A Phase 3, Randomized Double-Blind, Placebo-Controlled Multicenter Study to Evaluate Efficacy and Safety of Repeated Administration of NurOwn® (Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors) in Participants With ALS
Phase: PHASE3
Conditions: Amyotrophic Lateral Sclerosis (ALS)
Sponsor: Brainstorm-Cell Therapeutics

 
 
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Clinical Study Protocol  
BCT-002 US 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED MULTICENTER STUDY 
TO EVALUATE EFFICACY AND SAFETY OF 
REPEATED ADMINISTRATIONS OF NUROWN® 
(AUTOLOGOUS MESENCHYMAL STEM CELLS 
SECRETING NEUROTROPHIC FACTORS) IN 
PARTICIPANTS WITH AMYOTROPHIC LATERAL 
SCLEROSIS (ALS) 
 
IND 15878 
 
 
 
Brainstorm Cell Therapeutics 
 
12 N Route 17- Suite 201 
Paramus, NJ 07652 
 
 

 
 
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CLINICAL STUDY PROTOCOL [BCT-002 US]  
PROTOCOL TITLE 
A PHASE 3, RANDOMIZED, DOUBLE-BLIND, 
PLACEBO-CONTROLLED MULTICENTER STUDY TO 
EVALUATE EFFICACY AND SAFETY OF REPEATED 
ADMINISTRATIONS OF NUROWN® (AUTOLOGOUS 
MESENCHYMAL STEM CELLS SECRETING 
NEUROTROPHIC FACTORS) IN PARTICIPANTS WITH 
AMYOTROPHIC LATERAL SCLEROSIS (ALS)  
PROTOCOL NUMBER  
BCT-002 US 
STUDY DESIGN 
(PHASE)  
Phase 3  
PROTOCOL  
DATE/VERSION  
Amendment 2.1: March, 2020/v2.1 
IND NUMBER  
IND 15878 
INVESTIGATIONAL 
PRODUCT  
NurOwn®: Mesenchymal Stromal Stem Cells Secreting 
Neurotrophic Factors (MSC-NTF cells)  
INDICATION  
Amyotrophic Lateral Sclerosis (ALS)  
SPONSOR  
Brainstorm Cell Therapeutics  
3 University Plaza Drive, Suite 320  
Hackensack, NJ 07601 
PRINCIPAL  
INVESTIGATORS  
Robert H. Brown, MD, 
DPhil 
Professor of Neurology, 
University of Massachusetts 
Medical School/Memorial 
Medical Center, Neurology 
Department Chair, University 
of Massachusetts, USA 
Merit E. Cudkowicz, MD, 
MSc  
Professor of Neurology, 
Harvard School of Medicine 
Chief of Neurology, 
Massachusetts General 
Hospital, USA 
Anthony Windebank, MD 
Professor of Neurology, Mayo 
Clinic College of Medicine, 
USA 
Robert G. Miller, MD 
Clinical Professor 
Neurosciences, Norris Center 
MDA/ALS Program Director 

 
 
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Sutter Pacific Medical 
Foundation, California Pacific 
Medical Center, USA 
Namita A. Goyal, MD 
Associate Clinical Professor, 
Dept. of Neurology, Associate 
Director, UC Irvine-MDA ALS 
and Neuromuscular Center, 
USA 
Robert H. Baloh, MD, PhD Associate Professor, Neurology 
Director, Neuromuscular 
Medicine, Cedars-Sinai Medical 
Center, Los Angeles, USA 
GOOD CLINICAL PRACTICES  
This study will be conducted under Good Clinical Practices International Conference on 
Harmonization (ICH) E6 guidelines which has its origins in the Declaration of Helsinki.  
 
CONFIDENTIAL  
This Clinical protocol contains confidential information of Brainstorm Cell Therapeutics. 
("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.  
 
 
 

 
 
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PROTOCOL APPROVAL  
 
A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter Study to Evaluate 
Efficacy and Safety of Repeated Administrations of NurOwn® (Autologous Mesenchymal 
Stem Cells Secreting Neurotrophic Factors) in Participants with Amyotrophic Lateral 
Sclerosis (ALS); BCT-002-US. 
 
Approved by: 
 
 
Name  
Title/Company  
Signature 
Date 
Yael Gothelf, Ph.D.  
VP Regulatory Affairs  
Brainstorm Cell Therapeutics  
 
 
Ralph Kern, MD, 
MHSc 
COO and CMO Brainstorm 
Cell Therapeutics 
 
 
Chaim Lebovits 
CEO Brainstorm Cell 
Therapeutics 
 
 
Munish Mehra, Ph.D.  Biostatistics   
Tigermed-BDM Inc.  
 
 
Stuart Apfel, MD 
 
Medical Monitor Parallax 
Clinical Research, LLC 
 
 
 
 

 
 
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INVESTIGATOR’S AGREEMENT  
  
  
I have received and read the Clinical Protocol BCT-002 US, for Brainstorm Cell Therapeutics, 
NurOwn® (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 
12 N Route 17- Suite 201 
Paramus, NJ 07652 
Investigational Product 
NurOwn®: Mesenchymal Stromal Stem Cells Secreting Neurotrophic 
Factors (MSC-NTF cells) 
Indication  
Amyotrophic Lateral Sclerosis (ALS) 
Study number 
BCT-002 US 
Title of Study 
A Phase 3, Randomized, Double-blind, Placebo-controlled Multicenter 
Study to Evaluate Efficacy and Safety of Repeated Administrations of 
NurOwn® 
(Autologous 
Mesenchymal 
Stem 
Cells 
Secreting 
Neurotrophic Factors) in Participants with Amyotrophic Lateral 
Sclerosis (ALS) 
Protocol Date/Version 
March 2020, Amendment 2.1  
OBJECTIVES 
To determine efficacy and safety of repeat administrations of intrathecal injections of NurOwn® (MSC-NTF 
cells), autologous Mesenchymal Stem Cells [MSC] Secreting Neurotrophic Factors [NTF]) as compared to 
Placebo given three times two months apart to participants with Amyotrophic Lateral Sclerosis. 
Primary: 
• 
To evaluate the efficacy of NurOwn® (MSC-NTF cells) as compared to placebo as measured by the 
proportion of participants with a ≥1.25 points/month improvement in the post-treatment slope vs. pre-
treatment slope in the amyotrophic lateral sclerosis functional rating scale (ALSFRS-R) score at 28 
weeks following the first treatment.  
• 
To evaluate the safety of NurOwn® (MSC-NTF cells) as compared to placebo based upon incidence of 
adverse events, laboratory evaluations, physical examinations, vital signs, electrocardiogram (ECG) 
assessments and suicidal ideation as measured by the Columbia-Suicide Severity Rating Scale 
(C-SSRS). 
Secondary:  
• 
To evaluate the efficacy of NurOwn® (MSC-NTF cells) vs. placebo as measured by the proportion of 
participants whose disease progression is halted or improved as measured by a 100% or greater 
improvement in post-treatment slope vs. pre-treatment slope in the ALSFRS-R score at 28 weeks 
following the first treatment. 
• 
To evaluate the efficacy of NurOwn® (MSC-NTF cells) vs. placebo as measured by improvements in 
ALSFRS-R score between baseline and 28 weeks following the first treatment. 
• 
To evaluate the efficacy of NurOwn® (MSC-NTF cells) as compared to placebo as measured by 
improvements in the ALSFRS-R slope using different responder definitions. 
• 
To evaluate the efficacy of NurOwn® (MSC-NTF cells) as compared to placebo by a comparison 
between treatment groups of (a) tracheostomy free survival; (b) change in ALSFRS-R slope over each 
post baseline visit (2 – 28 weeks) as compared to pre-treatment slope and (c) the change from baseline 
in the ALSFRS-R score to each post-baseline time point. 
• 
To evaluate the efficacy of NurOwn® (MSC-NTF cells) vs. placebo as measured by the change in SVC 
(% predicted) from baseline to 28 weeks following the first treatment. 
• 
To evaluate biomarkers (NTFs, inflammatory factors, and cytokines) in the cerebrospinal fluid (CSF) 
before each treatment and at select time points as well as in serum or blood samples (T regulatory cells) 
throughout the study to evaluate their relationship to treatment with NurOwn® (MSC-NTF cells). 

 
 
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• 
To study whether response to NurOwn® treatment correlates with specific ALS genetic mutations or 
gene variants related to ALS   
METHODOLOGY 
Study Design 
This is a Phase 3 randomized, double-blind, placebo-controlled multicenter study that will be 
conducted in approximately 200 participants with early ALS at multiple investigational study 
sites. After providing informed consent, each participant will be observed over an 
approximately 18-week screening period and undergo monthly ALSFRS-R scores along with 
safety assessments and recording of concomitant medications and adverse events (AEs) will 
be obtained. During this period of time, participants meeting the inclusion and exclusion 
criteria will be randomized and a week later will undergo bone-marrow aspiration. MSC of 
the participants randomized to the treatment group will be isolated, propagated for 
approximately 2 weeks and then cryopreserved. Approximately 2 weeks prior to each 
treatment, MSC will be thawed, propagated and induced into MSC-NTF cells. Participants 
will undergo a total of three intrathecal (IT) transplantations with NurOwn® (MSC-NTF cells) 
or matching placebo. The first transplantation will be at Visit 6 (Week 0) approximately 18 
weeks after screening, with the subsequent transplantations at Visit 9 (Week 8) and Visit 11 
(Week 16). Following the third and last treatment, participants will be followed for three 
additional monthly visits (through week 28) during which the ALSFRS-R assessment, 
neurological examination, biomarkers assessment, assessment of blinding, safety assessments 
and recording of concomitant medications and AEs will be performed.  
See study scheme below and schedule of assessments in Table 1 in Section 1.15 Appendix 1 
In consideration of contingency measures implemented at participating investigative sites due 
to the outbreak of the Coronavirus Disease 2019 (COVID-19) pandemic, and to minimize or 
eliminate immediate hazards or to protect the life and well-being of research participants (e.g., 
to limit exposure to COVID-19), some study visits may be rescheduled and/or conducted 
remotely according to the implemented institutional policies at individual sites, until such a 
time when investigational sites are able to fully comply with the schedule of assessments.  
Study 
Schematic 
 
Number of 
sites 
This is a multi-center study to be conducted at six Medical Centers in the US. 
Treatments 
Intrathecal administrations of NurOwn® (MSC-NTF cells) or excipient will be given at Visit 6 
(Week 0), Visit 9 (Week 8) and Visit 11 (Week 16). 
Randomization  Participants who meet all eligibility criteria at randomization, will be randomized at a 1:1 ratio 
to NurOwn® (MSC-NTF cells) or placebo 
-10 
-12
-5
-6 
-9
0
4
8
12
16
20
24
Pre-treatment period                         Treatment Period                  Follow-up period
Weeks
Visit:    1        2         3         4       5        6         7      8         9          10         11         12
13         14          
Screening
RNZ
T1
Primary Efficacy
Endpoint
T3
T2
BMA
2
-14 
-16
-18 
-20
28
Screening period
BMA: Bone Marrow Aspiration
RNZ: Randomization
T1, T2, T3: Treatments  1, 2 and 3, respectively
ALSFRS-R: Revised amyotrophic lateral sclerosis functional rating scale will be assessed at all time points except  at  Week -5

 
 
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Treatment 
Duration 
Each subject’s participation will last for up to approximately 12 months, consisting of: 
• 
An up to 5-month pre-treatment period, during which screening assessments will 
be captured, participants will be randomized and a bone marrow aspiration (BMA) 
will be completed. In addition, efficacy and safety assessments will be performed. 
• 
A 4-month treatment period, during which the subject will receive 3 
transplantations (T1, T2, and T3) of NurOwn® (MSC-NTF cells) and will be assessed 
for efficacy and safety.  
• 
A 3-month post-treatment follow-up period, after the last treatment to assess efficacy 
and safety 
Study Drug 
and 
Formulation 
Study drug will be supplied in one 5 mL syringe containing 4 mL of NurOwn®(MSC-NTF 
cells) suspension at a dose of 125 x106 cells or a 5 mL syringe containing placebo (excipient) 
for IT administration. 
Dose and 
Route of 
Administration  
Doses of 125 x106 NurOwn® (MSC-NTF cells) or placebo transplanted intrathecally at Visit 6 
(Week 0), Visit 9 (Week 8) and Visit 11 (Week 16). 
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.  Study participants 
may not have taken RADICAVA (edaravone injection) for at least 30 days prior to screening, 
nor plan to begin edaravone during the study period.  Study participants who begin an excluded 
medication during the study period will be discontinued from treatment. In order to minimize 
the amount and impact of missing data, study investigators will make all reasonable efforts to 
collect key efficacy and safety data on participants who discontinue treatment or discontinue 
from the study. 
SUBJECT POPULATION 
Number of 
Participants  
Approximately 200 total randomized participants (1:1 randomization with approximately 100 
participants each in the active treatment arm and placebo arm).  
Major 
Inclusion 
Criteria 
1. Males and females ages 18 to 60 years old, inclusive, at the Screening Visit. 
2. ALS diagnosed as possible, laboratory-supported probable, probable, or definite as 
defined by revised El Escorial criteria. 
3. Having onset of ALS disease symptoms, including limb weakness within 24 months at 
the Screening Visit. 
4. ALSFRS-R ≥ 25 at the screening Visit. 
5. Upright slow vital capacity (SVC) measure ≥ 65% of predicted for gender, height, and 
age at the screening Visit. 
6. Decline in ALSFRS-R total score of 3 or more points in the three months before 
randomization.  
7. Taking a stable dose of riluzole, or no riluzole at all (riluzole-naïve participants are 
permitted in the study), for at least 30 days prior to the Screening Visit and be willing to 
maintain the riluzole dose for the duration of the study. 
Major 
Exclusion 
Criteria 
1. Prior stem cell therapy of any kind.  
2. Active participation in any other ALS interventional study  
3. 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.  
4. History of autoimmune disease that may confound study results myelodysplastic or 
myeloproliferative disorder, leukemia or lymphoma, whole body irradiation, hip fracture, 
or severe scoliosis.  

