with their arm at their side, not 
resting on the armrest and their elbow flexed to 90 degrees. The subject’s feet are on the 
floor. The forearm is in neutral (thumb is pointing toward the ceiling) The hand held 
dynamometer is placed 1 inch proximal to the wrist on the ulnar (5th finger) side. The 
evaluator stabilizes at the lateral elbow and applies force in an upward direction.  
Evaluator should match the subject’s resistance for at least two seconds before increasing 
their force to break the contraction.   The number is recorded, the dynamometer is reset to 
zero, and the test is repeated. 
6.15.2.4. Wrist Extension 
The subject is seated in a hard back chair with the elbow flexed to 90 degrees. The 
forearm is pronated and rests on the armrest.  The wrist is neutral (not flexed or extended). 
The subject’s feet are on the floor.  The hand held dynamometer is placed just proximal to 
the metacarpal joints. The evaluator stabilizes at the lateral elbow.  Do not allow elbow 
flexion.  Evaluator should match the subject’s resistance for at least two seconds before 
increasing their force to break the contraction.  The number is recorded, the dynamometer 
is reset to zero, and the test repeated. 
6.15.2.5. First Dorsal Interosseous 
The subject is seated in a hard back chair with the elbow flexed to 90 degrees.  The 
subject’s feet are on the floor. The forearm is pronated and resting on the armrest, the 
index finger is abducted. The hand held dynamometer with the finger attachment is placed 
at the proximal interphalangeal joint on the lateral (thumb) side. The evaluator stabilizes at 
the wrist on the ulnar side proximal to the MCP.  Take care not to exert a counter force 
with stabilizing hand.  Evaluator should match the subject’s resistance for at least two 
seconds before increasing their force to break the contraction.  The number is recorded, 
the dynamometer is reset to zero, and the test repeated. 
6.15.2.6. Hip Flexion 
The subject is seated in a hard back chair with the hip flexed to 90 degrees.  They should 
rest their hands in their lap or at their side, and not hold onto the chair.  The subject must 
have adequate strength to flex their hip to the point where the back of their thigh comes off 
of the chair.  The leg being tested is raised into hip flexion with the opposite foot on the 
floor. The hand held dynamometer is placed 1 inch proximal to the knee. The evaluator 
stabilizes at the lateral hip. The evaluator should match the subject’s resistance for at least 
two seconds before increasing their force to break the contraction.   The number is 
recorded, the dynamometer is reset to zero, and the test repeated. 

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6.15.2.7. Knee Extension 
The subject is seated in a hard back chair with the hip flexed to 90 degrees and a towel roll 
is placed under the knee of the leg being tested.  They should rest their hands in their lap 
or at their side, and not hold onto the chair.  The knee partially extended to 45 degrees. 
The subject must have adequate strength to extend their knee into this position.  The hand 
held dynamometer is placed 1 inch proximal to the ankle.  The evaluator stabilizes behind 
the knee, just proximal to the knee joint. Evaluator should match the subject’s resistance 
for at least two seconds before increasing their force to break the contraction.  The number 
is recorded, the dynamometer is reset to zero, and the test repeated. 
6.15.2.8. Knee Flexion 
The subject is seated in a hardback chair with the hip flexed to 90 degrees and a towel roll 
placed under the knee of the leg being.  They should rest their hands in their lap or at their 
side, and not hold onto the chair.  The knee is partially extended to 45 degrees. The leg 
being tested is raised off the floor, with the opposite foot on the floor. The hand held 
dynamometer is placed 2 (two) inches proximal to the posterior ankle. The evaluator 
stabilizes at the anterior proximal knee joint to prevent hip flexion.  The subject bends 
their knee against the resistance of the dynamometer.  Evaluator should match the 
subject’s resistance for at least two seconds before increasing their force to break the 
contraction. The number is recorded, the dynamometer is reset to zero, and the test 
repeated. 
6.15.2.9. Ankle Dorsiflexion 
The subject is seated in a hard back chair with the knee extended and the heel resting on a 
towel roll placed on the floor.  They should rest their hands in their lap or at their side, and 
not hold onto the chair.  The ankle is in 0 degrees (neutral) dorsiflexion (foot 
perpendicular to the lower leg).   The opposite foot remains flat on the floor.  The hand 
held dynamometer is placed proximal to the metatarsal joints on the dorsum of the foot 
just lateral to the great toe.  The evaluator stabilizes at the anterior proximal knee joint.  
Evaluator should match the subject’s resistance for at least two seconds before increasing 
their force to break the contraction.  The number is recorded, the dynamometer is reset to 
zero and the test repeated. 
 
