A Phase 2 Open-label Multicenter Study to Evaluate the Safety and Efficacy of Repeated Administration of NurOwn® [Autologous Mesenchymal Stem Cells Secreting Neurotrophic Factors (NTF), MSC-NTF] Cells in Participants With Progressive MS
Phase: PHASE2
Conditions: Multiple Sclerosis, Chronic Progressive
Sponsor: Brainstorm-Cell Therapeutics

 
1 
 
Study Title: 
A Phase 2, open-label, multicenter study to evaluate the safety and efficacy of repeated 
administration of NurOwn® (Autologous Mesenchymal Stem Cells Secreting 
Neurotrophic Factors; MSC-NTF cells) in participants with Progressive Multiple Sclerosis 
(MS)  
 
NCT: NCT03799718 
 
June 2019  
 
 
 
 
 

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 1 of 59 
 
Confidential 
 
Clinical Study Protocol 
BCT-101-US 
 
A PHASE 2, OPEN-LABEL MULTICENTER STUDY TO 
EVALUATE THE SAFETY AND EFFICACY OF 
REPEATED ADMINISTRATION OF NUROWN® 
(AUTOLOGOUS MESENCHYMAL STEM CELLS 
SECRETING NEUROTROPHIC FACTORS; MSC-NTF 
CELLS) IN PARTICIPANTS WITH PROGRESSIVE 
MULTIPLE SCLEROSIS (MS) 
 
IND 018615 
 
 
 
 
Brainstorm Cell Therapeutics, Ltd. 
3 University Plaza Drive, Suite 320  
Hackensack, NJ 07601 
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DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 2 of 59 
 
Confidential 
CLINICAL STUDY PROTOCOL [BCT-101-US]  
PROTOCOL TITLE 
A Phase 2, open-label, multicenter study to evaluate the safety and 
efficacy of repeated administration of NurOwn® (Autologous 
Mesenchymal Stem Cells Secreting Neurotrophic Factors; MSC-NTF 
cells) in participants with Progressive Multiple Sclerosis (MS)  
PROTOCOL NUMBER  BCT-101-US 
STUDY DESIGN 
(PHASE)  
Phase 2  
PROTOCOL  
DATE/VERSION  
June 2019/Amendment 1.1 
IND NUMBER  
IND 018615 
INVESTIGATIONAL 
PRODUCT  
NurOwn®: Mesenchymal Stromal Stem Cells Secreting Neurotrophic 
Factors (MSC-NTF cells)  
INDICATION  
Progressive Multiple Sclerosis (MS) 
SPONSOR  
Brainstorm Cell Therapeutics, Ltd.  
3 University Plaza Drive, Suite 320  
Hackensack, NJ 07601 
PRINCIPAL 
INVESTIGATOR  
Jeffrey Cohen, MD. Director, Mellen Center for MS, Cleveland Clinic 
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, Ltd. 
("Brainstorm"). The information in this document is confidential and may not be disclosed to 
others without the prior written authorization of Brainstorm, except to the extent necessary to 
obtain informed consent from persons receiving the investigational product or their legal 
guardians, or for discussions with local regulatory authorities, institutional review boards, ethics 
committees, or persons participating in the conduct of the study. 
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Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 3 of 59 
 
Confidential 
PROTOCOL APPROVAL  
A Phase 2 open-label multicenter study to evaluate the safety and efficacy of repeated 
administration of NurOwn® (Autologous Mesenchymal Stem Cells Secreting Neurotrophic 
Factors; MSC-NTF cells) in participants with Progressive Multiple Sclerosis (MS). 
Approved by: 
Name  
Title/Company  
Signature 
Date 
Yael Gothelf, Ph.D.  
VP Regulatory Affairs  
Brainstorm Cell Therapeutics  
 
 
Susan Ward Ph.D. 
Head of Clinical Operations  
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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June 21, 2019 | 8:32 AM EDT
June 21, 2019 | 8:32 AM EDT
June 21, 2019 | 8:32 AM EDT
June 21, 2019 | 5:07 AM PDT
June 21, 2019 | 8:13 AM EDT
June 20, 2019 | 4:30 PM EDT
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Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 4 of 59 
 
Confidential 
INVESTIGATOR’S AGREEMENT  
 
 
I have received and read the Clinical Protocol BCT-101 US, for Brainstorm Cell Therapeutics, 
Ltd. 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.  
  
  
  
Jeffrey Cohen, MD 
 
Printed Name of Investigator  
  
  
 
Signature of Investigator  
  
  
 
Date  
 
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June 21, 2019 | 3:10 PM EDT

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 5 of 59 
 
Confidential 
STUDY SYNOPSIS  
Name of Sponsor 
Brainstorm Cell Therapeutics, Ltd. 
3 University Plaza Drive, Suite 320  
Hackensack, NJ 07601 
Investigational Product 
NurOwn®: Mesenchymal Stem Cells Secreting Neurotrophic Factors 
(MSC-NTF cells) 
Indication  
Progressive Multiple Sclerosis (MS) 
Study number 
BCT-101-US 
Title of Study 
A Phase 2, Open-label, Multicenter Study to Evaluate Efficacy and 
Safety of Repeated Administration of NurOwn® (Autologous 
Mesenchymal Stem Cells Secreting Neurotrophic Factors; MSC-NTF 
cells) in Participants with Progressive MS 
Protocol Date/Version 
June 2019/Amendment 1.1 
OBJECTIVES 
To determine the safety and efficacy of repeated administration of intrathecal injections (doses) of NurOwn® 
(MSC-NTF: autologous Mesenchymal Stem Cells [MSC] Secreting Neurotrophic Factors [NTF]) given three 
times at two monthly intervals to participants with Progressive MS. 
Primary: 
• 
To evaluate safety and tolerability of 3 intrathecal (IT) doses of NurOwn® (MSC-NTF cells)   
Secondary:  
• 
To evaluate the efficacy of NurOwn® using improvement in either Timed 25-foot walk (T25FW) speed 
or 9-Hole Peg Test (9HPT) 
• 
To evaluate the modulation of cerebrospinal fluid (CSF) and blood biomarkers (neurotrophic factors, 
neurodegenerative, and inflammatory biomarkers) following NurOwn® transplantation 
• 
To evaluate the efficacy of NurOwn® using: 
• 
The Expanded Disability Status Scale (EDSS). 
• 
The 12 item MS Walking Scale (MSWS-12) 
• 
Physical function (including average daily step count using a wrist wearable sensor) 
• 
Low Contrast Letter Acuity (LCLA)  
• 
Symbol Digit Modalities Test (SDMT)  
• 
MSFC Composite scores 
METHODOLOGY 
Study Design 
This is an open-label study with a single treatment arm involving 20 participants with 
progressive MS at multiple investigational study sites. After providing informed consent, 
participants meeting the inclusion and exclusion criteria will be enrolled and 1- 4 weeks later 
will undergo a bone-marrow aspiration (BMA). The first IT transplantation will be at Visit 3 
(Day 0), 6-10 weeks after screening/enrollment visit, with the subsequent transplantations at 
Visit 4 (Week 8) and Visit 5 (Week 16). Following the third and last treatment, participants 
will be followed for 12 weeks with two additional visits, approximately 6 weeks apart. 
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Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 6 of 59 
 