 
 
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5. 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 participants.  
6. Any history of malignancy within the previous 5 years, with the exception of non-
melanoma localized skin cancers (with no evidence of metastasis, significant invasion, or 
re-occurrence within three years of baseline).   
7. Current use of immunosuppressant medication or use of such medication within 4 weeks 
of Screening visit (Visit 1).  
8. Any history of acquired or inherited immune deficiency syndrome.  
9. Use of RADICAVA (edaravone injection) within 30 days of screening or intent to use 
edaravone at any time during the course of the study including the follow up period 
10. 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).  
11. Use of non-invasive ventilation (NIV), diaphragm pacing system or invasive ventilation 
(tracheostomy) at the screening or randomization visit.  
12. Usage of feeding tube at the screening or randomization visit.  
13. Pregnant women or women currently breastfeeding.  
ASSESSMENTS 
Safety  
Changes in vital signs and physical examination findings, hematology, blood chemistry, 
urinalysis, and tabulation of AEs, and changes in concomitant medications. Note AE due to 
disease progression will be categorized as such. 
Efficacy 
Efficacy assessments will be based upon the 12 item ALSFRS-R total score and its subscale 
scores. Efficacy endpoints are further described in the statistical section below.  If an ALSFRS-
R assessment cannot be completed in-person, it will be administered remotely. The ALSFRS-
R has been validated for administration over the telephone.  During the COVID-19 pandemic, 
SVC will not be performed until such a time as institutional policies permit, to prevent viral 
contamination and reduce the risk to study participants and clinical trial staff. 
Biomarkers 
CSF samples and serum samples will be collected prior to each administration of cells as well 
as at selected time points per schedule of assessments below. CSF and/or serum or blood 
samples will be evaluated for levels of biomarkers (such as neurotrophic and inflammatory 
factors, cytokines) and T regulatory cells.  
DATA SAFETY MONITORING BOARD 
DSMB 
An independent, Data Safety and Monitoring Board (DSMB) will be assembled for this Phase 
3 clinical trial. Previous clinical studies with NurOwn® (MSC-NTF cells) were not associated 
with any deaths or treatment-related SAEs.  The DSMB will review key safety data (at intervals 
and as requested) as outlined in the DSMB charter. 
STATISTICAL METHODS AND ANALYSIS 
Sample Size 
Calculation 
Since the primary efficacy endpoint is based upon the percentage of responders who 
demonstrate a ≥ 1.25 points/month improvement in ALSFRS-R post treatment slope as 
compared to their pre-treatment slope, the sample size for this study is based upon extrapolation 
of the percentage of participants on NurOwn® (excluding slow progressors) who were 
responders at 12 weeks as observed in the previous Phase 2 BCT-001 US study.   
At 12 weeks post-treatment 53% of NurOwn® (MSC-NTF cells) treated participants were 
observed to have an improvement in post-treatment slope using either the thresholds of ≥ 1.0 
Points / month or ≥ 1.5 points / month.  

 
 
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The best estimate of the percentage of placebo participants who will be responders is based 
upon the % of responders at 24 weeks.  At 24 weeks post-treatment there were 17% of placebo 
participants who were responders using the threshold of ≥ 1.0 points /month improvement in 
ALSFRS-R slope and 0% using the threshold of ≥ 1.5 points /month improvement in ALSFRS-
R slope. 
Accounting for the longer duration of the proposed study, missing data due to discontinuations 
and potentially fewer responders in the NurOwn® treated group, we estimate the true percentage 
of responders who are expected to improve ≥ 1.25 points/month on NurOwn® to be 35% and 
on Placebo to be 15%. Utilizing a Chi-square test with Type I error rate of 0.05 two-sided and 
90% power we would require 97 participants per treatment arm. 
The true % of responders in each treatment group using the criteria of ≥ 100% improvement is 
also expected to be around 35% treated and 15 % placebo. 
A sample size of  approximately 100 participants per arm (approximately 200 participants total) 
will be randomized. 
The COVID-19 pandemic may result in additional missing data or longer duration between 
visits. The full impact of this cannot be estimated at this point, however during analyses, 
considerations may be made for data collected prior to and after the start of the pandemic to 
address impact of missing data as well as longer durations between visits. 
Efficacy 
The primary efficacy endpoint is based upon the ALSFRS-R functional rating scale which is a 
validated scale based upon 12 items, each rated from 0 to 4. Scores of 4 are Normal and 0 are 
the worst. Note the ALSFRS-R overall total score is between 0 and 48. The slope is determined 
by fitting a linear regression using all assessments between the time points mentioned.  
The primary efficacy endpoint will be the proportion of participants with a ≥1.25 point/month 
improvement in post-treatment slope vs. pre-treatment slope in ALSFRS-R score at 28 weeks 
from the first treatment.  
The primary and secondary efficacy endpoints will be analyzed using the ITT population which 
will be defined as all subjects randomized.  
The modified intent to treat (mITT) population will be defined in this study as all participants 
who were randomized, treated and have at least three ALSFRS-R assessments: one pre-
treatment assessments of ALSFRS-R prior to the baseline assessment, a baseline assessment 
and one post-treatment assessment.  Baseline will be the ALSFRS-R assessment at the first 
transplantation visit (Week 0, Visit 6 in the Study scheme) prior to treatment. This will permit 
computing the slope from a linear regression pre- and post-treatment to get a rate of decline in 
ALSFRS-R per month pre-treatment and post- treatment.  
No to minimal differences are expected between the mITT and ITT populations, however if 
there are differences, analysis of the primary endpoint and other select efficacy analyses will 
also be generated using the mITT population.  
The ITT and mITT population will be analyzed based upon the treatment groups subjects are 
randomized to. 
Supporting efficacy analyses will be conducted using the Efficacy Evaluable (EE) population 
which will be a subset of the mITT population. The exact criteria used to define the EE 
population will be finalized prior to locking the database and unblinding the study. 
Each statistical test will be performed at Type I error α=0.05 (Two-sided). The primary and key 
secondary efficacy endpoints will be tested sequentially to account for multiplicity and preserve 
overall Type I error. No adjustments will be made for multiple comparisons in testing additional 
secondary exploratory efficacy endpoints. 
A subject is defined as a responder if his/her rate of disease progression as measured by the 
ALSFRS-R slope (rate of decline per month fit using linear regression) over 28 weeks from 
baseline improves by ≥ 1.25 points/month as compared to the disease progression over the pre-

 
 
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treatment period. All deaths related to disease progression will be defined as non-responders. 
Baseline will be the first transplantation visit (Week 0, Visit 6 in the Study scheme).  
The null and alternative hypothesis are as follows: 
Ho: Pt=Pp 
Ha: Pt≠Pp 
Where Ho and Ha are the null and alternative hypothesis respectively and Pt and Pp are the 
proportion of participants in the treated group and placebo group whose post-treatment slope 
over 28 weeks from baseline as compared to the pre-treatment slope in the overall ALSFRS-R 
score improves by ≥ 1.25 points/month.  
The hypothesis testing to compare the percentage of responders between the two treatment 
groups will be based upon the ITT population, using logistic regression adjusting for site, and 
ALSFRS-R slope pre-treatment. Other explanatory variables may be added to the logistic 
regression model which will be finalized and described in the SAP prior to locking the database 
and unblinding the study. 
The two key secondary endpoints to be tested if the null hypothesis for the primary endpoint is 
rejected are a comparison between the NurOwn® (MSC-NTF cells) and placebo group of the 
(a) percentage of participants whose post-treatment slope in the overall ALSFRS-R score as 
compared to their pre-treatment slope improves by ≥ 100% (b) change in ALSFRS-R score 
from baseline to week 28. These two secondary endpoints will be tested in this order to preserve 
Type I error. 
Additional supportive endpoints will include comparison between treatment groups of (a) 
survival or time to tracheostomy; (b) mean change in slope of ALSFRS-R score over each post 
baseline visit and the entire follow-up period (2 – 28 weeks) as compared to pre-treatment slope 
and (c) the change from baseline in ALSFRS-R score to each post baseline time points.  
Two sensitivity analyses will be performed using multiple imputations with unobserved data 
imputed prior to fitting the linear regression. In both sensitivity analyses, the method of multiple 
imputations (MI) using Pattern Mixture Model (Little, 1996) will be used. An ALSFRS-R 
overall score will be considered to be non-missing if at least 6 out of the 12 items were assessed 
and have valid scores. Based upon prior trials the amount of non-monotone missing data are 
expected to be minimal and hence any non-monotone missing ALSFRS-R overall scores will 
be imputed using the Markov Chain Monte-Carlo method.  
In the first sensitivity analysis, an assumption of Missing at Random (MAR) will be made and 
subject’s missing data will be imputed using those with available data within the treatment 
group they were randomized to. In the second sensitivity analysis, an assumption of Missing 
Not at Random (MNAR) will be used where missing data for all participants will be imputed 
using available data for Placebo participants.  
The analysis for ALSFRS-R subscales will employ a similar approach as described for the 
primary and secondary efficacy analyses. 
Analysis of change in SVC will be detailed in the SAP. 
Details of all statistical analyses will be provided in the statistical analysis plan which will be 
finalized prior to database lock and unblinding the study. 
Safety 
All safety analyses will be conducted on the Safety Population, which will be defined as all 
participants who were randomized and had at least one treatment performed. 
When evaluating changes in safety parameters, Baseline will be defined as the last measurement 
prior to the first treatment. 
For physical examination, concomitant medications, hematology and blood chemistry, ECG 
assessments, shifts from baseline in categorization of results (e.g. normal/abnormal or 
above/below normal range) will also be summarized.  
All continuous data obtained in this study and documented in the electronic case report forms 
(eCRFs) will be listed and tabulated with descriptive group statistics (n, mean, standard 

 
 
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deviation, median, minimum, maximum). For discrete data, counts and percentages will be 
summarized. 
Biomarkers 
CSF and/or serum or blood samples will be analyzed for the concentration of biomarkers and 
their relationship to efficacy outcomes. In addition, relationships between neurotropic factors, 
inflammatory markers and clinical outcomes will be evaluated to determine if any biomarkers 
can be predictive to treatment outcome or prognostic to disease progression. 

 
 
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TABLE OF CONTENTS 
STUDY SYNOPSIS .................................................................................................................. 6 
TABLE OF CONTENTS ....................................................................................................... 13 
ABBREVIATIONS ................................................................................................................. 15 
1. 
CLINICAL STUDY PROTOCOL ..................................................................... 17 
1.1 
INTRODUCTION ................................................................................................. 17 
1.1.1. 
COVID-19 Pandemic............................................................................................. 18 
1.2 
STUDY OBJECTIVES ......................................................................................... 19 
1.2.1. 
Primary objectives ................................................................................................. 19 
1.2.2. 
Secondary Objectives ............................................................................................ 19 
1.3 
INVESTIGATIONAL PLAN ................................................................................ 20 
1.3.1 
Overall Study Design and Plan .............................................................................. 20 
1.3.2 
Study Schematic .................................................................................................... 21 
1.3.3 
Treatment Plan ....................................................................................................... 22 
1.3.4 
Blinding and Randomization ................................................................................. 22 
1.3.5 
Duration of study ................................................................................................... 23 
1.3.6 
Discussion of Dose ................................................................................................ 23 
1.3.7 
Discussion of Study Design, Including Choice of Control Group ........................ 24 
1.4 
PATIENT POPULATION..................................................................................... 24 
1.4.1. 
Inclusion Criteria ................................................................................................... 24 
1.4.2. 
Exclusion Criteria .................................................................................................. 25 
1.5. 
STUDY ASSESSMENTS ..................................................................................... 26 
1.5.1. 
Anticoagulation therapy......................................................................................... 26 
1.5.2. 
CSF and Blood collection for assessments of Biomarkers .................................... 27 
1.5.3. 
Genetic Analyses ................................................................................................... 27 
1.5.4. 
Clinical Laboratory Safety Tests ........................................................................... 27 
1.5.5. 
Physical Examinations, Vital Signs, and Electrocardiograms ............................... 27 
1.5.6. 
Pre-transplantation Visits....................................................................................... 28 
1.5.5 
Transplantation Visits ............................................................................................ 30 
1.5.6. 
Post transplantations follow-up ............................................................................. 35 
1.5.7. 
Safety Follow-Up................................................................................................... 36 
1.5.8. 
Lost to Follow-Up ................................................................................................. 36 
1.6. 
INVESTIGATIONAL PRODUCT INFORMATION .......................................... 37 
1.6.1. 
General Information............................................................................................... 37 
1.6.2. 
NurOwn® (MSC-NTF cells) Product Characteristics ............................................ 37 
1.6.3. 
Treatment Compliance........................................................................................... 38 
1.6.4. 
Test product, Dose and Administration ................................................................. 38 
1.7. 
PRIOR AND CONCOMITANT THERAPY ........................................................ 38 
1.7.1. 
Prior Therapy ......................................................................................................... 38 
1.7.2. 
Concomitant Therapy ............................................................................................ 38 

 
 
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1.8. 
SAFETY REPORTING ......................................................................................... 39 
1.8.1. 
Adverse Events definitions and reporting.............................................................. 39 
1.8.2. 
Reporting Responsibilities and Procedures for AEs and SAEs ............................. 42 
1.8.3. 
Reporting Responsibilities and Procedures for Pregnancies ................................. 43 
1.8.4. 
Prospective assessment of the occurrence of suicidality ....................................... 44 
1.8.5. 
Study discontinuation ............................................................................................ 44 
1.9. 
ASSESSMENT OF ENDPOINTS ........................................................................ 45 
1.9.1. 
Primary Endpoint ................................................................................................... 46 
1.9.2. 
Secondary Endpoints ............................................................................................. 46 
1.9.3. 
Statistical Methods and Sample Size Determination ............................................. 47 
1.10. 
STUDY COMMITTEES AND COMMUNICATIONS ....................................... 51 
1.10.1. 
Data and Safety Monitoring Board (DSMB) ......................................................... 51 
1.11. 
LABORATORY REQUIREMENTS .................................................................... 51 
1.12. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS ..................... 51 
1.12.1. 
Ethics ..................................................................................................................... 51 
1.12.2. 
Data Quality Assurance ......................................................................................... 52 
1.12.3. 
Investigational Product Accountability ................................................................. 53 
1.12.4. 
Compensation, Insurance, and Indemnity ............................................................. 54 
1.12.5. 
Data recording/ eCRF Completion ........................................................................ 54 
1.12.6. 
Record maintenance and retention......................................................................... 54 
1.12.7. 
Study Termination ................................................................................................. 55 
1.13. 
USE OF STUDY INFORMATION AND PUBLICATION ................................. 55 
1.14. 
REFERENCES ...................................................................................................... 56 
1.15. 
APPENDICES ....................................................................................................... 57 
1.15.1. 
Appendix 1: Listing of study activities .................................................................. 57 
1.15.2. 
Appendix 2: ALSFRS-R ........................................................................................ 63 
1.15.3. 
Appendix 3: SVC ................................................................................................... 64 
1.15.4. 
Appendix 4: C-SSRS ............................................................................................. 64 
1.15.5. 
Appendix 5: Procedure for IT transplantation of NurOwn® (MSC-NTF 
cells) or placebo ..................................................................................................... 65 
 
FIGURES 
Figure 1 
Clinical study flowchart ......................................................................................... 21 
Figure 2 
Study groups flowchart .......................................................................................... 22 
TABLES 
Table 1 
Schedule of Assessments: ...................................................................................... 57 
Table 2 
Detailed Schedule of Assessments for Cell Transplantation Visits (V6, V9 and V11)
 
61 
Table 3 
ALSFRS-R and Domains ...................................................................................... 63 

 
 