 
 

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6.15.3. Appendix 3: Procedure for IT transplantation of MSC-NTF cells  
The purpose of this document is to describe the procedure and define the basic 
requirements for Intrathecal (IT) Transplantation of BrainStorm's proprietary MSC-NTF 
cells in clinical trials. 
The procedure described here is based on common clinical practice (standard lumbar 
puncture procedure) as well as the experience of the medical staff currently conducting the 
company's clinical trial at the Neurology Department of the Hadassah Medical Center in 
Jerusalem. 
6.15.3.1. Product Handling and injection procedures 
All syringes should be gently rotated for 20-30 seconds until all cells are in suspension. 
For IM injections remove syringe cap and connect a 25Gx5/8” (0.5 x 16 mm) needle.  
With the needle in the upright position gently flick the syringe to surface any trapped 
bubbles. Push the plunger up until the first drop is visible at the tip of the needle. At this 
point the product is ready for injection. 
For IT injections gently remove syringe cap. With the syringe in the upright position 
gently flick syringe to surface any trapped bubbles. Slowly and carefully push plunger up, 
until the liquid meniscus is visible at the top of the (needle-less) syringe. Connect syringe 
to the 3rd outlet of the valve, and inject the cells over roughly 2 minutes (see section 
6.15.3.2. below).  
6.15.3.2. IT Injection Procedure:  
1. 
When performing IT transplantation of MSC-NTF cells, the patient is typically 
placed in a left (or right) lateral position with his/her neck bent in full flexion and knees 
bent in full flexion up to his/her chest, approximating a fetal position as much as possible.  
2. 
The area around the lower back is prepped using aseptic technique.  A 20 G, 3.5 
inch, 0.9x90 mm spinal needle (such as: BD Cat. No. 405253) is inserted between the 
lumbar vertebrae L3/L4 or L4/L5 to a depth at which there is a "give" indicating that the 
needle is past the ligamentum flavum.  
3. 
The needle is inserted further until there is a second 'give', indicating that the 
needle is now past the dura mater and in the subarachnoid space.  
4. 
The stylet from the spinal needle is then withdrawn and a 3-way stopcock (such as 
Elcam Medical Cat. No. 582682) is immediately attached to the spinal needle.  
5. 
A 3 to 5 ml syringe, with the plunger drawn back, is attached to the 2nd outlet of 
the stopcock, and approximately 3 ml of cerebrospinal fluid (CSF) is removed (CSF is not 
’aspirated’ since any negative pressure can be harmful, so the syringe plunger is drawn 
back before connecting the syringe, and the syringe with the drawn-back plunger is then 
connected to the 2nd outlet of the stopcock and the CSF thus flows into the syringe).  
6. 
The syringe containing the CSF is removed and closed, the air is removed from the 
syringe and the syringe is then again placed at the 2nd outlet of the stopcock. The CSF is 
injected back only after the injection of the MSC-NTF as described below.  
7. 
A second syringe containing a 4 ml suspension of MSC-NTF cells is attached to 
the 3rd outlet of the valve, and the cells are injected over roughly 2 minutes.  
8. 
The stopcock is then immediately turned back to the 2nd outlet and approximately 
1 ml of the previously collected CSF is injected, "washing" the spinal needle and ensuring 
that the entire cell suspension is transplanted into the patient.  

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9. 
The procedure is completed by withdrawing the needle and immediately placing 
pressure on the puncture site.  
10. 
The syringe containing the remaining 2 mL of CSF is removed and capped and 
should be transferred to storage at -80ºC within 30 minutes of the completion of the 
procedure. 
11. 
The patient is typically asked to lie on his/her back for at least 2 hours, on an anti- 
Trendelenburg position and is monitored for signs of neurological problems. 
 
 
 

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6.15.4. Appendix 4: Procedure for IM transplantation of MSC-NTF cells  
The purpose of this document is to describe the procedure and define the basic 
requirements for Intramuscular (IM) transplantation of BrainStorm's proprietary 
MSC-NTF cells in clinical trials. 
The procedure described here is based on common clinical practice (IM injection) as well 
as the experience of the medical staff currently conducting the company's clinical trial at 
the Neurology Department of the Hadassah Medical Center in Jerusalem. 
6.15.4.1. Product Handling and injection procedures 
All syringes should be gently rotated for 20-30 seconds until all cells are in suspension. 
For IM injections remove syringe cap and connect a 25Gx5/8” (0.5x16mm) needle.  
With the needle in the upright position gently flick the syringe to surface any trapped 
bubbles. Push the plunger up until the first drop is visible at the tip of the needle. At this 
point the product is ready for injection. 
6.15.4.2. Procedure: 
1. 
For IM transplantation of MSC-NTF cells, the patient may be in a reclining or 
upright position. The upper arm area is prepped using aseptic technique.  In case of a hairy 
arm the arm is shaved prior to IM injections. 
2. 
The syringes for IM injection contain an 0.32 ml suspension of MSC-NTF cells, in 
a 1 ml Luer-Lock syringe (such as: Becton Dickinson Cat. No. 309628), attached to a 
25Gx5/8” (0.5 x 16 mm, such as Becton Dickinson Cat. No. 300600) needle.  
3. 
The MSC-NTF cell suspension (0.2 ml) is transplanted into the patient by multiple 
intramuscular injections (IM) to a 1.5 cm depth (ensuring that injection is into the muscle 
and not into adipose tissue) at 24 separate sites on the patient's right upper arm biceps and 
triceps muscles, according to a map based on the designed grid (see below).  
4. 
The procedure is completed by withdrawing the needle. 
5. 
The patient's arm is bandaged with a pressure bandage 
6. 
The patient is typically asked to remain in the clinic area for at least 2 hours, and is 
monitored for signs of neurological problems. 
 
 

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6.15.4.3. GRID FOR BICEPS & TRICEPS MUSCLES IM INJECTION 
6.15.4.3.1. Grid of Triceps 
 
 
 

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6.15.4.3.2. Grid of Biceps