Confidential 
Study Schematic 
 
Study Duration 
Approximately 38 weeks (up to 10 weeks pre-treatment and 28 weeks post-treatment). 
Number of sites 
This is a multi-center phase 2 study to be conducted at 5 US Medical Centers.  
Treatments 
Three NurOwn® (MSC-NTF cells) treatments will be given by intrathecal administration 
every two months. 
Randomization  
None 
Treatment 
Duration 
Each subject’s participation in the study will last for approximately 38 weeks (9-10 
months), consisting of: 
• 
An approximate 10-week pretreatment period during which participants will 
undergo bone marrow aspiration and baseline evaluations 
• 
A 16-week treatment period during which participants will be administered 3 doses 
of NurOwn® (MSC-NTF cells) at 8-week intervals (Day 0-1, week 8, and week 
16), 
• 
A 12-week follow-up period 
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 100-125 x106 cells for IT administration. 
Dose and Route 
of 
Administration  
Doses of 100-125 x106 NurOwn® (MSC-NTF cells) transplanted intrathecally at visits 3, 4 
and 5.   
Concomitant 
Excluded 
Therapy 
Current use of immunosuppressive medication or use of such medication within 6 months 
of study enrollment (aside from approved B-cell immunotherapy).  Alemtuzumab 
(Lemtrada), Cladribine (NDA submitted), Natalizumab (Tysabri), S1P modulators 
(Gilenya) pulse intravenous methylprednisolone (IVMP, 1 gram) to treat a relapse within 
the 6 months prior to study entry or other investigative MS therapies. However, a single 
dose of IVMP 100 mg as part of the Ocrevus (or Rituxan) infusion protocol q6M is not 
exclusionary and would be allowed in the study. 
SUBJECT POPULATION 
Number of 
Participants  
20 total participants (approximately 4 participants per site) 
↓Phone-call follow-up
CSF collection at each Transplantation visit
In-person visits
BMA: Bone Marrow Aspiration
Visit#:     1             2                   3 T
4 T
5 T                 6
7
-10
Screening\
Enrollment 
BMA
~ 9-10 months
-6
0
T1
T2
8
T3
16
22
Week
28
Pre-treatment period                 Treatment Period                      Follow-up period
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Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 7 of 59 
 
Confidential 
Major Inclusion 
Criteria 
1. Males and females ages 18 to 65 years old, inclusive, at the Screening Visit (Visit 1).  
2. Clinical diagnosis of Progressive MS (Primary and Secondary) based on the 2017 
revised MacDonald Criteria and confirmation by the Investigator that the disease has 
entered the progressive stage at least 6 months prior to enrollment. 
3. No evidence of clinical MS relapse or high dose pulse corticosteroid treatment within 6 
months prior to screening 
4. Disability status at screening with an Expanded Disability Status Scale (EDSS) 3.0-6.5. 
5. Able to walk 25 feet in 60 seconds or less.  
6. Stable dose of non-excluded MS Disease Modifying Therapy for at least 6 months prior 
to Screening Visit (Visit 1). 
Major Exclusion 
Criteria 
1. Prior stem cell therapy of any kind.  
2. Active participation in any other MS interventional study or of unapproved MS 
investigational therapy within 90 days prior to the Screening Visit (Visit 1).  
3. Inability to lie flat for the duration of intrathecal cell transplantation and/or bone 
marrow aspiration, or inability to tolerate study procedures for any other reason.  
4. History of clinically significant autoimmune disease (excluding thyroid disease) that 
may confound study results, myelodysplastic or myeloproliferative disorder, leukemia 
or lymphoma, whole body irradiation, hip fracture, or severe scoliosis.  
5. Any unstable clinically significant medical condition other than multiple sclerosis (e.g., 
within six months of Screening Visit (Visit 1), had myocardial infarction, angina 
pectoris, and/or congestive heart failure), any clinically significant coagulopathy, 
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, except for non-melanoma 
localized skin cancers (with no evidence of metastasis, significant invasion, or re-
occurrence within three years of Screening Visit (Visit 1)).   
7. Current use of immunosuppressant medication or use of such medication within 6 
months of study enrollment (aside from approved B-cell immunotherapy). 
8. Any history of acquired or inherited immune deficiency syndrome.  
9. Pregnant women or women currently breastfeeding.  
10. Subjects for whom MRI is contraindicated (i.e., have a pacemaker or other metallic 
implanted device) or are unable to remain in the machine for period of time needed to 
acquire a scan. 
11. Positive test result for Hepatitis B virus (HBV; surface antigen (HBsAg) and antibodies 
to core antigen (IgG and IgM anti-HBc)), Hepatitis C virus (HCV), Human Immune 
deficiency Virus (HIV) 1 and 2. 
ASSESSMENTS 
Safety  
Changes in vital signs and physical examination findings, hematology, blood chemistry, 
urinalysis, AEs, and changes in concomitant medications. New MRI lesions (new - or 
newly enlarging – T1 and T2 weighted images will be evaluated for safety). 
Efficacy 
Efficacy assessments will be based upon: T25FW, 9-HPT, blood and CSF biomarkers, 
EDSS, MSWS-12, Physical function measured with wearable sensor, LCLA, and SDMT.  
The efficacy endpoints are further described in the statistical section below.  
Biomarkers 
Paired CSF samples and serum samples will be collected prior to each intrathecal 
administration of MSC-NTF cells. CSF and/or blood samples will be evaluated for levels of 
disease and other relevant biomarkers (such as neurotrophic and inflammatory factors, 
miRNAs and other relevant cytokines) and their potential relation to efficacy outcomes.  
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IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 8 of 59 
 
Confidential 
DATA SAFETY MONITORING BOARD 
DSMB 
An independent Data Safety Monitoring Board (DSMB) will be established for the study. The 
DSMB will review key safety and efficacy data (at intervals and as requested) as outlined in 
the DSMB charter. 
STATISTICAL METHODS AND ANALYSIS 
Sample Size 
Calculation 
No formal sample size calculation is performed. Efficacy and safety data in the 20 
participants will provide information to inform the design of a future randomized study. 
Efficacy 
Efficacy analyses will be performed using the modified intent to treat (mITT) and Efficacy 
Evaluable (EE) populations. The mITT population will be defined as all participants who 
received at least one treatment and had at least one T25FW or a 9HPT assessment post 
treatment. The EE population will be defined as a subset of the mITT population that 
receive all 3 treatments and do not have any important protocol deviations impacting 
efficacy evaluation. If the EE population is identical or very similar to the mITT population, 
analyses may only be generated for the mITT population. 
Efficacy assessments will be based upon, T25FW, 9-HPT, blood and CSF biomarkers, 
EDSS, MSWS-12, Physical function measured with wearable sensor outputs LCLA and 
SDMT. 
Efficacy analyses of continuous data will be based upon change from baseline to each post-
baseline timepoint. Baseline will be defined as the last measurement prior to the first 
treatment.  
Responder analyses will compare the proportion of responders using various definitions of 
responders for the different efficacy endpoints. 
Safety 
All safety analyses will be conducted on the Safety Population, which will be defined as all 
participants who were enrolled and had at least one transplantation performed. 
Only observed data will be analyzed and no imputations will be performed for any missing 
safety data. 
Safety analysis of continuous data will be based upon change from baseline to each post-
baseline timepoint.  Baseline will be defined as the last measurement prior to the first 
treatment.  
Abnormalities in hematology, blood chemistry, MRI and electrocardiogram (ECG) 
assessment will be summarized.  
Biomarkers 
 