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ABBREVIATIONS  
AE 
Adverse Event  
ALP 
Alkaline phosphatase 
ALS 
Amyotrophic Lateral Sclerosis  
ALSFRS-R 
ALS Functional Rating Scale–Revised  
ALT 
Alanine aminotransferase (alanine transaminase)  
AST 
Aspartate aminotransferase (aspartate transaminase)  
BA 
Bioavailability 
BDNF 
Brain Derived Neurotrophic Factor  
BE 
Bioequivalence 
BMA 
Bone marrow aspiration 
BUN 
Blood urea nitrogen 
CBC 
Complete Blood Count  
COVID-19 
Coronavirus Disease 2019 
CFR 
Code of Federal Regulations 
CRO 
Clinical Research Organization 
CSF 
Cerebrospinal Fluid  
C-SSRS 
Columbia-Suicide Severity Rating Scale  
DMEM 
Dulbecco Modified Eagle Medium  
DSMB 
Data and Safety Monitoring Board  
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EE 
Efficacy Evaluable Analysis Set  
EMG 
Electromyography 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FVC 
Forced Vital Capacity  
GDNF 
Glial Derived Neurotrophic Factor  
GOT 
Glutamic oxaloacetic transaminase 
GPT 
Glutamic pyruvic transaminase 
Hb 
Hemoglobin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
HGF 
Hepatocyte Growth Factor  
HIV 
Human immunodeficiency virus 
hMSCs 
Human Mesenchymal Stem Cells 

 
 
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Ht 
Hematocrit 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IM 
Intramuscular 
IND 
Investigational New Drug 
IRB 
Institutional Review Board  
IT 
Intrathecal  
IXRS 
Interactive Voice/Web Response System (IVRS/IWRS) 
LDL 
Low-density lipoprotein 
MAR 
Missing at Random 
MedDRA  
Medical Dictionary for Regulatory Activities  
MI 
Multiple imputations 
mITT 
Modified intent to treat 
MNAR 
Missing Not at Random 
MRI 
Magnetic Resonance Imaging 
MSC  
Mesenchymal Stromal Cells  
MSC-NTF 
Mesenchymal Stromal Cells Secreting Neurotrophic 
Factors  
MVIC 
Maximum Voluntary Isometric Contraction 
NIV 
Non-invasive Ventilation 
NTF 
Neurotrophic Factors  
PT 
MedDRA Preferred Term  
PTT 
Partial thromboplastin 
RBC 
Red blood cells 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan  
SOA 
Schedule of Assessments  
SOC 
MedDRA System Organ Class  
SVC 
Slow Vital Capacity  
TEAE 
Treatment-Emergent Adverse Event  
US 
United States 
VEGF 
Vascular Endothelial Growth Factor  
WBC 
White blood cells 
WHO-DD  
World Health Organization Drug Dictionary 

 
 
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1. 
CLINICAL STUDY PROTOCOL 
1.1 
INTRODUCTION 
Amyotrophic lateral sclerosis (ALS) is a devastating and relentlessly progressive 
neurodegenerative disease. There is currently no available treatment that has been shown to 
stop or reverse its progression. There remains an unmet medical need for safe and effective 
treatments for people with ALS. 
Neurotrophic factors (NTFs) are potent survival factors for embryonic, neonatal, and adult 
neurons and are considered potential therapeutic candidates for ALS. Delivery of multiple 
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. NTF-secreting 
mesenchymal stromal cells (MSC-NTF cells) are a novel cell-therapeutic approach aimed at 
effectively delivering NTFs directly to the site of damage in ALS patients. 
The NurOwn® (MSC-NTF cells) therapy is based on transplantation of autologous bone 
marrow derived mesenchymal stromal cells (MSC), which are enriched from the patient’s own 
bone marrow, propagated ex vivo and induced to secrete NTFs such as Glial Derived Growth 
Factor (GDNF) and Brain Derived Neurotrophic Factor (BDNF), Vascular Endothelial Growth 
Factor (VEGF) and Hepatocyte Growth Factor (HGF). The autologous NurOwn® (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 are expected to take up the neurotrophic factors secreted by 
the transplanted cells.  
The NurOwn® (MSC-NTF cells) has been evaluated in two open label clinical studies and 
several compassionate treated patients.  
The first two open label studies, carried out at the Hadassah Medical Center in Jerusalem, Israel 
(ClinicalTrials.gov Identifier: NCT01051882 and NCT01777646), as well as the 8 
compassionate treatments, confirmed the treatment was safe and well tolerated either by the IT 
or by the IM route of administration as well as by the combined IT and IM administration, and 
showed some initial indications of efficacy, slowing the slope of disease progression. 
The Phase 1/2 first-in-man study evaluated the safety of a single initial dose of NurOwn® 
(MSC-NTF cell) administered by two different routes. NurOwn® (MSC-NTF cells) were 
administered intramuscularly (IM) in a cohort of 6 early stage ALS patients (ALSFRS-R score 
≥25) and intrathecally (IT) in 6 ALS patients with more progressive disease (ALSFRS-R score 
15-30) and insufficient muscle bulk. The 6 patients with early stage ALS received 24 IM 
injections of NurOwn® (MSC-NTF cells) (~1 x 106 cells/site into 24 sites along the biceps and 
triceps muscles of one arm for a total of ~24x106 cells/patient), and the 6 patients with more 
progressive disease received NurOwn® (MSC-NTF cells) by IT administration (one dose of 1 x 
106 NurOwn® (MSC-NTF cells)/kg of body weight). This study established the safety of 
NurOwn® (MSC-NTF cells) administration via IT and IM at these IM and IT doses. 
The first Phase 2 trial was a dose-escalating study in three cohorts of 4 early-stage ALS patients 
(ALSFRS-R score ≥30) aimed at evaluating safety and collecting efficacy data of the combined 
IT and IM administration. The three patient cohorts received the initial Phase 1/2 dose, a 1.5 
fold, and a 2-fold dose respectively by combined IT and IM administration. This study 

 
 
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established the higher doses to be safe and showed early signs of change in slope in the 
ALSFRS-R post-treatment compared to the slope pre-treatment.  
In both these studies, patients were followed for 3 months before and 6 months after 
transplantation. Additional outcome measures in these studies included change in: muscle 
strength grading (maximal voluntary isometric contraction [MVIC]) by grip, forced vital 
capacity (FVC %), muscle bulk estimated by magnetic resonance imaging (MRI) of the upper 
extremities, upper and lower extremities circumference, electromyography (EMG) parameters. 
Results from the above studies were published in JAMA Neurology (Petrou et al 2016). 
The second Phase 2a trial was a multicenter study conducted in U.S in 48 patients with early 
ALS to evaluate the safety and efficacy of NurOwn® (MSC-NTF cells) administered as single 
dose through a combination of IT and IM routes at a dose of 100 x 106 to 125 x 106 cells 
compared to placebo. The safety profile of the single dose of NurOwn® (MSC-NTF cells) was 
well tolerated with majority of AEs being mild or moderate. Significant improvement was 
observed in the total ALSFRS-R scores based upon percent improvement in slope, 
post-transplantation compared to pre-transplantation through the 24-week follow-up period.  
The purpose of the proposed BCT-002 Phase 3 study is to evaluate the efficacy and safety of 
three successive administrations of intrathecal injections of NurOwn® (MSC-NTF cells) as 
compared to placebo given every two months to participants with ALS (ALSFRS-R ≥ 25 at the 
Screening Visit). The primary and some secondary efficacy endpoints will be assessed based 
upon improvement in ALSFRS-R scores. Blood and CSF samples will be collected for 
biomarker analyses and DNA will be collected to identify specific ALS mutations and ALS 
related genes that may reveal important prognostic variables in post hoc analyses (Van den 
Berg, et al 2019). 
1.1.1. COVID-19 Pandemic 
This study protocol is amended in consideration of the current outbreak of respiratory disease 
caused by a novel coronavirus that was first detected in Wuhan City, Hubei Province, China, 
and that has now been detected in many locations internationally, including cases in the United 
States. The virus has been named “SARSCoV-2” and the disease it causes has been named 
“Coronavirus Disease 2019” (COVID-19). On January 31, 2020, the Department of Health and 
Human Services (HHS) issued a declaration of a public health emergency related to COVID-
19 and mobilized the Operating Divisions of HHS. In addition, on March 13, 2020, the 
President declared a national emergency in response to COVID-19 (FDA guidance on Conduct 
of Clinical Trials of Medical Products during COVID-19 Pandemic, March 2020). 
Brainstorm considers ensuring the safety and welfare of trial participants to be of paramount 
importance. This amendment is aimed at considering each circumstance, focusing on the 
potential impact on the safety and welfare of trial participants, and stresses the importance to 
modify study conduct accordingly. The sponsor may determine that the protection of a 
participant’s safety, welfare, and rights is best served by continuing the study participant in the 
trial as per the protocol or by delaying or discontinuing the administration or use of the 
investigational product or even participation in the trial.  

 
 
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The need to put new processes in place or to modify existing processes may vary in specific 
institutions and by geography depending on local public health initiatives. This assessment 
could include consideration of whether it is appropriate to delay some assessments and/or to 
perform some assessments remotely by telephone or through the use of telemedicine 
technology.  Furthermore, specific assessments, such as SVC that may be viewed by institutions 
as “high risk” during the COVID-19 pandemic, may not be performed until such a time as 
institutional policies permit, to prevent viral contamination and reduce the risk to study 
participants, their caregivers, and clinical trial staff. 
1.2 
STUDY OBJECTIVES  
To determine efficacy and safety of repeat administrations of IT injections of NurOwn®, 
autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors (MSC-NTF) as compared 
to Placebo given three times two months apart to participants with early ALS. 
1.2.1. Primary objectives  
• To evaluate the efficacy of NurOwn® (MSC-NTF cells) as compared to placebo as 
measured by the proportion of participants with a ≥1.25 points/month improvement in 
post-treatment slope vs. pre-treatment slope of the ALSFRS-R score at 28 weeks 
following the first treatment.  
• To evaluate the safety of NurOwn® (MSC-NTF cells) as compared to placebo based 
upon incidence of AEs, laboratory evaluations, physical examinations, vital signs, 
electrocardiogram (ECG) assessments and suicidal ideation as measured by the 
Columbia-Suicide Severity Rating Scale (C-SSRS). 
1.2.2. Secondary Objectives 
• To evaluate the efficacy of NurOwn® (MSC-NTF cells) vs. placebo as measured by the 
proportion of participants whose disease progression is halted or improved as measured 
by a 100% or greater improvement in post-treatment slope vs. pre-treatment slope in the 
ALSFRS-R at 28 weeks following the first treatment. 
• To evaluate the efficacy of NurOwn® (MSC-NTF cells) vs. placebo as measured by 
improvements in ALSFRS-R score between baseline and 28 weeks following the first 
treatment. 
• To evaluate the efficacy of NurOwn® (MSC-NTF cells) as compared to placebo as 
measured by improvements in ALSFRS-R slope using different responder definitions. 
• To evaluate the efficacy of NurOwn® (MSC-NTF cells) as compared to placebo by a 
comparison between treatment groups of (a) tracheostomy free survival; (b) change in 
slope of ALSFRS-R over each post baseline visit (2 – 28 weeks) as compared to pre-
treatment slope and (c) the change from baseline in the ALSFRS-R score to each post 
baseline time point. 
• To evaluate the efficacy of NurOwn® (MSC-NTF cells) vs. placebo as measured by the 
change of SVC (% predicted) from baseline to 28 weeks following the first treatment. 
• To evaluate biomarkers (NTFs, inflammatory factors and cytokines) in the 
cerebrospinal fluid (CSF) before each treatment and at select time points as well as in 

 
 
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serum or blood samples throughout the study to evaluate their relationship to treatment 
with NurOwn® (MSC-NTF cells).  
• To study whether response to NurOwn® treatment correlates with specific ALS genetic 
mutations or gene variants related to ALS 
1.3 
INVESTIGATIONAL PLAN  
1.3.1 Overall Study Design and Plan  
This is the fourth clinical study conducted by Brainstorm Cell Therapeutics to study autologous 
NurOwn® (MSC-NTF cells) and the second study under this Investigational New Drug (IND) 
conducted in the U.S. This is a Phase 3 randomized, double-blind, placebo-controlled study that 
will be conducted in approximately 200 participants with ALSFRS-R scores ≥ 25 at the 
Screening Visit at multiple study sites. After providing informed consent and signing a written 
informed consent document all participants will be observed for a total of approximately 12 
weeks prior to randomization and bone marrow aspiration to establish each individual’s rate of 
progression of ALS for comparison against the post-treatment measures (see Figure 1). 
Participants will be randomized at a 1:1 ratio to receive NurOwn® (MSC-NTF cells) or placebo 
(week -5). At Visit 5 (week -4), the participants’ bone-marrow will be harvested and MSC from 
participants in the treatment group will be isolated, expanded and cryopreserved. Prior to each 
treatment cells will be thawed, cultured and induced to differentiate into MSC-NTF cells. A 
dose of ~125 x 106 MSC-NTF cells will be administered at each treatment. At the time of 
consent, participants will be informed that they may not receive the transplant in case their 
autologous bone marrow fails to grow and reach the adequate numbers of MSC and/or MSC-
NTF cells. 
Participants will undergo three IT transplantations with NurOwn® (MSC-NTF cells) or 
matching placebo approximately every 8 weeks (Figure 2). The first transplantation will be at 
Visit 6 (Week 0) approximately 16 weeks after screening, with the subsequent transplantations 
at Visit 9 (Week 8) and Visit 11 (Week 16). Throughout the study, participants will be 
monitored by evaluators blinded to the treatment allocation group. Assessments and procedures 
that will be performed during the study are provided in Table 1 and Table 2. Following the third 
and last treatment participants will be followed for three additional monthly visits (through 
week 28) during which the ALSFRS-R score will be obtained, along with vital signs, laboratory 
tests and recording of concomitant medications and AEs (see schedule of assessments (SOA) 
in Table 1). 
In consideration of contingency measures implemented due to the outbreak of the COVID-19 
pandemic, to minimize or eliminate immediate hazards or to protect the life and well-being of 
research participants (e.g., to limit exposure to COVID-19) specific study visits and 
assessments may be rescheduled and/or conducted remotely according to the institutional 
differences at the individual clinical sites. 
The autologous production process is on a per-subject basis and begins upon fresh bone marrow 
aspirate arrival to the cleanroom facility and is completed once the cells are ready for 
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1.3.2 Study Schematic 
The study comprises an up to 20-week pre-treatment period including an approximately up to 
12 weeks screening period, a 16-week treatment period, during which three transplantations will 
be performed followed by a 12-week post-treatment follow-up period (Figure 1).  
Participants' bone marrow will be aspirated up to approximately 15 weeks following the first 
screening visit. The MSC isolation and cell propagation processes will last about 4-5 weeks and 
will be followed by NurOwn® (MSC-NTF cells) transplantation.  
At each transplantation visits [up to about 20 weeks after the screening visit, up to 28 weeks 
after the screening visit (8 weeks after first transplantation) and up to 36 weeks after the 
screening visit (8 weeks after second transplantation)], participants will be admitted to an 
inpatient study unit for study procedures and will be followed for 24-72 hours post 
transplantation. In consideration of the COVID-19 pandemic, patients may be released from the 
inpatient units after observation for less than 24 hours, per Principal Investigator’s judgment of 
their clinical status, as the risk of prolonged stay in the hospital may outweigh the potential 
benefit.  
Following each treatment, participants will be assessed at visits described in Table 1. After 
receiving the third treatment dose (at Week 16 weeks after the first transplantation), all 
participants will be followed for 12 weeks for evaluation of key efficacy and safety assessments.  
Each participant will thus be followed for a total of up to about 48 weeks (~12 months) from the 
first visit (Figure 1).  
 
 
Figure 1 
Clinical study flowchart 
Clinical study flowchart outlining the pre-treatment and screening periods, the treatment period and the post-
transplant follow-up visits.  RNZ: Randomization; BMA: Bone Marrow Aspiration;  
-10 
-12
-5
-6 
-9
0
4
8
12
16
20
24
Pre-treatment period                         Treatment Period                  Follow-up period
Weeks
Visit:    1        2         3         4       5        6         7      8         9          10         11         12
13         14          
Screening
RNZ
T1
Primary Efficacy
Endpoint
T3
T2
BMA
2
-14 
-16
-18 
-20
28
Screening period

 
 
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1.3.3 Treatment Plan 
1.3.3.1. Bone Marrow aspiration procedure 
Human bone marrow will be aspirated by a credentialed health care provider as per Medical 
Centre standard procedures, bilaterally from multiple punctures of the iliac crest of the pelvic 
bone of participants into 20 mL syringes prefilled with approximately 1 mL of a Heparin-
containing solution (Heparin Solution, USP, 350 units/mL) in PlasmaLyte. A Transfer Pack 
container with Male Luer – 600 mL bag (Fenwal Item no. 4R2024) or equivalent, containing 
Heparin will be pre-labelled. The bone marrow aspirated from each single puncture (~5 ml), 
will be injected into the bag through the male Luer. Immediately after bone marrow from each 
syringe is injected into the bag, the bag will be thoroughly mixed twice to avoid clotting of the 
bone marrow sample.  
A total of 80 to 100 mL of bone marrow will be aspirated from each participant.  
1.3.3.2. Intrathecal Transplant Procedure  
Participants will undergo a lumbar puncture (Spinal needle 20GA 3.50 IN (0.9 x 90 mm)) 
followed by IT injection of cells or placebo (Dulbecco Modified Eagle Medium, DMEM; 
Figure 2). IT injection is to be performed by an unblinded site team/physician that will not have 
further contact with the study participants or with the investigator and blinded site staff. The 
detailed transplantation procedure is provided in Appendix 5.  
Participants will be eligible for their 2nd and 3rd treatments if, in the judgment of the study team, 
there are no medical contraindications to proceeding. 
 
Figure 2 
Study groups flowchart 
Diagram delineating placebo and cells transplantation in the treatment and placebo groups.  
1.3.4 Blinding and Randomization  
Randomization will be used to avoid bias in the assignment of participants to treatment, to 
increase the likelihood that known and unknown attributes (e.g., demographics and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance the validity of 
statistical comparisons. 
IT Transplantation
Placebo group
Treatment group
Bone Marrow Aspiration

 
 
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This is a double-blind study where the investigators, participants and all sponsor and CRO 
personnel involved in the conduct, data management or analysis of the study will remain 
blinded to the treatment assignments. The exceptions to this blinding are the physician who 
administers the IT injection of MSC-NTF cells, the unblinded statistician who will create the 
final randomization schedule but will not otherwise be involved in the trial, the personnel at the 
vendor responsible for configuration of the IXRS (Interactive Voice/Web Response System 
(IVRS/IWRS or IXRS) system and the Manufacturing team (unblinded personnel) at the cell 
culture facility who will distribute the NurOwn® (MSC-NTF cells). Each of these groups will 
have standard operating procedures in place for maintaining the treatment blind.  
The Production manager will access the IXRS system for randomization information when 
assigning treatment to a participant and will allocate the treatment corresponding to the 
participants' randomization number. Randomization will occur at Visit 4 (one week prior to 
Bone Marrow aspiration) after the eligibility has been confirmed. The participant's 
randomization number will be obtained by the cell culture facility and recorded in the 
participant's batch record in preparation for MSC isolation and cell propagation process.  
The randomization code may be broken only in the event of an emergency, when it is essential 
to know which treatment the participant received in order to provide appropriate care. If 
unblinding becomes necessary, the investigator will discuss the reason for unblinding with the 
medical monitor prior to unblinding, and the medical monitor will provide the identification of 
the treatment if there is agreement that unblinding is necessary. Whenever the code is broken 
for safety reasons, the IXRS system will record the date, time, and reason for unblinding. The 
Sponsor and responsible CRO will be notified immediately of such unblinding without 
revealing details of the treatment of the participants.  
To minimize bias, all efforts will be made to minimize participants discontinuing the study 
between randomization (Visit 4) and treatment (Visit 6). For any Participant that discontinue 
during this period the reasons for discontinuation will be recorded.  
1.3.5 Duration of study  
Participants will be screened and then eligible participants will undergo bone marrow aspiration 
after up to 14 weeks. Following aspiration, MSC will be isolated, propagated for about 2 weeks 
and cryopreserved. About 2 weeks prior to each treatment, MSC will be thawed, propagated 
and induced into MSC-NTF cells. Participants in both the treatment and placebo groups will 
undergo IT cell transplantation with either NurOwn® (MSC-NTF cells) or the placebo (DMEM) 
on Day 0 (Visit 6), Week 8 (Visit 9) and Week 16 (Visit 11). Following each cell 
transplantation, participants will be monitored as inpatients for a period of approximately 24 
hours. Participants will be discharged after approximately 24 hours and up to 72 hours unless a 
clinical AE(s) occurs and requires continued inpatient monitoring and/or treatment. After the 
last dose, participants will be followed for approximately 12 weeks for efficacy and safety 
assessment. Each subject’s participation in the study will last for approximately 48 weeks.  
1.3.6 Discussion of Dose  
The IT transplantation dose (~125 x106 cells) is the highest dose of NurOwn® (MSC-NTF cells) 
that has been safely administered in the previous clinical trials in early ALS participants.  

 
 
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1.3.7 Discussion of Study Design, Including Choice of Control Group  
ALS is a fatal, progressive, neurodegenerative disease characterized by motorneuron cell death 
in the brain and spinal cord, accompanied by rapid loss of muscle control and eventual complete 
paralysis. There is currently no available treatment to prevent its progressive course, and life 
expectancy of patients is usually 3 to 5 years after diagnosis.  
The current study is a 1:1 randomized, double-blind, placebo-controlled multicenter study. The 
control group will be given placebo. It is expected that approximately 100 participants each in 
the NurOwn® (MSC-NTF cells) and placebo arm will provide an adequate number of 
participants demonstrate a higher proportion of participants in the MSC-NTF group responding 
to treatment compared to Placebo. 
1.4 
PATIENT POPULATION  
This study will be conducted in participants with a clinical diagnosis of ALS who meet the El 
Escorial criteria (Brooks BR et al 2000) for possible, laboratory-supported probable, probable, 
or definite ALS. To be enrolled in this study, participants must meet all inclusion criteria in 
Section 1.4.1 below and must not have any of the exclusion criteria listed in Section 1.4.2.  
The participants' 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 also allow for identifying trends in efficacy outcomes.  
1.4.1. Inclusion Criteria  
Study participants meeting all of the following criteria will be allowed to enroll in the study:  
1. Males and females ages 18 to 60 years old, inclusive, at the Screening Visit.  
2. ALS diagnosed as possible, laboratory-supported probable, probable, or definite as 
defined by revised El Escorial criteria. 
3. Having onset of ALS disease symptoms, including limb weakness within 24 months at 
the Screening Visit.  
4. ALSFRS-R ≥ 25 at the screening visit.  
5. Upright Slow Vital Capacity (SVC) measure ≥ 65% of predicted for gender, height, and 
age at the Screening Visit (See Appendix 3).  
6. Decline in ALSFRS-R total score of 3 or more points in the 12 weeks preceding 
randomization. 
7. Participants must be taking a stable dose of riluzole, or no riluzole at all (riluzole-naïve 
participants are permitted in the study), for at least 30 days prior to the Screening Visit 
and be willing to maintain the riluzole dose for the duration of the study. 
8. Women of childbearing potential shall either be surgically sterile, or must agree not to 
become pregnant for the duration of the study. Women must be willing to undergo a 
serum pregnancy test at screening, one week before bone marrow aspiration, at the visit 
prior to each MSC-NTF transplantation and at the conclusion of the study. Participants 

 
 
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of childbearing potential must agree to use a medically approved form of birth control 
(abstinence, intrauterine device (IUD), oral contraception, barrier and spermicide or 
hormonal implant) throughout the duration of the study and for at least 3 months 
following the last transplantation.  For those women who are sexually active and using 
oral contraceptives, a second form of barrier contraception is required. Men must be 
willing to consistently use two forms of contraceptive if their partners are of 
childbearing age.  
9. Capable of providing informed consent and willing and able to follow study procedures, 
including willingness to undergo multiple/repeated lumbar puncture.  
10. Geographic accessibility to the study site and willingness and ability to comply with 
follow-up.  
11. Citizen or permanent resident of the US or Canadian citizen able to travel to a US site for 
all follow-up study visits 
1.4.2. Exclusion Criteria  
Study participants 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. Active participation in any other ALS interventional study 
3. 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.  
4. History of autoimmune disease that may confound study results myelodysplastic or 
myeloproliferative disorder, leukemia or lymphoma, whole body irradiation, hip 
fracture, or severe scoliosis. If in doubt, the subject’s eligibility should be discussed 
with the medical monitor. 
5. 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 participants.  
6. Any history of malignancy, 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).  
7. Serum AST or ALT value >3.0 times the upper normal limit.  
8. Serum creatinine value >2.0 times the upper normal limit.  
9. Positive test for Hepatitis B, Hepatitis C, HIV.  
10. Current use of immunosuppressant medication or use of such medication within 4 weeks 
of Screening visit (Visit 1).  
11. Any history of acquired or inherited immune deficiency syndrome.  

 
 
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12. Use of RADICAVA (edaravone injection) within 30 days of screening or intent to use 
RADICAVA at any time during the course of the study including the follow up period. 
13. 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).  
14. Use of non-invasive ventilation (NIV), diaphragm pacing system or invasive ventilation 
(tracheostomy) at the screening or randomization visit.  
15. Any history of either substance abuse within the past year, or unstable psychiatric 
disease according to PI judgment.  
16. Usage of feeding tube at screening or the randomization visit.  
17. Pregnant women or women currently breastfeeding.  
1.5. STUDY ASSESSMENTS  
The SOA provides a visual listing of study assessments at each visit.  
The study assessments at each visit are provided in Table 1 in Appendix 1. The timing of the 
key study visits, Randomization (V4), BMA (V5), T1 (V6), T2 (V9) and T3 (V11) that are 
driven by manufacturing availability, may require a more flexible window to align with the 
manufacturing slot allocated to the individual participant.   
The study manual with details of assessments are provided in Appendix 2 (ALSFRS-R) 
Appendix 3 (SVC) and Appendix 4 (C-SSRS).  
This is a multicenter 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.  
Any evaluator performing ALSFRS-R assessments will be trained and certified. ALSFRS-R 
assessments will be done in person at in-clinic visits. If an ALSFRS-R cannot be provided in-
person it will be administered via the telephone. The ALSFRS-R has been validated for 
administration over the phone (Kasarski EJ et al 2005, Mannino M et al 2007). 
1.5.1. Anticoagulation therapy 
Anticoagulation treatment increases the risk of bleeding-related complications associated with 
any invasive procedure.   
In this study, this may impact the bone marrow aspiration at Visit 5, three stem cell transplants 
by lumbar puncture at visits 6, 9 and 11, and other lumbar punctures to collect CSF at visits 7, 
8, 10 and 12 (a total of 7 lumbar punctures).  
Due to the risk involved in performing a lumbar puncture while on anticoagulation therapy it 
would be medically necessary to withhold anticoagulation prior to and immediately after any 
of these procedures. There are several variables that would determine individual patient risk of 
withholding anticoagulation prior to the procedure, including: the indication for the 
anticoagulation and the type of anticoagulation therapy. Consequently, the risk for study 
participants must be considered by the study investigator on an individual, case-by-case basis, 

 
 
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and a risk benefit assessment should be conducted, evaluating the risks of discontinuing 
anticoagulation with the potential benefits of participating in the clinical trial for each subject.  
1.5.2. CSF and Blood collection for assessments of Biomarkers 
The CSF and blood samples will be collected for the detection of biomarkers at visits described 
in Table 1. 
1.5.3. Genetic Analyses 
Bone marrow derived mononuclear cells or MSC of study participants derived from the Bone 
Marrow aspirated at Visit 5, will be collected for DNA isolation and genetic profiling of ALS 
related genes to assess whether response to NurOwn® treatment correlates with specific ALS 
genetic mutations or gene variants.  Patients that have already completed or discontinued the 
study will be reconsented and asked to provide buccal swabs for DNA analysis. They will not 
be required to return to the clinic to provide the sample. 
1.5.4. Clinical Laboratory Safety Tests  
Clinical laboratory safety tests will be monitored throughout the trial at Visits 1, 4, 6, 9, 11, 13 
and 14 as listed in the Schedule of Assessments (Table 1 and Table 2).  
Tests include:  
Hematology: Complete blood count (CBC) (Red blood cells [RBC] with Indices, White blood 
cells [WBCs] with differential and platelet count, hemoglobin [Hb], hematocrit[Ht]).  
Serum pregnancy test: hCG 
Blood Biochemistry: Sodium (Na), Potassium (K), Calcium (Ca), Bicarbonate (HCO3), blood 
urea nitrogen (BUN), Creatinine (Cr), Glucose (Gluc), Chloride (Cl), Magnesium (Mg), 
Phosphorus (Phos), total protein, triglycerides (TG), Total cholesterol, high-density lipoprotein 
(HDL), low-density lipoprotein (LDL), urea, total bilirubin, aspartate aminotransferase 
(glutamic oxaloacetic transaminase) (AST[GOT]), alanine aminotransferase (glutamic pyruvic 
transaminase) (ALT [GPT]), alkaline phosphatase (ALP), uric acid. 
Coagulation: Prothrombin time, Partial thromboplastin (PTT).  
Urinalysis - Specific Gravity, pH, glucose, protein, ketones, blood.  
1.5.5. Physical Examinations, Vital Signs, and Electrocardiograms  
Participants will undergo physical examinations at Screening (Visit 1), Visit 6, and from Visit 8 
through Visit 13. Height will be measured at Screening (Visit 1), whereas body weight will be 
measured at Screening (Visit 1), Visit 3, Visit 6, and Visit 8 through Visit 14. Vital Signs 
measurements (including blood pressure, body temperature, pulse and respiration rate after 
sitting for at least 3 minutes) will be monitored at Screening (Visit 1) and from Visit 2 through 
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Vital sign values will be categorized into the following potential clinical concern categories if 
applicable, appropriately addressed and summarized.  
 