Paired CSF and blood samples will be analyzed for the disease relevant biomarkers and 
their relationship to efficacy outcomes. In addition, relationships between neurotrophic 
factors, inflammatory markers, miRNAs and clinical outcomes will be evaluated to 
determine if any biomarkers can be predictive of treatment outcome. 
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IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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TABLE OF CONTENTS 
Description 
Page 
CLINICAL STUDY PROTOCOL ...............................................................................................1 
CLINICAL STUDY PROTOCOL [BCT-101-US] .....................................................................2 
PROTOCOL APPROVAL ...........................................................................................................3 
STUDY SYNOPSIS .......................................................................................................................5 
ABBREVIATIONS ......................................................................................................................14 
1. 
INTRODUCTION .....................................................................................................17 
1.1. 
STUDY OBJECTIVES .............................................................................................19 
1.1.1. 
Primary objectives ......................................................................................................19 
1.1.2. 
Secondary Objectives .................................................................................................19 
2. 
INVESTIGATIONAL PLAN...................................................................................20 
2.1. 
OVERALL STUDY DESIGN AND PLAN ............................................................20 
2.2. 
STUDY SCHEMATIC .............................................................................................21 
2.3. 
TREATMENT PLAN ...............................................................................................22 
2.3.1. 
Bone Marrow aspiration procedure ..........................................................................22 
2.3.2. 
Intrathecal Transplant Procedure .............................................................................22 
2.4. 
DURATION OF STUDY ..........................................................................................23 
2.5. 
DISCUSSION OF DOSE ..........................................................................................23 
2.6. 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL 
GROUP ......................................................................................................................23 
3. 
PATIENT POPULATION .......................................................................................23 
3.1. 
INCLUSION CRITERIA .........................................................................................24 
3.2. 
EXCLUSION CRITERIA ........................................................................................24 
4. 
STUDY ASSESSMENTS .........................................................................................25 
4.1. 
CSF AND BLOOD COLLECTION FOR ASSESSMENTS OF 
BIOMARKERS .........................................................................................................26 
4.2. 
MRI ............................................................................................................................26 
4.3. 
WEARABLE SENSOR DEVICE ............................................................................26 
4.4. 
CLINICAL LABORATORY SAFETY TESTS .....................................................26 
4.5. 
PHYSICAL EXAMINATIONS, VITAL SIGNS, AND 
ELECTROCARDIOGRAMS ..................................................................................27 
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IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
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4.6. 
PRE-TRANSPLANTATION VISITS .....................................................................27 
4.6.1. 
Visit 1: Screening Visit...............................................................................................27 
4.6.2. 
Visit 2: Bone Marrow Aspiration Visit (Week -5, - -6) .............................................28 
4.7. 
TRANSPLANTATION VISITS ..............................................................................29 
4.7.1. 
Visit 3 (T1): 1st Cell Transplantation (Day 0- up to Day 1) ......................................29 
4.7.2. 
Visit 3T: Post-transplant follow-up telephone call visit (Week 1-2) ........................30 
4.7.3. 
Visit 4 (T2): 2nd Cell Transplantation (Week 8) ........................................................30 
4.7.4. 
Visit 4T: Post-transplant follow-up telephone call visit (Week 9-10) ......................31 
4.7.5. 
Visit 5 (T3): 3rd Cell Transplantation (Week 16) ......................................................31 
4.8. 
POST TRANSPLANTATIONS FOLLOW-UP .....................................................32 
4.8.1. 
Visit 5T: Post-transplant follow-up telephone call visit (Week 17-18) ....................32 
4.8.2. 
Visit 6: Week 22 (± 5 days) Follow-Up ......................................................................33 
4.8.3. 
Visit 7: Week 28 (± 5 days) Follow-Up ......................................................................33 
4.9. 
SAFETY FOLLOW-UP ...........................................................................................34 
4.10. 
LOST TO FOLLOW-UP..........................................................................................34 
5. 
INVESTIGATIONAL PRODUCT INFORMATION ...........................................34 
5.1. 
GENERAL INFORMATION ..................................................................................34 
5.2. 
NUROWN® (MSC-NTF CELLS) PRODUCT CHARACTERISTICS ...............35 
6. 
PRIOR AND CONCOMITANT THERAPY .........................................................35 
6.1. 
PRIOR THERAPY ...................................................................................................35 
6.2. 
CONCOMITANT AND EXCLUDED THERAPY ................................................35 
6.3. 
ANTICOAGULATION THERAPY .......................................................................36 
7. 
SAFETY REPORTING ............................................................................................36 
7.1. 
ADVERSE EVENTS DEFINITIONS .....................................................................36 
7.1.1. 
Adverse Event (21 CFR 312.32(a)) ............................................................................36 
7.1.2. 
Serious Adverse Event (21 CFR 312.32(a)) ..............................................................37 
7.1.3. 
Relatedness (Causality) ..............................................................................................37 
7.1.4. 
Severity (Intensity) .....................................................................................................38 
7.1.5. 
Follow-Up of AEs .......................................................................................................38 
7.1.6. 
Outcome ......................................................................................................................38 
7.1.7. 
Clinically Significant Laboratory Abnormalities ......................................................39 
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7.2. 
REPORTING RESPONSIBILITIES AND PROCEDURES FOR AES AND 
SAES ...........................................................................................................................39 
7.3. 
REPORTING RESPONSIBILITIES AND PROCEDURES FOR 
PREGNANCIES........................................................................................................40 
7.4. 
PROSPECTIVE ASSESSMENT OF THE OCCURRENCE OF 
SUICIDALITY ..........................................................................................................41 
8. 
STUDY DISCONTINUATION ...............................................................................41 
8.1. 
STUDY OR SITE TERMINATION .......................................................................41 
8.2. 
SUBJECT WITHDRAWAL FROM STUDY ........................................................42 
8.3. 
TEMPORARY DISCONTINUATION FROM THE STUDY..............................42 
9. 
ASSESSMENT OF ENDPOINTS ...........................................................................43 
9.1. 
PRIMARY ENDPOINT ...........................................................................................43 
9.1.1. 
Safety ..........................................................................................................................43 
9.2. 
SECONDARY ENDPOINTS ...................................................................................43 
9.2.1. 
Timed 25-foot walking speed (T25FW) or 9-Hole Peg Test (9-HPT) ......................43 
9.2.2. 
Modulation of Cerebrospinal Fluid (CSF) and blood Biomarkers: ........................43 
9.2.3. 
The Expanded Disability Status Scale (EDSS) .........................................................43 
9.2.4. 
The Multiple Sclerosis Walking Scale (MSWS-12) ..................................................43 
9.2.5. 
Daily average step count and other measures of Physical Activity ..........................43 
9.2.6. 
Low Contrast Letter Acuity (LCLA) ..........................................................................43 
9.2.7. 
The Symbol Digit Modalities test (SDMT) ................................................................44 
9.3. 
STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION ...........44 
9.3.1. 
Sample Size Determination ........................................................................................44 
9.3.2. 
Statistical Methods .....................................................................................................44 
9.3.3. 
Analysis Population ...................................................................................................44 
9.3.4. 
Efficacy Analyses .......................................................................................................44 
9.3.5. 
Safety analyses ...........................................................................................................46 
9.3.6. 
Biomarker Analysis ....................................................................................................46 
10. 
STUDY COMMITTEES AND COMMUNICATIONS ........................................47 
10.1. 
DATA AND SAFETY MONITORING BOARD (DSMB) ....................................47 
11. 
LABORATORY REQUIREMENTS ......................................................................47 
12. 
INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS .....................47 
12.1. 
ETHICS......................................................................................................................47 
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12.2. 
DATA QUALITY ASSURANCE ............................................................................48 
12.2.1. 
Data Management ......................................................................................................48 
12.2.2. 
Electronic Case Report Forms (eCRFs)....................................................................48 
12.2.3. 
Study Monitoring .......................................................................................................48 
12.3. 
STUDY AUDITS .......................................................................................................48 
12.4. 
INVESTIGATIONAL PRODUCT ACCOUNTABILITY....................................49 
12.5. 
COMPENSATION, INSURANCE, AND INDEMNITY ......................................49 
12.6. 
DATA RECORDING/ ECRF COMPLETION ......................................................49 
12.7. 
RECORD MAINTENANCE AND RETENTION .................................................50 
12.8. 
STUDY TERMINATION.........................................................................................50 
13. 
USE OF STUDY INFORMATION AND PUBLICATION ..................................50 
14. 
REFERENCES ..........................................................................................................50 
15. 
APPENDICES ...........................................................................................................51 
15.1. 
APPENDIX 1: LISTING OF STUDY ACTIVITIES ............................................51 
15.1.1. 
Scheduled monitoring events .....................................................................................51 
Table 1. 
Schedule of Assessments: ..........................................................................................52 
15.2. 
APPENDIX 2: EFFICACY OUTCOME MEASURES .........................................55 
15.2.1. 
Multiple Sclerosis Functional Composite (MSFC) ..................................................55 
15.2.2. 
Timed 25 Foot Walk (T25FW) ..................................................................................55 
15.2.3. 
9-Hole Peg Test (9-HPT) ...........................................................................................55 
15.2.4. 
Expanded Disability Status Scale (EDSS, Kurtzke)..................................................56 
15.2.5. 
Multiple Sclerosis Walking Scale (MSWS-12)..........................................................57 
15.2.6. 
Low Contrast Letter Acuity (LCLA) ..........................................................................58 
15.2.7. 
Symbol Digit Modalities Test (SDMT) ......................................................................58 
15.3. 
APPENDIX 3: C-SSRS .............................................................................................59 
 