Vital Sign 
Potential Clinical Concern Categories 
Systolic blood pressure 
≥160 mmHg 
Diastolic blood pressure 
≥100 mmHg 
Heart rate 
<55 or >120 bpm 
Standard 12-Lead ECG will be performed at Visits 1 and 6, 9 and 11 (Up to 6 hours pre-
transplant and 24 hours post-transplant ± 30 mins.). ECG results must be manually read, 
preferably by a cardiologist, and the results entered on the CRF forms. 
1.5.6. Pre-transplantation Visits  
1.5.4.1. Visit 1: Screening Visit  
Visit 1 is the Screening Visit and precedes Visit 2 by approximately 4 weeks (± 7 days). 
Participants will undergo the following screening assessments:  
• 
Informed consent (to be obtained by the PI or co-PI) 
• 
Determine study eligibility, review of Inclusion/Exclusion Criteria 
• 
Collect demographic data  
• 
Medical history  
• 
Medical history of ALS symptoms and date of diagnosis  
• 
Review of prior concomitant medications  
• 
Directed physical examination, including height and weight  
• 
El Escorial criteria  
• 
Neurological examination (Abbreviated as appropriate to ALS) 
• 
Blood collection for hematology, coagulation, biochemistry evaluations and a serum 
pregnancy test (Female participants)  
• 
Blood collection for hepatitis B virus (HBV; surface antigen (HBsAg) and IgM 
antibodies to core antigen (IgM anti-HBc)), hepatitis C virus (HCV), human immune 
deficiency virus (HIV) 1 and 2.  
• 
Urinalysis  
• 
Standard 12-Lead ECG  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
SVC pulmonary function test  
• 
ALSFRS-R questionnaire  

 
 
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• 
C-SSRS baseline  
1.5.4.2. Visit 2 (Week -14 to -16 ± 7 days) and Visit 3 (Week -10 to -12 ± 7 days): screening 
period visits 
During Visit 2 and Visit 3, participants will undergo the following assessments: 
• ALSFRS-R questionnaire,  
• Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes)  
• Review of adverse events 
• Review of Prior/concomitant medications 
1.5.4.3. Visit 4: Randomization  
At Visit 4, (Week -6 to -9, in coordination with patient-assigned manufacturing slots) eligibility 
will be confirmed and participants will be randomized to NurOwn® (MSC-NTF cells) ( 
approximately 100 participants) or placebo group (approximately 100 participants) at a 1:1 
ratio.  
Participants, the medical team at the site (with the exception of the teams performing the IT 
injection of the cells), sponsor and CRO personnel involved with the conduct of the study, data 
monitoring, data management and analyses will be blinded to subject randomization.  
Participants will also undergo the following assessments: 
• 
Eligibility Criteria 
• 
Review of concomitant medications  
• 
Blood collection for hematology, coagulation, and biochemistry evaluations  
• 
Blood collection for hepatitis B virus (HBV; surface antigen (HBsAg) and IgM 
antibodies to core antigen (IgM anti-HBc)), hepatitis C virus (HCV), human immune 
deficiency virus (HIV) 1 and 2.  
• 
Urinalysis  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Neurological examination  
• 
Review of adverse events  
• 
ALSFRS-R questionnaire 
• 
Serum pregnancy test (female participants) 
• 
Body weight measurement 

 
 
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1.5.4.4. Visit 5: Bone Marrow Aspiration Visit  
At Visit 5 (Week-5-6, coordinated with patient-assigned manufacturing slots), all participants 
consenting to participate in the study and meeting the eligibility criteria who have been 
randomized at Visit 4 (Week -5) will undergo bone marrow aspiration. The bone marrow 
aspiration (BMA) procedure will be performed by a credentialed health care provider as per 
Medical Centre procedures from multiple punctures of the iliac crest of the participants' pelvic 
bone. Participants will also undergo the following assessments: 
• 
Review of concomitant medications  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Review of Adverse events  
• 
Bone Marrow Aspiration 
1.5.5 Transplantation Visits 
1.5.5.1. Visit 6 (T1): 1st Cell Transplantation (Day 0- up to Day 3)  
At the 1st transplantation visit, approximately 5-6 weeks from BMA, coordinated with patient-
assigned manufacturing slots, participants will be admitted to an inpatient study unit for study 
procedures. Pre-transplant assessments will include:  
• 
Admit to Inpatient Ward 
• 
Body weight (in pounds) measurement  
• 
Directed physical examination 
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
ALSFRS-R questionnaire 
• 
SVC pulmonary function test  
• 
Neurological examination 
• 
Review of concomitant medications  
• 
Blood for hematology, coagulation, biochemistry, and biomarker evaluations; as well 
as urinalysis will be collected  
• 
Review of adverse events  
• 
Standard 12-Lead ECG 
Following pre-transplant procedures, participants will undergo (Hr. 0 - Estimated Time 12:00-
14:00):  
• Immediately prior to the IT administration of cells or placebo, CSF will be removed 
and retained for analysis.  

 
 
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• IT injection of cells or placebo by an un-blinded team/physician.  
Concomitant medications and AEs will be monitored throughout the study visit, as necessary. 
Post-transplant procedures, participants will undergo the following:  
• 
Vital signs will be monitored at 2, 4 (± 15 mins.), 7, 20, and 24 hours (± 30 mins.) post-
transplant and/or upon discharge at approximately 24 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 site will be performed at 2 (±15 mins.), and 20 (±30 
mins.) hours post-transplant.  
• 
Directed physical examinations will be performed upon discharge (at up to 72 hours 
post transplantation). 
• 
Blood for hematology, coagulation, biochemistry, and biomarker evaluations, as well 
as urinalysis will be collected 20 hours (± 30 mins.) post-transplant. 
Prior to discharge, assessments will include:  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Directed physical examinations will be performed at approximately 24 hours or up to 
72 hours post transplantation). 
• 
Review of concomitant medications  
• 
Review of adverse events  
• 
Assessment of blinding (subject and investigator) 
• 
Discharge from Inpatient Setting 
1.5.5.2. Visit 7: Week 2 (± 3 days) Follow-up 
After 2 weeks, at the first post- transplantation follow-up visit, participants will undergo:  
• 
Review of concomitant medications  
• 
Review of adverse events 
• 
Vital sign measurements (including blood pressure, body temperature, pulse and 
respiration rate, after sitting for at least 3 minutes) 
• 
Neurological examination  
• 
ALSFRS-R questionnaire  
• 
Blood collection for biomarker evaluation. 
• 
Lumbar puncture and collection of CSF.  

 
 
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1.5.5.3. Visit 8: Week 4 (± 3 days) Follow-Up  
At the Week 4 follow-up visit, participants will undergo:  
• 
Review of concomitant medications  
• 
Review of adverse events  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Directed physical examination, including weight  
• 
Neurological examination  
• 
ALSFRS-R questionnaire  
• 
Blood collection for biomarker evaluation. 
• 
Lumbar puncture and collection of CSF. 
• 
 Serum pregnancy test (female participants) 
1.5.5.4. Visit 9: 2nd Cell Transplantation (Week 8 ± 5 days) 
At the second transplantation visit, coordinated with patient-assigned manufacturing slots, 
participants will be admitted to an inpatient study unit for study procedures (See Tables 1 and 
2).  
Pre-transplant assessments (Up to 8 hours before transplant - Estimated Time 06:00-14:00) will 
include:  
• 
Admit to Inpatient Ward 
• 
Body weight measurement  
• 
Directed physical examination 
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
ALSFRS-R questionnaire 
• 
SVC pulmonary function test (if permitted) 
• 
Neurological examination 
• 
Review of concomitant medications  
• 
Blood for hematology, coagulation, biochemistry, and biomarker evaluations; as well 
as urinalysis will be collected  
• 
Review of adverse events  
• 
Standard 12-Lead ECG 
Following pre-transplant procedures, participants will undergo (Hr. 0 - Estimated Time 12:00): 

 
 
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• Immediately prior to the IT administration of cells or placebo, CSF will be removed 
and retained for analysis.  
• IT injection of cells or placebo. 
Concomitant medications and AEs will be monitored throughout the study visit, as necessary.  
Post-transplant, participants will undergo the following:  
• 
Vital signs will be monitored at 2, 4 (± 15 mins.), 7, 20, and 24 hours (± 30 mins.), post-
transplant and/or upon discharge at 24 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 site will be performed at 2 (±15 mins.), and 20 (±30 
mins.) hours post-transplant.  
• 
Blood for hematology, coagulation, biochemistry, and biomarker evaluations; as well 
as urinalysis) will be collected 20 hours (± 30 mins.), post-transplant.  
Prior to discharge, assessments will include:  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Directed physical examinations will be performed at 24 hours or up to 72 hours post 
transplantation). 
• 
Review of concomitant medications  
• 
Review of adverse events  
• 
Discharge from Inpatient Setting 
1.5.5.5. Visit 10: Week 12 (± 5 days) Follow-Up  
At the Week 12 follow-up visit, participants will undergo:  
• 
Review of concomitant medications  
• 
Review of adverse events  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Directed physical examination, including weight  
• 
Neurological examination  
• 
ALSFRS-R questionnaire  
• 
Blood collection for biomarker evaluation 
• 
Lumbar puncture and collection of CSF 
• 
 Serum pregnancy test (female participants) 

 
 
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1.5.5.6. Visit 11: 3rd Cell Transplantation (Week 16 ± 5 days)  
At the third transplantation visit, coordinated with patient-assigned manufacturing slots, 
participants will be admitted to an inpatient study unit for study procedures. (See Tables 1 and 
2). 
Pre-transplant assessments (Up to 8 hours before transplant - Estimated Time 06:00-14:00) will 
include:  
• 
Admit to Inpatient Ward 
• 
Body weight measurement  
• 
Directed physical examination 
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Standard 12-Lead ECG 
• 
ALSFRS-R questionnaire 
• 
SVC pulmonary function test (if permitted) 
• 
C-SSRS (since last visit) 
• 
Neurological examination 
• 
Review of concomitant medications  
• 
Blood for hematology, coagulation, biochemistry, and biomarker evaluations; as well 
as urinalysis will be collected 
• 
Review of adverse events  
Following pre-transplant procedures, participants will undergo (Hr. 0 - Estimated Time 12:00): 
• 
Immediately prior to the IT administration of cells or placebo, CSF will be removed and 
retained for analysis. 
• 
IT injection of cells or placebo. 
Concomitant medications and AEs will be monitored throughout the study visit, as necessary.  
Post-transplant, participants will undergo the following:  
• 
Vital signs will be monitored at 2, 4 (± 15 mins.), 7, 20, and 24 hours (± 30 mins.), post-
transplant and/or upon discharge at 24 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 site will be performed at 2 (±15 mins.), and 20 (±30 
mins.) hours post-transplant.  
• 
Blood for hematology, coagulation, biochemistry, and biomarker evaluations; as well 
as urinalysis will be collected 20 hours (± 30 mins.), post-transplant.  
• 
Standard 12-Lead ECG at 24 hours (± 4 hrs.), post-transplant. 

 
 
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Prior to discharge, assessments will include:  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Directed physical examinations will be performed at 24 hours or up to 72 hours post 
transplantation). 
• 
Review of concomitant medications  
• 
Review of adverse events  
• 
Assessment of blinding (participant and investigator) 
• 
Discharge from Inpatient Setting  
1.5.6. Post transplantations follow-up  
1.5.6.1. Visit 12: Week 20 (± 5 days) Follow-Up  
At the Week 20 follow-up visit, participants will undergo:  
• 
Review of concomitant medications  
• 
Review of adverse events 
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Directed physical examination, including weight  
• 
Neurological examination  
• 
ALSFRS-R questionnaire  
• 
Blood collection for biomarker evaluation 
• 
Lumbar puncture and collection of CSF.  
1.5.6.2. Visit 13: Week 24 (± 5 days) Follow-Up  
At the Week 24 follow-up visit, participants will undergo:  
• 
Review of concomitant medications  
• 
Review of adverse events  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Directed physical examination, including weight  
• 
Neurological examination  
• 
Blood collection for hematology, and biochemistry evaluations  
• 
Urinalysis  

 
 
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• 
ALSFRS-R questionnaire  
1.5.6.3. Visit 14: Week 28 (± 5 days) Follow-Up  
At week 28 post transplantation follow-up, all participants will undergo: 
• 
Review of concomitant medications  
• 
Review of adverse events  
• 
Vital sign measurements (including blood pressure, body temperature; pulse and 
respiration rate after sitting for at least 3 minutes) 
• 
Directed physical examination, including weight (in pounds) 
• 
Neurological examination  
• 
Blood collection for hematology and biochemistry evaluations  
• 
Urinalysis  
• 
ALSFRS-R questionnaire  
• 
SVC pulmonary function test (if permitted) 
• 
Assessment of blinding (subject and investigator) 
• 
C-SSRS since last visit  
• 
Serum pregnancy test (female participants) 
1.5.7. Safety Follow-Up  
For participants who refuse further clinic study visits, telephone contact by study staff shall be 
attempted and documented to review for AEs at each scheduled visit through the remainder of 
the study. AEs and serious adverse events will be followed up as described in Section 1.8.  
1.5.8. Lost to Follow-Up  
Every reasonable effort will be made to contact any subject apparently lost to follow-up during 
the course of the study to complete study-related assessments and record outstanding data. If a 
participant cannot be reached, the site should document that at least 3 reasonable attempts were 
made to contact the participant over a period of 30 days from the time the site last had contact 
with the participant.  Following 3 telephone contact attempts, the subject will be contacted by 
mail using a method that provides proof of receipt. Alternate contacts will be used if the subject 
is not reachable (e.g., primary care providers, referring physician, relatives).  
Such efforts shall be documented in the subject’s source documents.  
If all efforts fail to establish contact, the subject will be considered lost to follow-up.  

 
 
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1.6. 
INVESTIGATIONAL PRODUCT INFORMATION  
1.6.1. General Information  
The cell therapy (NurOwn®) is based on the autologous transplantation of adult bone marrow 
derived human mesenchymal stem cells (hMSC) that are induced ex-vivo, using a medium 
based procedure, to secrete NTFs such as GDNF, BDNF, VEGF and HGF and are thus 
designated MSC-NTF cells.  
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 subject'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.  
NurOwn® (MSC-NTF cells) delivery is easy and safe by standard procedures (IT injections) 
and does not require surgical intervention.  
1.6.2. NurOwn® (MSC-NTF cells) Product Characteristics  
Participants’ bone marrow will be aspirated and MSC cells will be isolated from the total bone 
marrow mononuclear cell population, propagated in culture and induced to secrete NTFs. The 
NurOwn® propagated MSC-NTF cells will then be transplanted back into the subject 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 shall be administered, provided at least 100 x 106 
cells are administered).  
The NurOwn® (MSC-NTF cells) production process will be carried out in the absence of 
antibiotics, phenol red, and animal derived components. The production process will be cGMP 
compliant and will be 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) Biosafety 
cabinet.  
NurOwn® (MSC-NTF cells) will be provided in a ready-to-use subject-personalized unique 
treatment package with the appropriate primary and secondary labels. The treatment package 
consists of one 5 mL syringe for IT transplantation containing freshly harvested autologous 
cultured NurOwn® (MSC-NTF cells) at the dose defined in this protocol (see section 1.6.4).  
Syringes will be capped with a stopper (not a needle). The 5 mL syringe for IT transplantation 
will be packed in a pouch.  
The treatment/placebo package will be 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 will be shipped to the clinical site. The product shall be 
administered to the subject within the established shelf life of the product.  
Placebo will be provided in the same volume and syringes size as the cell containing syringes.  

 
 
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The sponsor will make every effort to ensure blinding of the study by assigning a different team 
(preferably from a different department) to the transplantation procedures that will not be 
otherwise involved in evaluation of the participants through the course of the study.  
The cell production process, including the in-process controls is described in full detail in the 
Chemistry, Manufacturing and Controls (CMC) section and in the Investigator's brochure (IB).  
1.6.3. Treatment Compliance  
Since participants are recruited with onset of disease symptoms within 24 months, and 
ALSFRS-R ≥ 25 and ≥ 65% SVC at the screening Visit, they are expected to be able to complete 
the three transplantations.  
To increase chances of post-treatment compliance, efforts will be made to recruit participants 
living in the geographical proximity of the medical centers or previously known to the 
Investigators.  
1.6.4. Test product, Dose and Administration  
Placebo or NurOwn® (MSC-NTF cells) at a dose of 125 x 106 cells will be administered 
intrathecally (however, if less than 125 x 106 cells are available, then the total available dose of 
cells shall be administered, provided at least 100 x 106 cells are administered).  
1.7. 
PRIOR AND CONCOMITANT THERAPY  
1.7.1. Prior Therapy  
Participants who received prior cell therapy of any kind will be excluded from the study (see 
Section 1.4.2).  
Rilutek (riluzole), Nuedexta (dextromethorphan hydrobromide and quinidine sulfate), and 
Radicava or Radicut (edaravone) are the only Food and Drug Administration (FDA)-approved 
drugs for participants with ALS (Nuedexta is approved only to treat pseudobulbar affect that 
occurs in some participants 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. Participants may not have taken Edaravone within 
30 days of screening and must not plan to begin therapy with edaravone for the duration of the 
study. Study participants who begin an excluded medication during the study period will be 
discontinued from treatment. In order to minimize the amount and impact of missing data, study 
investigators will make all reasonable efforts to collect key efficacy and safety data on 
participants who discontinue treatment or discontinue from the study.  
All medications taken prior to the first transplantation will be recorded as Prior medications. 
1.7.2. Concomitant Therapy  
Concomitant medications are those given to the subject during or after the first transplantation. 
All concomitant medications will be recorded. 

 
 
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Participants 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 during the 
study for standard side-effects.  
In addition, the use of non-invasive procedures including continuous positive airway pressure 
and diaphragmatic pacing systems will be recorded. 
1.8. 
SAFETY REPORTING  
For this study, AEs and SAEs will be collected from the screening visit through the end of the 
study period as detailed in Section 1.8.1.  
1.8.1. Adverse Events definitions and reporting  
Standard definitions for AEs are provided in this section for informational purposes.  
1.8.1.1. 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.  
Within this investigation, adverse events also encompass procedurally related observations 
based upon physical examination of the patient, or laboratory assessments or spontaneously 
reported by the subject which are temporally associated with the administration of study 
medication. 
For adverse events requiring medical interventions such as surgeries, diagnostic procedures and 
therapeutic procedures it is recommended that these be recorded as treatment of the adverse 
event or action taken rather than an additional adverse event 
1.8.1.2. 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 subject 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 excluding: 
▪ A visit to the emergency room or other hospital department for <24 hours that 
does not result in admission (unless considered an important medical event or 
life-threatening) 
▪ An elective surgery planned prior to signing informed consent  

 
 
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▪ Protocol specified admissions for planned procedures 
▪ Admission for social circumstance that has no bearing on health status and 
requires no intervention (e.g., economic inadequacy, family circumstances, 
administrative 
• 
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.  
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.  
SAEs reported through 12 weeks following the last transplantation will be entered in the study 
safety database and reported as such. 
1.8.1.3. Relatedness (Causality)  
Investigators will assess relatedness of AEs to study drug using the following terms:  
• 
Definite: An AE that has a clear temporal association with investigational product 
administration (e.g., within 72 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.  
1.8.1.4. Severity (Intensity)  
The severity of an AE 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 

 
 
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• 
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. 
1.8.1.5. Follow-Up of AEs  
After the initial recording of an AE, the Investigator shall proactively follow the subject. Any 
non-serious AEs that are still on-going at the end of the study shall 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 subject exits the study. If in doubt, 
the Investigator shall consult the study Medical Monitor.  
All SAEs shall be followed until resolution, until the condition stabilizes, or until the subject is 
lost to follow-up, or otherwise explained. Once the SAE is resolved, the corresponding AE 
eCRF page shall 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 shall be transmitted to the Sponsor.  
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.  
1.8.1.6. Outcome  
The following terms will be used during this study:  
• 
Fatal  
• 
Not Recovered/not resolved  
• 
Recovering/resolving  
• 
Recovered/resolved  
• 
Recovered/resolved with sequelae  
• 
Unknown  
1.8.1.7. Clinically Significant Laboratory Abnormalities  
Any laboratory abnormalities deemed clinically significant by the Investigator shall be reported 
on the AE eCRF. A clinically significant abnormality is a confirmed abnormality (by repeat 
test) that is changed sufficiently from screening visit 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 eCRF. Repeated additional tests and/or other evaluations 

 
 
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required to establish the significance and etiology of an abnormal result shall be obtained when 
clinically indicated.  
1.8.2. 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 non-serious, shall 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 on the eCRF within 24 hours of learning 
about the event regardless of relationship to study drug.  
If the site experiences a temporary disruption of the eCRF system, a back-up paper SAE 
Report Form will be available for site staff to complete. 
• Site staff will complete the paper SAE report form and e-mail it within 24 hours to the 
following address: drugsafety@worldwide.com 
• In cases where the email system is unavailable, site staff will send the SAE by fax to: 
+1-866-387-5539 (US). 
If notification is made via email or fax, site staff must enter the SAE information into the 
eCRF system as soon as the system becomes available. Should a back-up SAE form be used, 
the original SAE form should be kept at the study site. 
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). Additional follow-up information must be 
reported in the eCRF within 24 hours of awareness following Investigator (or site) awareness 
of the information. However, the Investigator should not delay reporting an SAE in order to 
obtain additional information. Additional information, when available, should be reported per 
the reporting procedures described above. 
The following information and assessments will be recorded in the eCRF:  
• 
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 AE severity using the criteria outlined above.  
• 
The relationship of the event to the investigational product as outlined above.  
• 
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 
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• 
Any additional data which might be relevant to the event.  
A written report is also required for all participants who died during the study. This report must 
document the events surrounding the subject’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 shall be directed to responsible personnel’s 
as detailed in table below: 
Responsible  
Title/Company  
Drug Safety.  
Worldwide Clinical Trials  
3800 Paramount Parkway, Suite 400 
Morrisville, NC 27560 USA 
drugsafety@worldwide.com 
Medical Monitor 
Stuart Apfel, MD 
Office: 516-505-0935 
Cell: 516-712-0884 
Email: sapfel@parallaxclinical.com 
Sponsor 
Yael Gothelf, Ph.D. 
Office: (646) 666-3188 Ext. 102 
Email: ygothelf@brainstorm-cell.com 
Brainstorm Cell Therapeutics  
3 University Plaza Drive, Suite 320  
Hackensack, NJ 07601 
The Sponsor or designated CRO (Worldwide Clinical Trials) will report 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 
bioavailability 
(BA)/bioequivalence (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 unexpected AEs when this 
information is of global importance to subject safety and welfare.  
1.8.3. Reporting Responsibilities and Procedures for Pregnancies 
Pregnancy occurring in a female subject (and female partners of male subjects) should be 
reported in the pregnancy eCRF within 24 hours of becoming aware of the event. Pregnancy 
outcome information should be forwarded to Sponsor/Worldwide when available.  

 
 
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Any pregnancies will be followed through delivery or premature termination.  If a female 
subject (or female partner of male subject) becomes pregnant during the study, any 
complications of that pregnancy such as abortion (spontaneous or induced), premature birth, or 
congenital abnormality will be captured as SAEs.  In the event the eCRF system is unavailable, 
a back-up paper Pregnancy Reporting Form will be available for site staff to complete following 
the reporting guidelines as outlined in Section 1.8.2. 
Following delivery or termination of pregnancy, follow-up information regarding the outcome 
of the pregnancy and any postnatal sequelae in the infant will be required. 
1.8.4. Prospective assessment of the occurrence of suicidality  
There is no evidence from animal or previous human studies to suggest that NurOwn® (MSC-
NTF cells) 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 during the trial.  
Suicidal 
ideation 
and 
behavior 
will 
be 
monitored 
using 
the 
C-SSRS 
(http://www.cssrs.columbia.edu), as per the SOA. All study staff delivering the C-SSRS will 
be fully trained in its appropriate use and only study staff prepared to appropriately respond to 
participants 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 (See Appendix 4).  
1.8.5. Study discontinuation   
1.8.5.1. 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 participants enrolled 
in the study.  
2. A decision on the part of the Data and Safety Monitoring Board (DSMB) to recommend 
suspending or discontinuing 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 enroll eligible participants 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;  

 
 
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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.  
1.8.5.2. Subject Withdrawal from Study  
Participants may voluntarily withdraw from the study at any time during the course of the study 
for any reason, specified or unspecified, and without prejudice. The Investigator will document 
the reason/circumstances for withdrawal in the appropriate eCRF.  
Participants can discontinue from the study for any of the following reasons: 
• Participants whose MSC or MSC-NTF cells fail to proliferate and to produce a sufficient 
number of cells for transplantation (See Section 1.3.1) 
• For any reason related to safety or tolerability 
• At the subject’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 
Efforts will be made to follow all participants who discontinue study for any reason and 
encourage participant to return to the site for an End of Study visit (Visit 14). Such follow-up 
will include all relevant evaluations for safety and efficacy including clinical assessments and 
collection of laboratory study results as set out in this protocol.  
Efforts will be made to have participants who discontinue from the study for any reason, return 
to the site for an End of Study follow up visit.  Such follow-up will include all relevant 
evaluations for safety and efficacy including clinical assessments and collection of laboratory 
study results as set out in this protocol.  
If a participant refuses to return for any further clinic visits, every effort will be made to follow 
the patient over the phone for the remaining study visits. This should be documented in the End 
of Study page eCRF in the electronic database including the reason/circumstances for 
withdrawal in a timely manner (preferably within 24-48 hours).  The documentation should 
include the date the participant withdrew consent/discontinued, the reason for discontinuation, 
and the fact that the participant refuses to return for the end of study visit.  The date documented 
will be considered the last date of contact and thus the participant’s last day on study. Despite 
discontinuing from the study, if the site becomes aware of any adverse events or SAEs within 
12 weeks of the last transplant, they should be recorded in the database adverse event log. 
1.8.5.3. Temporary Discontinuation from the Study 
Study treatment can be temporarily withheld in case of any serious adverse event (SAE) or 
significant inter-current illness 
1.9. 
ASSESSMENT OF ENDPOINTS  
The study endpoints are detailed below. 

 
 
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1.9.1. Primary Endpoint  
1.9.1.1. Efficacy 
The primary efficacy endpoint will be to evaluate the proportion of NurOwn® treated 
participants with a ≥1.25 points/month improvement in post-treatment slope vs. pre-treatment 
slope in ALSFRS-R score at 28 weeks following the first treatment as compared to placebo.  
Efficacy assessments will be based upon the 12 item ALSFRS-R total score and its subscale 
scores as described in Appendix 2. ALSFRS-R scores should be collected in-person.  
Participants who refuse clinic study visits (or temporarily unable to attend) will be contacted 
by phone call by the trained site personnel.  
The ALSFRS-R is a quickly administered (10 minutes) ordinal, validated rating scale (ratings 
0-4) used to determine participants' 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 JM et al 1999). 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, and has been also validated over the phone (Kasarski EJ et al 
2005, Mannino M et al 2007).  
1.9.1.2. Safety 
Safety endpoints include AEs, changes in physical and neurological examination findings, 
hematology, serum chemistry, urinalysis, vital signs, and requirement of concomitant 
medications. 
1.9.2. Secondary Endpoints  
1.9.2.1. Revised ALS Functional Rating Scale (ALSFRS-R)  
The first secondary efficacy endpoint is to evaluate the efficacy of NurOwn® (MSC-NTF cells) 
vs. placebo as measured by the proportion of participants whose disease progression is halted 
or improved as measured by a 100% or greater improvement in post-treatment slope vs. pre-
treatment slope in ALSFRS-R score at 28 weeks following the first treatment.  
The second secondary endpoint is to evaluate the efficacy of NurOwn® (MSC-NTF cells) vs. 
placebo as measured by improvements in the ALSFRS R score between baseline and 28 weeks 
following the first treatment. 
In order to preserve Type I error, the above two secondary endpoints will be tested sequentially 
in the above order if the null hypothesis corresponding to the primary endpoint is rejected. 
Other efficacy endpoints will measure improvement in ALSFRS-R in participants treated with 
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(percent change improvement in slope and point change improvement in slope). Detailed 
definitions will be provided in statistical analysis plan (SAP). 
To evaluate the efficacy of NurOwn® (MSC-NTF cells) as compared to placebo by a 
comparison between treatment groups of (a) tracheostomy free survival; (b) change in 
ALSFRS-R slope over each post baseline visit (2 – 28 weeks) as compared to pre-treatment 
slope and (c) the change from baseline in ALSFRS-R score to each post baseline time point. 
To evaluate the efficacy of NurOwn® (MSC-NTF cells) vs. placebo as measured by the change 
in SVC (% predicted) from baseline to 28 weeks following the first treatment. 
1.9.2.2. Analysis of Cerebrospinal Fluid (CSF) and Serum or Blood 
CSF samples and serum or blood samples will be collected as per the schedule of assessments 
to evaluate biomarkers (NTFs, inflammatory factors, and cytokines) in the cerebrospinal fluid 
(CSF) before each treatment and at select time points as well as in serum or blood samples (T 
regulatory cells) throughout the study, to evaluate their relationship to treatment with NurOwn® 
(MSC-NTF cells).  
1.9.3. Statistical Methods and Sample Size Determination 
1.9.3.1. Sample Size Determination 
Since the primary efficacy endpoint is based upon the percentage of responders who 
demonstrate a ≥ 1.25 points/month improvement in ALSFRS-R post treatment slope as 
compared to their pre-treatment slope, the sample size for this study is based upon extrapolation 
of the percentage of participants on NurOwn® (excluding slow progressors) who were 
responders at 12 weeks as observed in the previous Phase 2 BCT-001 US study.   
At 12 weeks post-treatment 53% of NurOwn® (MSC-NTF cells) treated Participants were 
observed to have an improvement in post-treatment slope using either the thresholds of ≥ 1.0 
Points / month or ≥ 1.5 points / month. 
The best estimate of the percentage of placebo participants who will be responders is based 
upon the % of responders at 24 weeks.  At 24 weeks post-treatment there were 17% of placebo 
participants who were responders using ≥ 1.0 Points / month and 0% using the threshold of ≥ 
1.5 points / month. 
Accounting for the longer duration of the study, missing data due to discontinuations and 
potentially fewer responders is in the NurOwn® treated group we estimate the true percentage 
of responders who improve ≥ 1.25 point/month on NurOwn® to be 35% and on Placebo to be 
15%. Utilizing a Chi-square test with Type I error rate of 0.05 two-sided and 90% power we 
would require 97 participants per treatment arm.  
The true % of responders using the criteria of ≥ 100% improvement is also expected to be 
around 35% treated and 15 % placebo.  
A sample size of approximately 100 participants per arm (approximately 200 participants total) 
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1.9.3.2. Statistical Methods 
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%). The baseline visit will be defined as the last non-missing measure prior to initiation 
of investigational treatment (first treatment at Visit 6, Day 0).  
A detailed Statistical Analysis Plan (SAP) will be prepared and finalized prior to database lock, 
unblinding and analysis of study results.  
1.9.3.3. Analysis Population  
The primary, secondary and exploratory efficacy endpoints will be analyzed using the ITT 
population which will be defined as all subjects randomized.  
The modified intent to treat (mITT) population will be defined in this study as all participants 
who were randomized, treated and have at least three ALSFRS-R assessments: one pre-
treatment assessments of ALSFRS-R prior to the baseline assessment, a baseline assessment 
and one post-treatment assessment. Baseline will be the ALSFRS-R assessment at the first 
transplantation visit (Week 0, Visit 6) prior to treatment. This will permit computing the slope 
from a linear regression pre- and post-treatment to get a rate of change in ALSFRS-R per month 
pre-treatment and post-treatment.  
No to minimal differences are expected between the mITT and ITT populations, however if 
there are differences, analysis of the primary endpoint and other select efficacy analyses will 
also be generated using the mITT population.  
The ITT and mITT populations will be analyzed based upon the treatment groups subjects are 
randomized to. 
Supporting efficacy analyses will be conducted using the Efficacy Evaluable (EE) population 
which will be a subset of the mITT population. The exact criteria used to define the EE 
population will be finalized prior to locking the database and unblinding the study. 
All safety analyses will be conducted on the Safety Population, which will be defined as all 
participants who were randomized and had at least one transplantation performed.  
1.9.3.4. Efficacy Analyses  
Each statistical test will be performed at Type I error α=0.05 (Two-sided). The primary and key 
secondary efficacy endpoints will be tested sequentially to account for multiplicity and preserve 
overall Type I error. No adjustments will be made for multiple comparisons in testing additional 
secondary exploratory efficacy endpoints. 
The primary efficacy endpoint is based upon the ALSFRS-R which is a validated scale based 
upon 12 items, each rated from 0 to 4. Scores of 4 are Normal and 0 are the worst. Note the 