 
 
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List of Tables 
Description 
Page 
Table 1. 
Schedule of Assessments: .........................................................................................52 
Table 2. 
Detailed Schedule of Assessments for Cell Transplantation 
Visits (V3, V4, and V5) .............................................................................................54 
Table 3. 
Kurtzke Expanded Disability Status Scale (EDSS) ...............................................56 
 
List of Figures 
Description 
Page 
Figure 1. 
Clinical study flowchart ...........................................................................................21 
 
 
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ABBREVIATIONS  
9-HPT 
9-Hole Peg Test  
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  
CFR 
Code of Federal Regulations 
CNS 
Central nervous system  
CSF 
Cerebrospinal Fluid  
C-SSRS 
Columbia-Suicide Severity Rating Scale  
DSMB 
Data and Safety Monitoring Board  
ECG 
Electrocardiogram  
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
EDSS 
Expanded Disability Status Scale  
EE 
Efficacy Evaluable Analysis Set  
EMG 
Electromyography 
ET 
Early Termination 
FDA 
Food and Drug Administration 
FS 
Functional System 
FVC 
Forced Vital Capacity  
GCP 
Good Clinical Practice 
GDNF 
Glial Derived Neurotrophic Factor  
GOT 
Glutamic oxaloacetic transaminase 
GPT 
Glutamic pyruvic transaminase 
Hb 
Hemoglobin 
HBV 
Hepatitis B virus 
HCV 
Hepatitis C virus 
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HDL 
High-density lipoprotein 
HGF 
Hepatocyte Growth Factor  
HIV 
Human immunodeficiency virus 
hMSCs 
Human Mesenchymal Stem Cells 
Ht 
Hematocrit 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonization 
IM 
Intramuscular 
IND 
Investigational New Drug 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board  
IT 
Intrathecal  
IVMP 
Intravenous methylprednisolone 
LCLA 
Low Contrast Letter Acuity 
LDL 
Low-density lipoprotein 
MedDRA  
Medical Dictionary for Regulatory Activities  
MI 
Multiple imputations 
mITT 
Modified intent to treat 
MRI 
Magnetic Resonance Imaging 
MS 
Multiple sclerosis 
MSC  
Mesenchymal Stem Cells  
MSC-NTF 
Mesenchymal Stem Cells Secreting Neurotrophic Factors  
MSFC 
Multiple Sclerosis Functional Composite 
MSWS-12 
12 item MS Walking Scale  
MVIC 
Maximum Voluntary Isometric Contraction 
NIV 
Non-invasive Ventilation 
NTF 
Neurotrophic Factors  
PPMS 
Primary progressive multiple sclerosis 
PT 
MedDRA Preferred Term  
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
RBC 
Red blood cells 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan  
SDMT 
Symbol Digit Modalities test  
SOA 
Schedule of Assessments  
SOC 
MedDRA System Organ Class  
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SPMS 
Secondary progressive multiple sclerosis 
T25FW 
Timed 25-foot Walk  
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. INTRODUCTION 
Multiple sclerosis (MS) may be caused by an autoimmune response to self-antigens in a genetically 
susceptible individual.  Symptoms of MS usually appear between the ages of 20 and 40 and affect 
1 million individuals in the US.  Approximately 50% of MS patients eventually develop 
progressive disease associated with increasing levels of motor, visual and cognitive functional 
impairment and disability.  Progressive MS can occur at disease onset (primary progressive) or 
more commonly be preceded by a relapsing disease course (secondary progressive)1,2. The loss of 
mobility and accumulating neurological dysfunction has an enormous impact on social 
functioning, activities of daily living, employment and socioeconomic status3.   
In progressive MS, the long-term accumulation of brain injury caused by inflammation, 
demyelination, axonal damage, neuronal degeneration and gliosis in both white and gray matter, 
is currently without effective therapy.  While inflammatory mechanisms predominate in the early 
stages of the disease, reflected most directly in relapses and Magnetic Resonance Imaging (MRI)-
detected lesion activity, in progressive MS there is gradual worsening of disability and 
neurodegeneration that progresses independent of relapses.  Central nervous system (CNS) repair 
processes do exist in MS; however, they are not able to fully compensate for the damage that is 
ongoing in most patients.  
Currently approved MS treatments primarily target CNS inflammation and are most effective 
when introduced early in the disease course, before the progressive phase of disease has started 
and in patients with significant inflammation as measured by standard brain MRI parameters1. 
Treatment strategies to prevent tissue damage or increase repair, remyelination and axonal 
regeneration, are greatly needed. Cell therapies, due to their combined immunomodulatory, 
neuroprotective and neuro-regenerative properties, make them an attractive candidate therapy. 
BrainStorm has developed a proprietary process based on autologous Mesenchymal Stem Cells 
(MSC) which are propagated ex-vivo and induced to differentiate into neurotrophic factor (NTF) 
secreting cells, designated MSC-NTF cells (NurOwn®).  A repeat dose randomized (1:1) placebo-
controlled US phase 3 study of NurOwn® in 200 ALS patients is currently underway.  Study 
participants are receiving 3 intrathecal administrations of cells or placebo 2 months apart.  Three 
previous ALS studies have demonstrated the feasibility, safety and tolerability of intrathecal 
administration of NurOwn® and a well characterized safety profile.  
The intrinsic immunomodulatory properties of MSC-NTF cells, the potential of neurotrophic 
factors to promote neuronal repair and remyelination, the ease of access of intrathecally 
administered MSC-NTF cells to areas of the brain and spinal cord, and the documented and 
growing NurOwn® safety experience in amyotrophic lateral sclerosis (ALS), makes intrathecal 
repeated administration of NurOwn® an attractive treatment candidate to evaluate in an open label 
study in progressive MS patients. 
                                                 
 
1 Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: The 2013 revisions. 
Neurology. 2014; 83(3):278–286. Revised definitions of SPMS which may help recruitment into clinical trials.  
2 Lorscheider et al. Defining secondary progressive multiple sclerosis. Brain 2016: 139; 2395–2405   
3 Salter AR, Cutter GR, Tyry T, Marrie RA, Vollmer T. Impact of loss of mobility on instrumental activities of daily 
living and socioeconomic status in patients with MS. Curr Med Res Opin. 2010; 26:493–500   
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Amendment 1.1, June 2019 
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Neurotrophic factors (NTFs) are potent survival factors for embryonic, neonatal, and adult neurons 
and are considered potential therapeutic candidates for MS. Delivery of multiple NTFs to the 
immediate environment of afflicted neurons in MS patients is expected to improve their survival 
and thus slow down disease progression and alleviate symptoms. NTF-secreting mesenchymal 
stem cells (MSC-NTF cells) are a novel cell-therapeutic approach aimed at effectively delivering 
NTFs directly to the site of damage in MS patients. 
The NurOwn® (MSC-NTF cells) therapy is based on transplantation of autologous bone marrow 
derived mesenchymal stem 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.  
NurOwn®, delivered by repeat intrathecal administration every 2 months, has the potential to 
address the unmet need in progressive MS through its unique combination of immunomodulation 
and neurotrophic factor support delivered directly to the areas of injury within the brain and spinal 
cord.  It is expected that study biomarkers may potentially inform the issue of duration of NurOwn® 
therapy and selection of optimal responders.  
NurOwn® (MSC-NTF cells) has been evaluated in two open label clinical studies and in 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 intrathecal (IT) or by 
the intramuscular (IM) route of administration as well as by the combined IT and IM 
administration, and showed some initial indications of efficacy, when administered to patients with 
ALS, 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 in a cohort of 6 early stage ALS patients (ALS Functional Rating Scale–Revised, 
ALSFRS-R score ≥25) and intrathecally 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 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.  
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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 MRI of the upper extremities, upper and lower extremities 
circumference, electromyography (EMG) parameters1. 
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) showed it was well 
tolerated with majority of AEs being mild or moderate. In this study a significant improvement 
was observed in the total ALSFRS-R scores based upon percent improvement in slope, 
post-transplantation compared to pre-transplantation in a pre-specified subgroup of rapid 
progressors.  
The purpose of the proposed BCT-101-US Phase 2 study is to evaluate the safety and efficacy of 
three successive administrations of intrathecal injections of NurOwn® (MSC-NTF cells) given 
every two months to participants with progressive MS (EDSS 3-6.5 at the Screening Visit). The 
clinical efficacy endpoints (Timed 25-Foot Walk [T25FW], 9-Hole Peg Test [9-HPT], Expanded 
Disability Status Scale [EDSS], 12 item MS walking scale [MSWS-12], Physical function 
measured with wearable sensor outputs, Low Contrast Letter Acuity [LCLA], and Symbol Digit 
Modalities test [SDMT]) and biomarkers will be assessed over the course of this study.  
1.1. 
STUDY OBJECTIVES  
To determine safety and efficacy of repeat administrations of IT injections of NurOwn®, 
autologous MSC-NTF cells given three times two months apart to participants with progressive 
MS. 
1.1.1. Primary objectives  
• To evaluate safety and tolerability of 3 IT doses of NurOwn® (MSC-NTF cells) 
1.1.2. Secondary Objectives 
• To evaluate the efficacy of NurOwn® using improvement in either Timed 25-Foot Walk 
(T25FW) speed or 9-Hole Peg Test (9HPT). 
• To evaluate the modulation of CSF and blood biomarkers (neurotrophic factors, 
neurodegenerative, and inflammatory biomarkers) following NurOwn® transplantation 
• To evaluate the efficacy of NurOwn® using: 
                                                 
 
1 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 
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▪ Expanded Disability Status Scale (EDSS) 
▪ 12 item MS walking scale (MSWS-12) 
▪ Physical function (as measured by average daily step count, etc. using a wrist 
wearable sensor) 
▪ Low Contrast Letter Acuity (LCLA) 
▪ Symbol Digit Modalities test (SDMT) 
▪ MSFC composite scores 
2. INVESTIGATIONAL PLAN  
2.1. 
OVERALL STUDY DESIGN AND PLAN  
This will be the fifth clinical study conducted by Brainstorm Cell Therapeutics to study autologous 
NurOwn® (MSC-NTF cells) in a neurodegenerative disease. 
The first three completed studies (two open label and one placebo-controlled study) in ALS patents 
demonstrated the safety of a single dose of NurOwn® administered either intramuscularly or 
intrathecally or by combined IM and IT administration. 
The ongoing Phase 3 double blind placebo-controlled study for 200 ALS patients (randomized 
1:1) will evaluate the safety and efficacy of three repeat transplantations, 2 months apart.  
This is a proof-of concept Phase 2 open label study that will be conducted in 20 participants with 
progressive MS with EDSS 3.0-6.5 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 9-10 months (38 weeks).  
During the up to 10-week pretreatment period patients will be screened and eligibility determined. 
Approximately 1-4 weeks after the screening visit, bone marrow will be harvested and transferred 
to the cell manufacturing facility for the isolation and cryopreservation of autologous MSCs. Prior 
to each treatment, MSC 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. The autologous manufacturing 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 
transplantation.  
The first transplantation visit (T1) will occur approximately 6 weeks after the bone marrow 
aspiration visit (6-10 weeks after screening/enrollment). The subsequent transplantation visits (T2 
and T3, at visits 4 and 5) will follow interspaced by approximately 8 weeks (±14 days) each (Figure 
1). The patients will then be followed for 12 additional weeks after the last transplant visit (T3) at 
two additional visits, approximately 6 weeks apart. 
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 two additional 
monthly visits (through week 28) during which the T25FW, 9HPT and other study outcomes will 
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be obtained, along with vital signs, laboratory tests and recording of concomitant medications and 
AEs (see schedule of assessments (SOA) in Table 1) 
2.2. 
STUDY SCHEMATIC 
The study comprises an up to 10-week pre-treatment period, an approximately 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 approximately 1-4 weeks following the first screening 
visit. The MSC isolation and cell propagation processes will last about 5-6 weeks and will be 
followed by NurOwn® (MSC-NTF cells) transplantation.  
At each transplantation visits, participants will be admitted to an inpatient study unit for study 
procedures and will be followed for up to 24 hours post transplantation.  
Following each treatment, participants will be assessed at visits described in 
. After receiving the third treatment dose (approximately 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 about 38 weeks (9-10 months) from the first 
visit (Figure 1).  
 
 
 
 
Figure 1. 
Clinical study flowchart 
 
Clinical study flowchart outlining the pre-treatment and the treatment period and the post-transplant follow-up 
visits.  BMA: Bone Marrow Aspiration; T1, T2 and T3, Transplantation visit 1, 2 and 3. T- Telephone call visit 
 
 
 
 
↓Phone-call follow-up
CSF collection at each Transplantation visit
In-person visits
BMA: Bone Marrow Aspiration
Visit#:     1             2                   3 T
4 T
5 T                 6
7
-10
Screening\
Enrollment 
BMA
~ 9-10 months
-6
0
T1
T2
8
T3
16
22
Week
28
Pre-treatment period                 Treatment Period                      Follow-up period
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2.3. 
TREATMENT PLAN 
2.3.1. 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 – 600 
mL bag, containing Heparin will be pre-labelled. The bone marrow aspirated from each single 
puncture (~5 ml), will be injected into the bag. 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.  
2.3.2. Intrathecal Transplant Procedure  
Participants will undergo a standard lumbar puncture followed by IT injection of cells. 
When performing the 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. 
Alternatively, the patient may be placed in a prone position.  
Prior to IT injections the syringe should be gently rotated for 20-30 seconds until all cells are in 
suspension.  
The spinal needle is inserted into the patient only once the cells are fully resuspended (in 
suspension). 
The area around the lower back is prepped using aseptic technique. A 20 G 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. 
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. 
The stylet from the spinal needle is then withdrawn for collecting about 5ml of CSF either directly 
from the spinal needle or after connecting a 3-way stopcock (such as Elcam Medical Cat. No. 
582682) to the spinal needle.  
Prior to the IT injection gently remove the syringe cap, with the syringe in the upright position. 
Slowly and carefully, push plunger up, until the cell suspension reaches the top of the syringe.  
Connect syringe to the 3-way stopcock, and inject the cells over at least 2 minutes.  
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. 
The procedure is completed by withdrawing the needle and immediately placing pressure on the 
puncture site.  
The participant is typically asked to lie on his/her back for at least 2 hours, in a Trendelenburg 
position and is monitored for signs of neurological problems. 
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2.4. 
DURATION OF STUDY  
Participants will be screened and eligible participants will be enrolled and will undergo viral safety 
testing within 7 days of the scheduled Bone Marrow Aspiration (BMA).  
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 will undergo IT administration of NurOwn® (MSC-NTF cells) on Day 0 
(Visit 3), Week 8 (Visit 4) and Week 16 (Visit 5). Following each cell transplantation, participants 
will be monitored as inpatients for a period of up to 24 hours. Participants will be discharged after 
up to 24 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 38 
weeks.  
2.5. 
DISCUSSION OF DOSE  
The IT transplantation dose (~125 x106 cells) is the dose of NurOwn® (MSC-NTF cells) that has 
been safely administered in the previous clinical trials in ALS study participants.  
2.6. 
DISCUSSION OF STUDY DESIGN, INCLUDING CHOICE OF CONTROL 
GROUP  
N/A. 
3. PATIENT POPULATION  
This study will be conducted in participants with a clinical diagnosis of Progressive MS (Primary 
and Secondary) with Diagnosis of MS based on the 2017 revised MacDonald Criteria1 and EDSS 
3.0-6.5, inclusive and have confirmation by the investigator that the disease has entered the 
progressive phase for at least 6 months prior to enrollment.  
This study will include primary (PPMS) and secondary progressive (SPMS) participants, as 
abundant clinical, imaging, and genetic data suggest that PPMS and SPMS form part of the 
spectrum of progressive MS phenotypes, and analyses of natural history cohorts demonstrate that 
clinical characteristics and rates of clinical worsening proceeds at a similar rate in SPMS and 
PPMS patients2. 
To be enrolled in this study, participants must meet all inclusion criteria in section 3.1 below and 
must not have any of the exclusion criteria listed in section 3.2.  
                                                 