 
 
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ALSFRS-R score is between 0 and 48. The slope is determined by fitting a linear regression 
using all assessments between the time points mentioned.  
A subject is defined as a responder if his/her rate of disease progression as measured by the 
ALSFRS-R slope (rate of decline per month fit using linear regression) over 28 weeks from 
baseline improves by ≥ 1.25 points/month as compared to the disease progression over the pre-
treatment period. All deaths related to disease progression will be defined as non-responders.  
The null and alternative hypothesis are as follows: 
Ho: Pt=Pp 
Ha: Pt≠Pp 
Where Ho and Ha are the null and alternative hypothesis respectively and Pt and Pp are the 
proportion of participants in the treated group and placebo group whose post-treatment slope 
over 28 weeks from baseline as compared to the pre-treatment slope in the overall ALSFRS-R 
score improves by ≥ 1.25 points/month.  
The hypothesis testing to compare the percentage of responders between the two treatment 
groups will be based upon the ITT population, using logistic regression adjusting for site, and 
ALSFRS-R slope pre-treatment. Other explanatory variables may be added to the logistic 
regression model which will be finalized and described in the SAP prior to locking the database 
and unblinding the study. 
The first key secondary endpoint to be tested if the null hypothesis for the primary endpoint is 
rejected is a comparison between the NurOwn® (MSC-NTF cells) and placebo group of the 
percentage of participants whose post-treatment slope in the overall ALSFRS-R score as 
compared to their pre-treatment slope improves by ≥ 100%. Note, an improvement of 100% or 
more indicates achieving a post-treatment slope of ≥ 0, which means halt or improvement in 
disease progression as measured by the ALSFRS-R. 
If the null hypothesis for the first key secondary endpoint is rejected, the second key secondary 
endpoint will be the comparison in change from baseline to Week 28 in ALSFRS-R. 
Additional supportive endpoints will include comparison between treatment groups of (a) 
survival or time to tracheostomy; (b) mean change in slope of ALSFRS-R score over each post 
baseline visit and the entire follow-up period (2 – 28 weeks) as compared to pre-treatment slope 
and (c) the change from baseline in ALSFRS-R score to each post baseline time point. 
Two sensitivity analyses will be performed using multiple imputations with unobserved data 
imputed prior to fitting the linear regression. In both sensitivity analyses, the method of multiple 
imputations (MI) (Ratitch et al 2013) using Pattern Mixture Model (Little 1996) will be used. 
An ALSFRS-R overall score will be considered to be non-missing if at least 6 out of the 12 
items were assessed and have valid ALSFRS-R scores. Based upon prior trials the amount of 
non-monotone missing data are expected to be minimal and hence any non-monotone missing 
ALSFRS-R scores will be imputed using the Markov Chain Monte-Carlo method. The COVID-
19 pandemic may result in additional missed visits resulting in a greater amount of non-
monotone or monotine missing data. As per ICH E9, during blinded data review prior to 
database lock other imputations may be considered. These will be documented in an 
Amendment to the SAP prior to locking the database and unblinding the study. The method of 

 
 
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multiple imputations uses SAS PROC MI and MIANALYZE to generate multiple complete 
datasets and combine the results from them.   
In the first sensitivity analysis, an assumption of Missing at Random (MAR) will be made and 
subject’s missing data will be imputed using those with available data within the treatment 
group they were assigned to. In the second sensitivity analysis, an assumption of Missing Not 
at Random (MNAR) will be made based upon an approach similar to above using multiple 
imputations with missing data for subject imputed using the available data for Placebo 
participants.  
The analysis for ALSFRS-R subscales will employ a similar approach as described for the 
primary and secondary efficacy analyses. 
Details of all statistical analyses will be provided in the SAP, which will be finalized prior to 
database lock and unblinding the study. 
1.9.3.5. Safety analyses  
All safety analyses will be analyzed in the Safety Population.  
All AEs will be coded to System Organ Class (SOC) and Preferred Term (PT) using the Medical 
Dictionary for Regulatory Activities (MedDRA®). The number of treatment-emergent adverse 
events (TEAEs) and the number of participants 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 participants 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 
and PT’s will be listed in descending alphabetical order.  
A TEAE is an AE that occurs for the first time after initiation of treatment or if had occurred 
prior to treatment, worsens in severity after initiation of treatment. 
Separate summaries will be provided for the following categories of AEs:  
• 
TEAEs  
• 
TEAEs by severity  
• 
Treatment-related TEAEs  
• 
Serious TEAEs  
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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All continuous data obtained in this study and documented in the eCRFs will be listed and 
tabulated with descriptive group statistics (n, mean, standard deviation, minimum, median, 
maximum). For discrete data, counts and percentages will be summarized. 
1.9.3.6. Biomarker Analysis 
CSF and/or serum or blood samples will be analyzed for the concentration of biomarkers and 
their relationship to efficacy outcomes at each visit. In addition, relationships between 
neurotropic factors, inflammatory markers, miRNA expression, T regulatory cells and clinical 
outcomes will be evaluated to determine if any biomarkers can be predictive to treatment 
outcome or prognostic to disease progression. Analyses will be detailed in the SAP. 
1.9.3.7. Genetic analyses 
Bone marrow derived mononuclear cells, or MSC of study participants, derived from the Bone 
Marrow aspirated at Visit 5, will be collected for DNA isolation and genetic profiling of ALS 
related genes to assess whether response to NurOwn® treatment correlates with specific ALS 
genetic mutations or gene variants.  Participants that have already completed or discontinued 
the study will be reconsented and asked to provide buccal swabs for DNA analysis. They will 
not be required to return to the clinic to provide the sample.  
1.10. STUDY COMMITTEES AND COMMUNICATIONS  
1.10.1. Data and Safety Monitoring Board (DSMB) 
An independent, three-member Data Safety and Monitoring Board (DSMB) will be assembled 
for this Phase 3 clinical trial. Previous clinical studies with NurOwn® (MSC-NTF cells) did not 
result in any deaths or treatment-related SAEs. The DSMB will review key safety data (at 
intervals and as requested) as outlined in the DSMB charter. 
1.11. LABORATORY REQUIREMENTS  
A central laboratory will analyze the clinical laboratory safety samples (hematology, serum 
chemistry) the serum pregnancy test and Urinalysis, as described in Section 1.5.4 for this study. 
Laboratory samples for safety and biomarker analyses (NTFs, anti-inflammatory markers and 
cytokines) will be sent to an independent laboratory for processing and analysis as specified by 
the Sponsor.  
1.12. INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS  
1.12.1. Ethics  
The Sponsor/Investigator will obtain, from the clinical sites 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 participants) for study recruitment.  

 
 
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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.  
Changes to the protocol to minimize or eliminate immediate hazards or to protect the life and 
well-being of research participants (e.g., to limit exposure to COVID-19) may be implemented 
without IRB approval or before filing an amendment to the IND (FDA guidance on Conduct of 
Clinical Trials of Medical Products during COVID-19 Pandemic). 
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) 
E6 Guidelines on GCP.  
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 protocol that significantly affects the 
safety of participants, the scope of the investigation, or the scientific quality of the study.  
Examples of clinical protocol changes requiring the submission of a Protocol Amendment 
include:  
• 
Any significant change in the number of participants 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 AE; or the dropping of a test intended to monitor the 
safety of the investigational drug.  
1.12.2. Data Quality Assurance  
1.12.2.1. 
Data Management  
Data from the study will be entered into a validated electronic 21CFR Part 11 compliant 
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.  
1.12.2.2. 
Electronic Case Report Forms (eCRFs)  
The study will use an electronic data capture system. All personnel accessing the electronic data 
capture system will be trained on the use of the system by the CRO responsible for data 
management. The CRO responsible for clinical data management will develop e-CRFs to 
collect all protocol-required data for this trial that will be recorded at the investigational sites. 
All eCRFs are to be filled out completely, reviewed, and signed by the Investigator or sub-
investigators listed on the Form FDA 1572.  

 
 
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Missing protocol-specified information (e.g., from missed study visits or study 
discontinuations) due to the COVID-19 pandemic as well as changes in study visit schedules, 
missed visits, or patient discontinuations that may lead to missing information for protocol-
specified procedures, should be captured in the electronic case report form as applicable, noting 
the reason for the missing data, including the relationship to the COVID-19 pandemic.  
1.12.2.3. 
Study Monitoring  
The Sponsor or designee will monitor this study in accordance with ICH E6 GCP guidelines as 
detailed in the monitoring plan. 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 eCRFs, it 
is mandatory that Sponsor representatives (e.g. study monitor) have direct access to original 
source documents (e.g. paper or electronic subject records, subject charts, and laboratory 
reports) needed to verify the entries on electronic case report forms. During the review of these 
documents, the anonymity of the subject 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 eCRFs at regular 
intervals throughout the study, to verify the adherence to the protocol, and the completeness 
and correctness of all eCRF 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.  
Study monitoring will be conducted in consideration of the outbreak of the COVID-19 
pandemic and in accordance with individual institutional guidelines.   
1.12.2.4. 
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 ICH E6 GCP guidelines and country specific regulations. If such 
audits 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.  
1.12.3. Investigational Product Accountability  
NurOwn® are autologous MSC-NTF cells prepared on a per-subject basis.  
At the end of the production process, the subject's MSC-NTF cells are loaded in the syringe and 
shipped to the medical center for transplantation.  
Any syringe not administered to the subject will be immediately discarded as biohazard waste.  
The manufacturing facility will be responsible for maintaining production records. The site will 
confirm that the syringe was administered to each subject at each treatment session.  

 
 
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1.12.4. 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 subject’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.  
1.12.5. Data recording/ eCRF Completion  
The eCRFs will be completed for each subject enrolled into the clinical study. The Investigator 
will review, approve and sign each completed eCRF; the Investigator’s signature serving as 
attestation of the Investigator’s responsibility for ensuring that all clinical and laboratory data 
entered on the eCRF 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-rays, etc. 
Information recorded on the eCRF shall match the Source Data recorded on the Source 
Documents.  
Any clinical study data that will be recorded directly on the eCRF, whereupon the eCRF data 
is to be considered the Source Data, will be identified.  
Subject names will not be supplied to the Sponsor. Participants will be identified by a unique 
subject number that will be recorded in the eCRF. Subject names appearing on any other 
document (e.g., 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 data 
protection laws. The participants 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.  
1.12.6. Record maintenance and retention  
The Sponsor and Investigator will maintain records in accordance with country specific 
regulations and ICH E6 GCP guidelines. 
The Investigator will retain the specified records and reports for up to 2 years or longer as per 
requirements of local or country specific regulations after the marketing application is approved 
for the investigational drug; or, if a marketing application is not submitted or approved for the 

 
 
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investigational drug, until 2 years after investigations under the IND have been discontinued 
and the FDA so notified.  
1.12.7. 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 and for any reason. 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.  
1.13. USE OF STUDY INFORMATION AND PUBLICATION  
All clinical and laboratory information and data obtained during the conduct of the study will 
be considered strictly confidential. Genetic samples and data will be handled with the same 
high standards of confidentiality as all clinical data and according to local and federal 
regulations. Written permission from the Sponsor is required before disclosing any data or 
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 at 
least 60 days before submission. 
 