 
1 Thompson AJ, et al. Diagnosis of multiple sclerosis: 2017 revisions of the McDonald criteria. Lancet Neurol. 2018; 
17(2):162-173. 
2 Confavreux C and Vukusic C. Natural history of multiple sclerosis: a unifying concept.  Brain 2006; 129: 606–616. 
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The participants' population is chosen from the group of MS 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.  
3.1. 
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 65 years old, inclusive, at the Screening Visit 
2. Clinical diagnosis of primary or secondary progressive MS (PPMS or SPMS) based on the 
2017 revised MacDonald Criteria and have confirmation by the Investigator that the disease 
has entered the progressive stage at least 6 months prior to enrollment.  
3. No evidence of clinical MS relapse or high dose pulse corticosteroid treatment within 6 
months prior to screening.  
4. Disability status at screening with an Expanded Disability Status Scale (EDSS) 3.0-6.5, 
inclusive  
5. Able to walk 25 feet in 60 seconds or less 
6. Stable dose of non-excluded MS Disease Modifying Therapy for at least 6 months prior to 
Screening Visit (Visit 1).  
7. 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, and at the conclusion of the study. Participants 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.  
8. Capable of providing informed consent and willing and able to follow study procedures, 
including willingness to undergo multiple/repeated lumbar puncture.  
3.2. 
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 MS interventional study or use of unapproved MS 
investigational therapy within 90 days prior to the Screening Visit (Visit 1).  
3. Inability to lie flat for the duration of intrathecal cell transplantation and/or bone marrow 
aspiration, or inability to tolerate study procedures for any other reason.  
4. History of clinically significant autoimmune disease (excluding thyroid disease) that may 
confound study results in the opinion of the Investigator and the medical monitor, 
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DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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myelodysplastic or myeloproliferative disorder, leukemia or lymphoma, whole body 
irradiation, hip fracture, or severe scoliosis. 
5. Any unstable clinically significant medical condition other than MS (e.g., within six months 
of Visit 1, had myocardial infarction, angina pectoris, and/or congestive heart failure), any 
clinically significant coagulopathy, treatment with anticoagulants that, in the opinion of the 
Investigator, would compromise the safety of the 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 the Screening Visit (Visit 1).  
7. Serum aspartate aminotransferase (AST) or alanine aminotransferase (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 (HBV; surface antigen (HBsAg) and antibodies to core antigen 
(IgG and IgM anti-HBc)), Hepatitis C (HCV), or human immunodeficiency virus (HIV) 1 
and 2.  
10. Current use of immunosuppressant medication or use of such medication within 6 months of 
study enrollment (aside from Rituximab or other approved B-cell immunotherapy). 
Alemtuzumab (Lemtrada), Cladribine (NDA submitted), Natalizumab (Tysabri), S1P 
modulators (Gilenya) are excluded for safety reasons due to the known risk of systemic 
autoimmune disease, malignancy, opportunistic infections, and cardiovascular toxicity 
associated with these therapies, as well as theoretical effects on MSC-NTF cell homing and 
migration, that may be associated with Natalizumab and/or S1P modulators (Gilenya).  
11. Any history of acquired or inherited immune deficiency syndrome.  
12. Any history of either substance abuse within the past year, or unstable psychiatric disease 
according to the Investigator's judgment.  
13. Pregnant women or women currently breastfeeding.  
14. Subjects for whom MRI is contraindicated (i.e., have a pacemaker or other metallic 
implanted device, or are unable to remain in the machine for period of time needed to acquire 
a scan. 
4. 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 key study visits, BMA (V2), T1 (V3), T2 (V4) and T3 (V5) 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 (T25FW, 9HPT, EDSS, 
MSWS-12, LCLA and SDMT) Appendix 3 (C-SSRS) and Appendix 4 (Procedure for IT 
transplantation of NurOwn® (MSC-NTF cells) 
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Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
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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 all sites.  
Any evaluator performing outcome measure/s assessments will be trained and certified. Outcome 
measure/s assessments will be done in person at in-clinic visits.  
4.1. CSF AND BLOOD COLLECTION FOR ASSESSMENTS OF BIOMARKERS 
CSF and blood samples will be collected for the detection of biomarkers at visits described in 
Table 1.  
4.2. MRI 
Standard MRI technologies will be used for T1 and T2 weighted imaging analyses. MRI data will 
be inspected and deidentified, as necessary, by an independent person who will not be involved in 
the research or analysis of the data. Brain MRI scan will be read and compared to previous MRI 
scans.  
4.3. WEARABLE SENSOR DEVICE 
A wrist wearable sensor device to measure step count and other physical activity (including step 
count) will be issued to eligible subjects at Visit 1 with instructions on its use. The device is to be 
worn on the wrist of the non-dominate hand, throughout the duration of the study. The device will 
be returned to the site at Visit 7, the final study visit. 
4.4. CLINICAL LABORATORY SAFETY TESTS  
Clinical laboratory safety tests will be monitored throughout the trial at Visits 1-7 as listed in the 
Schedule of Assessments (Table 1 and Table 2).  
Tests include:  
Viral Safety Testing: HBV; HBsAg and antibodies to core antigen (IgG and IgM anti-HBc), 
HCV, HIV 1 and 2. These tests must be performed within 7 days of Bone Marrow aspiration, and 
must be repeated if Bone Marrow aspiration is scheduled more than 7 days after the Screening 
visit. Viral safety tests must be performed by CLIA certified laboratories using FDA cleared kits. 
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), Total cholesterol, high-
density lipoprotein (HDL), low-density lipoprotein (LDL), total bilirubin, aspartate 
aminotransferase (glutamic oxaloacetic transaminase) (AST[GOT]), alanine aminotransferase 
(glutamic pyruvic transaminase) (ALT [GPT]), alkaline phosphatase (ALP), uric acid. 
Coagulation: Prothrombin time (PT), Partial thromboplastin (PTT), international normalized 
ration (INR).  
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DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

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IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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Urinalysis - Specific Gravity, pH, glucose, protein, ketones, blood.  
4.5. PHYSICAL EXAMINATIONS, VITAL SIGNS, AND 
ELECTROCARDIOGRAMS  
Participants will undergo a physical examination at the Screening (Visit 1), at each transplantation 
visit (Visit 3, Visit 4 and Visit 5), and at the last study visit (V7). Height will be measured at 
Screening (Visit 1), whereas body weight will be measured at Screening (Visit 1) and Visit 7. 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 at all in-clinic visits 
through Visit 7.  
Standard 12-Lead electrocardiogram ECG will be performed at Visit 1. ECG results must be 
manually read, preferably by a cardiologist, and the results entered on the electronic case report 
form (eCRF). 
4.6. PRE-TRANSPLANTATION VISITS  
4.6.1. Visit 1: Screening Visit  
Visit 1 is the Screening Visit and precedes Visit 2 by up to 4 weeks  
Participants will undergo the following screening assessments:  
• Informed consent (to be obtained by the Principal Investigator [PI] or Sub-Investigator [Sub-
I])) 
• Determine study eligibility, review of Inclusion/Exclusion Criteria 
• Collect demographic data  
• Medical history  
• Medical history of MS symptoms and date of diagnosis  
• Standard 12-Lead ECG  
• Neurological examination  
• Review of prior concomitant medications  
• Review of adverse events (AEs) 
• Directed physical examination, including height and weight  
• Vital sign measurements (including blood pressure, body temperature; pulse and respiration 
rate after sitting for at least 3 minutes) 
• Blood collection for hepatitis B virus (HBV; surface antigen (HBsAg) and antibodies to core 
antigen (IgG and IgM anti-HBc), hepatitis C virus (HCV), human immune deficiency virus 
(HIV) 1 and 2. These tests must be performed within 7 days of Bone Marrow aspiration, and 
must be repeated if Bone Marrow aspiration is scheduled more than 7 days after the 
DocuSign Envelope ID: 5A361921-DB14-4D03-A1FA-7DED20823A13
DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

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IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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Screening visit. Viral safety tests must be performed by CLIA certified laboratories using 
Food and Drug Administration (FDA) cleared kits. 
• Blood collection for hematology (CBC (hematology panel) - hemoglobin, hematocrit, white 
count (and differential), platelet count), coagulation (PT, PTT, INR), biochemistry 
evaluations (Sodium, potassium, chloride, glucose, BUN, creatinine, bicarbonate, calcium, 
total bilirubin, AST, ALT, ALP, uric acid, total cholesterol, HDL, LDL)  
• Blood collection for a serum pregnancy test (Female participants of childbearing potential)  
• Urinalysis (Specific gravity, pH, glucose, protein, ketones, blood)   
• Columbia-Suicide Severity Rating Scale (C-SSRS baseline)  
• MS functional composite (MSFC): T25FW and 9HPT 
• EDSS 
• MSWS-12  
• LCLA 
• SDMT 
• MRI  
• For eligible subjects: issue wearable sensor device and train on timing of use as well as 
maintenance of device 
4.6.2. Visit 2: Bone Marrow Aspiration Visit (Week -5, - -6)  
At Visit 2 (Week -5 to -6, coordinated with patient-assigned manufacturing slots), participants 
consenting to participate in the study and meeting the eligibility criteria will undergo a BMA. The 
BMA procedure will be performed by a credentialed health care provider per Medical Center 
procedures from multiple punctures of the iliac crest of the participants' pelvic bone. Participants 
will also undergo the following assessments: 
• Blood for CBC (hematology panel) - hemoglobin, hematocrit, white count (and differential), 
platelet count and coagulation (PT, PTT, INR).  Results will be reviewed prior to BMA. 
• Vital sign measurements (including blood pressure, body temperature; pulse and respiration 
rate after sitting for at least 3 minutes) 
• Review of concomitant medications  
• Review of adverse events  
• Bone Marrow Aspiration 
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DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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4.7. 
TRANSPLANTATION VISITS 
4.7.1. Visit 3 (T1): 1st Cell Transplantation (Day 0- up to Day 1)  
At the first 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 (See Table 1 and Table 2).  
Pre-transplant assessments (Up to 8 hours before transplant) will include:  
• Admission to Inpatient facility  
• Directed physical examination 
• Vital sign measurements (including blood pressure, body temperature; pulse and respiration 
rate after sitting for at least 3 minutes) 
• Review of concomitant medications  
• Review of adverse events  
• Blood will be collected for hematology (CBC (hematology panel), coagulation (PT, PTT, 
INR), biochemistry (sodium, potassium, chloride, glucose, BUN, creatinine), and biomarker 
evaluations.  Hematology, coagulation and chemistry lab results will be reviewed prior to the 
lumbar puncture.  
• MS functional composite (MSFC): T25FW and 9HPT 
• EDSS 
• MSWS-12  
• LCLA 
• SDMT 
Following pre-transplant procedures participants will undergo a lumbar puncture:  
• CSF will be removed and retained for analysis immediately prior to the IT administration of 
cells  
• MSC-NTF cells will be administered IT 
Post-transplant, participants will undergo the following:  
• Vital signs will be monitored at 2 (± 15 minutes), 8 (± 15 minutes) and 20 hours (±30 
minutes) post-transplantation.  
• Visual inspection of the injection site will be performed at 2 (±15 minutes), and 20 (±30 
minutes) hours post-transplant.  
• Blood will be collected 20 hours (± 30 minutes) post-transplant for biomarker evaluations. 
Prior to discharge at approximately 24 hours post transplantation, assessments will include:  
DocuSign Envelope ID: 5A361921-DB14-4D03-A1FA-7DED20823A13
DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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Confidential 
• Vital sign measurements (including blood pressure, body temperature; pulse and respiration 
rate after sitting for at least 3 minutes) 
• Directed physical examinations  
• Review of concomitant medications  
• Review of adverse events  
Patient will then be discharged from Inpatient Study facility 
4.7.2. Visit 3T: Post-transplant follow-up telephone call visit (Week 1-2) 
About 1-2 weeks after the first transplantation, participants will undergo a follow-up telephone 
visit that will include:  
• Review of concomitant medications  
• Review of adverse events 
4.7.3. Visit 4 (T2): 2nd Cell Transplantation (Week 8) 
For the second transplantation visit approximately 8 weeks (± 14 days) from the 1st transplantation 
(coordinated with patient-assigned manufacturing slots), participants will be admitted to an 
inpatient study facility for study procedures (See Table 1 and Table 2). 
Pre-transplant assessments (Up to 8 hours before transplant) will include:  
• Admission to Inpatient Study facility 
• Directed physical examination 
• Vital sign measurements (including blood pressure, body temperature; pulse and respiration 
rate after sitting for at least 3 minutes) 
• Review of concomitant medications  
• Review of adverse events  
• Blood will be collected for hematology (CBC (hematology panel), coagulation (PT, PTT, 
INR), biochemistry (sodium, potassium, chloride, glucose, BUN, creatinine), and biomarker 
evaluations. Hematology, coagulation and chemistry lab results will be reviewed prior to the 
lumbar puncture.  
• Low Contrast Letter Acuity (LCLA) 
• MS functional composite (MSFC) 
• MSWS-12  
• EDSS 
Following pre-transplant procedures participants will undergo a lumbar puncture:  
• CSF will be removed and retained for analysis immediately prior to the IT administration of 
cells  
DocuSign Envelope ID: 5A361921-DB14-4D03-A1FA-7DED20823A13
DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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Confidential 
• MSC-NTF cells will be administered IT 
Post-transplant, participants will undergo the following:  
• Vital signs will be monitored at 2 (± 15 minutes), 8 (± 15 minutes) and 20 hours (±30 
minutes) post-transplantation, and upon discharge at up to 24 hours (± 1 hour).  
• Visual inspection of the injection site will be performed at 2 (±15 minutes), and 20 (±30 
minutes) hours post-transplant.  
• Blood will be collected 20 hours (± 30 minutes) post-transplant for biomarker evaluations. 
Prior to discharge, at approximately 24 hours post transplantation, 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  
• Review of concomitant medications  
• Review of adverse events  
Patient will then be discharged from Inpatient Study facility 
4.7.4. Visit 4T: Post-transplant follow-up telephone call visit (Week 9-10)  
About 1-2 weeks after the second transplant, at Week 9, participants will undergo a follow-up 
telephone call that will include:  
• Review of concomitant medications  
• Review of adverse events 
4.7.5. Visit 5 (T3): 3rd Cell Transplantation (Week 16)  
For the third transplantation visit, approximately 16 weeks (± 14 days) from the 1st transplantation 
visit (V3) (coordinated with patient-assigned manufacturing slots) participants will be admitted to 
an inpatient study unit for study procedures (See Table 1 and Table 2). 
Pre-transplant assessments (Up to 8 hours before transplant) will include:  
• Admission to Inpatient Study facility 
• Directed physical examination 
• Vital sign measurements (including blood pressure, body temperature; pulse and respiration 
rate after sitting for at least 3 minutes) 
• Review of concomitant medications  
• Review of adverse events  
• Blood will be collected for hematology (CBC (hematology panel), coagulation (PT, PTT, 
INR), biochemistry (sodium, potassium, chloride, glucose, BUN, creatinine), and biomarker 
DocuSign Envelope ID: 5A361921-DB14-4D03-A1FA-7DED20823A13
DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 32 of 59 
 