 
 
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1.14. REFERENCES  
Brooks BR, Miller RG, Swash M, Munsat TL. El Escorial revisited: revised criteria for the 
diagnosis of amyotrophic lateral sclerosis. Amyotroph Lateral Scler Other Motor Neuron 
Disord. 2000; 1:293-9.  
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. 
Castrillo-Viguera C, Grasso DL, Simpson E, Clinical significance in the change of decline in 
ALSFRS-R. Amyotroph Lateral Scler. 2010; 11:178-80. 
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 
Little RJA. Pattern-Mixture models for multivariate incomplete data with covariates. 
Biometrics. 1996; 52: 98-111. 
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. 
Petrou P, Gothelf Y, Argov Z, Gotkine M, Levy YS, Kassis I, Vaknin-Dembinsky A, Ben-Hur 
T, Offen D, Abramsky O, Melamed E, Karussis D. Safety and Clinical Effects of Mesenchymal 
Stem Cells Secreting Neurotrophic Factor Transplantation in Patients With Amyotrophic 
Lateral Sclerosis: Results of Phase 1/2 and 2a Clinical Trials. JAMA Neurol. 2016 Mar; 
73(3):337-44. 
Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to 
statistical analysis using pattern mixture models. Pharmaceutical Statistics. 2013; 12: 337-47. 
Leonard H. van den Berg et al. Revised Airlie House consensus guidelines for design and 
implementation of ALS clinical trials Neurology 2019 92(14):e1610-e1623  
 
 

 
 
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1.15. APPENDICES  
1.15.1. Appendix 1: Listing of study activities  
1.15.1.1. 
Scheduled monitoring events  
Table 1 
Schedule of Assessments:  
Study Period 
Pre-treatment period 
Cells/Placebo Transplantation period 
Post-transplantation 
follow-up 
 
Screening period 
 
 
 
Visit  
V1 
V2 
V3 
V41 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V1412 
Procedure  
Screening 
ALSFRS-R 
Assessments 
Randomizatio
n 
BMA 
Cell 
Transplantation 
(T1) 
  
  
Cell 
Transplantation 
(T2) 
  
Cell 
Transplantat
ion (T3) 
 
 
 
Time 
Schedule 
Week -18-
20 
(± 7 days)  
Week -14 
to-16 
(± 7 days) 
Week -10 
to -12 
(± 7 days) 
Week -6 to-9 
Week -5 
to -610 
Day 0 - Day 311 
Week 2 
(± 3 
days) 
Week 4 
(± 3 
days) 
Week 811 (± 5 
days) 
 
Week 12 
(± 5 days) 
Week 1611 (± 
5 days) 
Week 
20 
(± 5 
days) 
Week 
24 
(± 5 
days) 
Week 
28 
(± 5 
days) 
Informed 
consent  
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
Eligibility 
criteria  
√ 
  
  
√ 
  
  
  
  
  
  
  
  
  
  
Demographic 
data  
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
Height  
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
Body weight  
√ 
  
√ 
  
  
√ 
  
 √ 
√ 
 √ 
√ 
√  
√ 
√ 
Physical 
examination  
√ 
  
  
  
  
√ 
  
√ 
√ 
√ 
√ 
√ 
√ 
√ 
12 lead ECG  
√ 
  
  
  
  
 √ 
  
  
 √ 
  
√ 
  
  
  
Vital signs2  
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 √ 
Medical 
History  
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
ALS Medical 
History 3 
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  

 
 
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Study Period 
Pre-treatment period 
Cells/Placebo Transplantation period 
Post-transplantation 
follow-up 
 
Screening period 
 
 
 
Visit  
V1 
V2 
V3 
V41 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V1412 
El Escorial 
Criteria  
√ 
  
  
  
  
  
  
  
  
  
  
  
  
  
ALSFRS-R4  
√ 
√ 
√ 
√ 
  
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Neurological 
Examination  
√ 
  
  
√ 
  
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Slow Vital 
Capacity 
(SVC)* 
√ 
  
  
  
  
 √ 
  
  
  √ 
  
  √ 
  
  
  √ 
Prior/Concom
itant 
medication 
review  
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 √ 
HIV 1 and 2  
√ 
  
  
√ 
  
  
  
  
  
  
  
  
  
  
HBV  
√ 
  
  
√ 
  
  
  
  
  
  
  
  
  
  
HCV  
√ 
  
  
√ 
  
  
  
  
  
  
  
  
  
  
Pregnancy 
test (for 
women with 
childbearing 
potential)  
√ 
  
  
√ 
  
  
  
√  
  
 √ 
  
  
  
 √ 
Hematology5 
√ 
  
  
√ 
  
√  
  
  
√ 
  
√ 
  
√ 
√ 
Blood 
biochemistry 6 
√ 
  
  
√ 
  
√ 
  
  
√ 
  
√ 
  
√ 
√ 
Coagulation 
tests 7  
√ 
  
  
√ 
  
√ 
  
  
√ 
  
√ 
  
 
 
Blood 
collection for 
biomarkers8 
  
  
  
  
  
√ 
√ 
√ 
√ 
√ 
√ 
√ 
 
 
Urinalysis 9  
√ 
  
  
√ 
  
√ 
  
  
√ 
  
√ 
  
√ 
 √ 
Bone marrow 
aspiration  
  
  
  
  
√ 
  
  
  
  
  
  
  
  
  
Transplant 
(IT)  
  
  
  
  
  
√ 
  
  
√ 
  
√ 
  
  
  
CSF 
collection  
  
  
  
  
  
√ 
√ 
√ 
√ 
√ 
√ 
√ 
  
  
Visual 
inspection of 
injection site  
  
  
  
  
  
√ 
  
  
√ 
  
√ 
  
  
  

 
 
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Study Period 
Pre-treatment period 
Cells/Placebo Transplantation period 
Post-transplantation 
follow-up 
 
Screening period 
 
 
 
Visit  
V1 
V2 
V3 
V41 
V5 
V6 
V7 
V8 
V9 
V10 
V11 
V12 
V13 
V1412 
Adverse 
events review 
  
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
C-SSRS  
√ 
  
  
  
  
  
  
  
  
  
√ 
  
  
√ 
Assessment 
of blinding 
(Subject, 
Investigator 
and person 
doing 
ALSFRS-R 
assessments)   
  
  
  
  
  
√ 
  
  
  
  
  
  
 
 √ 
Abbreviations: ALS=Amyotrophic Lateral Sclerosis; ALFRS-R=ALS Functional Rating Scale–Revised; CMV=cytomegalovirus; CSF=cerebral spinal fluid; 
C-SSRS=Columbia-Suicide Severity Rating Scale; ECG=electrocardiogram; HIV=human immune deficiency virus; HBV=hepatitis B virus; HCV=hepatitis C virus; 
IT=intrathecal; V=visit 
* SVC will be performed when permitted, following resolution of COVID-19 per institutional guidance 
1 
Driven by manufacturing availability. Prior to randomization complete a request for randomization form for Medical Monitor review and approval 
2 
,Blood pressure, Body temperature, Pulse and respiratory rate (after sitting for at least 3 minutes) 
3 
ALS Medical History to collect type and duration of ALS symptoms and Date of Diagnosis 
4 
Every effort will be made to collect the ALSFRS-R scores in-person, however by exception it may be collected by telephone. 
5 
Hematology: Complete blood count (red blood cells with indices, white blood cells with differential and platelet count, hemoglobin, hematocrit)  
6 
Blood Biochemistry: Sodium, Potassium, Calcium, Bicarbonate, blood urea nitrogen, Creatinine, Glucose, Chloride, Magnesium, Phosphorus, total protein, 
triglycerides, Total cholesterol, high-density lipoprotein, low-density lipoprotein, urea, total bilirubin, aspartate aminotransferase (glutamic oxaloacetic 
transaminase), alanine aminotransferase (glutamic pyruvic transaminase), alkaline phosphatase, uric acid  
7 
Coagulation: Prothrombin time (PT), Partial thromboplastin (PTT). 
8 
Blood samples for analysis of T regulatory cells will be collected at V6, V7 and V8 only 
9 
Urinalysis - Specific Gravity, pH, glucose, protein, ketones, blood 
10 Bone marrow derived mononuclear cells or MSC derived from the Bone Marrow aspirated at Visit 5, will be collected for DNA isolation and genetic analyses 
11 A more flexible window may be applied to the key study visits, Randomization (V4), BMA (V5), T1 (V6), T2 (V9) and T3 (V11) that are scheduled based on 
manufacturing availability.  

 
 
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12 An ET visit will be conducted only for participants who discontinue the study after treatment, post Visit 6. The ET visit will include all the procedures required 
at study Visit 14. For participants who refuse further clinic study visits, telephone contact by study staff shall be attempted and documented to review for 
adverse events at each scheduled visit through the remainder of study. 

 
 
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Table 2 
Detailed Schedule of Assessments for Cell Transplantation Visits (V6, V9 and V11) 
Estimated Time  
06:00-14:00 
12:00-
14:00 
14:00-
16:00 
16:00-
18:00 
19:00-
21:00  
08:00-
10:00 
12:00-
14:00 
  
Time\ Procedure  
Up to 6 hours 
before transplant 
Hr. 0 
Hr. 2 
(±15 min) 
Hr. 4 
(±15 min) 
Hr. 7 
(±30 min) 
Hr. 20 
(±30 min) 
Approxi
mately 
Hr. 24 
(±30 min) 
Hr. ≥ 24-72 (before 
discharge ±30 min) 
Admit to Inpatient Ward  
√ 
  
  
  
  
  
  
  
Body weight  
√ 
  
  
  
  
  
  
  
Physical Examination  
√ 
  
  
  
  
 
 √ 
  
Vital signs1 
√ 
  
√ 
√ 
√ 
√ 
√ 
√ 
12 lead ECG2 
√2 
  
  
  
  
  
√2 
  
ALSFRS-R 
√ 
  
  
  
  
  
  
  
Slow Vital Capacity (SVC)* 
√ 
 
 
 
 
 
 
 
Neurological Examination  
√ 
  
  
  
  
  
  
  
Concomitant medication review 3  
√ 
  
√ 
√ 
√ 
√ 
√ 
√ 
Hematology4  
√ 
  
  
  
  
√ 
  
  
Blood biochemistry5  
√ 
  
  
  
  
√ 
  
  
Urinalysis6  
√ 
  
  
  
  
√ 
  
  
Coagulation7  
√ 
  
  
  
  
√ 
  
  
Blood collection for biomarkers8 
√ 
  
  
  
  
√ 
  
  
Cell Transplant IT9  
  
√ 
  
  
  
  
  
  
Retention of CSF sample  
  
√ 
  
  
  
  
  
  
Visual inspection of injection site  
  
  
√ 
  
  
√9 
  
  
Adverse events review3  
√ 
  
√ 
√ 
√ 
√ 
√ 
√ 
C-SSRS10 
√ 
  
  
  
  
  
  
  
Assessment of blinding 
(Participant and Investigator)11 
 
 
 
 
 
 
 
√ 
Discharge from Inpatient Setting  
  
  
  
  
  
  
  
√ 

 
 
 
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Abbreviations: ALS=Amyotrophic Lateral Sclerosis; ALFRS-R=ALS Functional Rating Scale–Revised; CSF=cerebral spinal fluid; C-SSRS=Columbia-Suicide 
Severity Rating Scale ECG=electrocardiogram; IT=intrathecal 
* SVC will be performed when permitted, following resolution of COVID-19 per institutional guidance 
1 
Pulse rate, Blood pressure, Respiratory rate, Body temperature at the designated time-points. At 2, and 4 hours ± 15 minutes. At 8, 20 and 24 hours  ±30 
minutes 
2 
ECG will be performed at Visits 6, 9 and 11 – Time Window: +/- 30 min. 
3 
Concomitant medications and AEs will be monitored and ongoing data will be collected throughout the study visit, as necessary 
4 
Hematology: Complete blood count (Red blood cells with Indices, white blood cells with differential and platelet count, hemoglobin, hematocrit) - Time 
Window: +/- 30 min.  
5 
Blood Biochemistry: Sodium, Potassium, Calcium, Bicarbonate, blood urea nitrogen, Creatinine, Glucose, Chloride, Magnesium, Phosphorus, total protein, 
triglycerides, Total cholesterol, high-density lipoprotein, low-density lipoprotein, urea, total bilirubin, aspartate aminotransferase (glutamic oxaloacetic 
transaminase), alanine aminotransferase (glutamic pyruvic transaminase), alkaline phosphatase, uric acid - Time Window: +/- 30 min. 
6 
Urinalysis - Specific Gravity, pH, glucose, protein, ketones, blood.  Time Window: +/- 2 hours 
7 
Coagulation: Prothrombin time (PT), Partial thromboplastin time (PTT).  Time Window: +/- 30 min. 
8 
Blood samples for analysis of T regulatory cells will be collected at V6 only 
9 
Time Window: +/- 1 hour 
10 C-SSRS assessment will be performed at Visit 11 only. 
11 At Visit 6 assessment of blinding is performed prior to discharge 
 
 

 
 
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NurOwn® (MSC-NTF cells) 
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1.15.2. Appendix 2: ALSFRS-R 
The ALSFRS-R is an ordinal, validated rating scale used to evaluate level of impairment of 
patient with ALS in 12 functional activities. The 12 functional areas further group into four 
domains that encompass gross motor tasks, fine motor tasks, bulbar functions and respiratory 
function (Table 3). The ALSFRS-R motor score (gross and fine motor scores combined) will 
also be assessed. 
Each question is graded on a 5-point scale from 0 = unable to do to 4 = normal ability. 
Summation of all individual answers will be a reported score of 0 = worst to 48 = best. 
Summation of all answers within a domain will give the domain score.  
Table 3 
ALSFRS-R and Domains 
ALSFRS-R 
Question No 
Domain 
Functional activity 
1 
Bulbar 
Speech 
2 
Salivation 
3 
Swallowing 
4 
Fine Motor 
Handwriting 
5a 
Cutting food and handling utensils without 
gastrostomy 
5b 
Cutting food and handling utensils with 
gastrostomy 
6 
Dressing and hygiene 
7 
Gross Motor 
Turning in bed and adjusting bed clothes 
8 
Walking 
9 
Climbing stairs 
10 
Breathing 
Dyspnea 
11 
Orthopnea 
12 
Respiratory Insufficiency 
 

 
 
 
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1.15.3. Appendix 3: SVC 
SVC measures the maximum amount of air a subject can exhale in a single breath. SVC is 
reported as a percent of normal for gender, height, and age based on the highest of three trials 
as calculated in EDC.  
1.15.4. Appendix 4: C-SSRS 
Suicidal ideation and behavior is assessed using the Columbia-Suicide Severity Rating Scale 
(C-SSRS).  
The binary responses, yes or no, can be categorized in one of the following: 
Category 1 – Wish to be Dead  
Category 2 – Non-specific Active Suicidal Thoughts  
Category 3 – Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
Category 4 – Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
Category 5 – Active Suicidal Ideation with Specific Plan and Intent  
Category 6 – Preparatory Acts or Behavior  
Category 7 – Aborted Attempt 
Category 8 – Interrupted Attempt 
Category 9 – Actual Attempt (non-fatal) 
Category 10 – Suicidal Behavior 
The suicidal ideation score is the maximum suicidal ideation category (1-5 on the C-SSRS) 
present at the assessment. If no ideation is present, the suicidal ideation score is 0.  
A “yes” answer at any time during treatment to any one of the five suicidal ideation questions 
(categories 1-5) on the C-SSRS will be categorized as “Suicidal ideation”. A “yes” answer at 
any time during treatment to any one of the five suicidal behavior questions (categories 6-10) 
on the C-SSRS will be categorized as “Suicidal behavior”. A “yes” answer at any time during 
treatment to any one of the ten suicidal ideation and behavior questions (categories 1-10) on the 
C-SSRS will be categorized as “Suicidal ideation or behavior”. 
 
 

 
 
 
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1.15.5. Appendix 5: Procedure for IT transplantation of NurOwn® (MSC-NTF cells) or 
placebo 
The purpose of this document is to describe the procedure and define the basic requirements for 
Intrathecal (IT) transplantation of NurOwn® (MSC-NTF cells) or placebo in Brainstorm’s 
clinical trials.  
The procedure described here is based on common clinical practice (standard lumbar puncture 
procedure).  
1.15.5.1. 
Product Handling and injection procedures  
All syringes shall be gently rotated for 20-30 seconds until all cells are in suspension.  
Prior to 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 1.15.5.2. below).  
1.15.5.2. 
IT Injection Procedure:  
1. When performing IT transplantation of NurOwn® (MSC-NTF cells), the participant 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 5 mL syringe, with the plunger drawn back, is attached to the 2nd outlet of the stopcock, 
and approximately 4-5 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 the stopcock is 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 re-injected back only after the injection of the NurOwn® (MSC-NTF cells) 
or placebo as described below.  
7. A second syringe containing a 4 mL suspension of NurOwn® (MSC-NTF cells) or 
placebo is attached to the 3rd outlet of the valve, and the contents of the syringe are 
injected over roughly 2 minutes.  

 
 
 
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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 subject.  
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 shall be 
processed and transferred to storage at -80ºC within 1 hour of the completion of the 
procedure.  
11. The participant is typically asked to lie on his/her back for at least 2 hours, on a 
Trendelenburg position and is monitored for signs of neurological problems.