Confidential 
evaluations. Hematology, coagulation and chemistry lab results will be reviewed prior to the 
lumbar puncture.  
• MS functional composite (MSFC): T25FW and 9HPT 
• EDSS  
• MSWS-12  
• LCLA 
• SDMT 
Following pre-transplant procedures participants will undergo a lumbar puncture:  
• CSF will be removed and retained for analysis immediately prior to the IT administration of 
cells  
• MSC-NTF cells will be administered IT 
Post-transplant, participants will undergo the following:  
• Vital signs will be monitored at 2 (± 15 minutes), 8 (± 15 minutes), and 20 hours (± 30 
minutes) post-transplant.  
• Visual inspection of the injection site will be performed at 2 (±15 minutes), and 20 
(±30 minutes) hours post-transplant.  
• Blood will be collected 20 hours (± 30 minutes) post-transplant for biomarker evaluations. 
Prior to discharge, at approximately 24 hours post transplantation, 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. 
• Review of concomitant medications  
• Review of adverse events  
Patient will then be discharged from Inpatient Study facility 
4.8. 
POST TRANSPLANTATIONS FOLLOW-UP  
4.8.1. Visit 5T: Post-transplant follow-up telephone call visit (Week 17-18)  
About 1-2 weeks after the third transplantation, participants will undergo a follow-up telephone 
call visit that will include:  
• Review of concomitant medications  
• Review of adverse events 
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DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

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IND#018615 
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Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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4.8.2. Visit 6: Week 22 (± 5 days) Follow-Up  
At the Week 22 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  
• Blood collection for biomarker analyses 
• MS functional composite (MSFC): T25FW and 9HPT 
• EDSS 
• MSWS-12  
• LCLA 
• SDMT 
4.8.3. Visit 7: 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  
• Neurological examination  
• Blood collection for hematology (CBC (hematology panel) - hemoglobin, hematocrit, white 
count (and differential), platelet count), coagulation (PT, PTT, INR), biochemistry 
evaluations (Sodium, potassium, chloride, glucose, BUN, creatinine, bicarbonate, calcium, 
total bilirubin, AST, ALT, alkaline phosphatase, uric acid, total cholesterol, HDL, LDL)  
• Blood collection for a serum pregnancy test (Female participants)  
• Urinalysis (Specific gravity, pH, glucose, protein, ketones, blood)   
• MS functional composite (MSFC): T25FW and 9HPT 
• EDSS 
• MSWS-12  
• LCLA 
• SDMT 
DocuSign Envelope ID: 5A361921-DB14-4D03-A1FA-7DED20823A13
DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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Confidential 
• C-SSRS 
• MRI 
• Return wearable sensor device 
4.9. SAFETY FOLLOW-UP  
All subjects who are treated or partially treated will have safety and efficacy follow-up for 
approximately 12 weeks from last transplantation. Adverse events (AEs) and serious adverse 
events (SAEs) will be followed up as described in Section 7.1.5. For subjects who refuse further 
clinic study visits, telephone contact by study staff shall be attempted and documented to review 
for AEs and medication changes.  
4.10. 
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, an effort to contact the subject by mail using a method 
that provides proof of receipt will be attempted. Alternate contacts will be used if the subject is 
not reachable (e.g., primary care providers, referring physician). 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 and 
documented on the End of Study eCRF page and, as of the date documented, the subject will be 
considered discontinued from the study. 
5. INVESTIGATIONAL PRODUCT INFORMATION  
5.1. 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 among others, 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 issue related to the involvement of embryonic or fetal allogeneic 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.  
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DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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5.2. 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 participant as 
follows:  
• ~125 x106 cells by Intrathecal administration (however, if less than 125 x 106 cells are 
available 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. Each treatment package consists of a ready-
for-injection syringe containing freshly harvested autologous cultured NurOwn® (MSC-NTF cells) 
at the dose defined in this clinical study protocol.  
Syringes will be capped with a stopper (not a needle). The 5 mL syringe for IT transplantation will 
be packed in a pouch.  
The treatment 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.  
The cell manufacturing 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).  
6. PRIOR AND CONCOMITANT THERAPY  
6.1. PRIOR THERAPY  
Participants who received prior cell therapy of any kind will be excluded from the study (see 
Section 3.2).  
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. 
6.2. CONCOMITANT AND EXCLUDED 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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DocuSign Envelope ID: 520E593F-4D33-44B1-ADB8-65F43133DE5B

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IND#018615 
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Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
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Current use of immunosuppressive medication or use of such medication within 6 months of study 
enrollment (aside from approved B-cell immunotherapy) and anticoagulation therapy are 
exclusionary.  
Alemtuzumab (Lemtrada), Cladribine (NDA submitted), Natalizumab (Tysabri), S1P modulators 
(such as Gilenya) high dose pulse intravenous methylprednisolone (IVMP, 1 gram) to treat a 
relapse within the 6 months prior to study entry or other investigative MS therapies are 
exclusionary due to safety considerations. However, a single dose of IVMP 100 mg as part of the 
Ocrevus (or Rituxan) infusion protocol q6M is not exclusionary and would be allowed in the study. 
6.3. ANTICOAGULATION THERAPY 
Anticoagulation treatment increases the risk of bleeding-related complications associated with 
invasive procedures.  In this study the procedures of concern are the bone marrow aspiration at 
Visit 2, three stem cell transplants by lumbar puncture at visits 3, 4 and 5. 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 a number of 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, and a risk benefit assessment should be 
conducted, to evaluate the risks of discontinuing anticoagulation for each subject with the potential 
benefits of participating in the clinical trial.   
7. SAFETY REPORTING  
For this study, AEs and SAEs will be collected from the time of informed consent at the screening 
visit through the last study visit (Visit 7 or an Early Termination visit) as detailed in Sections 4.6.-
4.8. 
7.1. ADVERSE EVENTS DEFINITIONS  
Standard definitions for AEs are provided in this section for informational purposes.  
7.1.1. 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.  
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7.1.2. 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  
− 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.  
7.1.3. 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 
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• 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.  
7.1.4. 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 
• 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. 
7.1.5. 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.  
7.1.6. Outcome  
The following terms will be used during this study:  
• Fatal  
• Not Recovered/not resolved  
• Recovering/resolving  
• Recovered/resolved  
• Recovered/resolved with sequelae  
• Unknown  
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Amendment 1.1, June 2019 
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7.1.7. 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 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 required to establish the 
significance and etiology of an abnormal result shall be obtained when clinically indicated.  
7.2. 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 within 24 hours of learning about the event 
regardless of relationship to study drug.  
• Site staff will complete the paper SAE report form and e-mail it within 24 hours to the 
following address: clinicalsafety@propharmagroup.com 
• In cases where the email system is unavailable, site staff will send the SAE by fax to: 1-866-
681-1063. 
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 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. 
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 as 
detailed in the table below: 
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Responsible  
Title/Company  
Drug Safety  
ProPharma Group.  
2635 University Avenue West,  
Suite 195,  
St. Paul,  
Minnesota 55114 USA 
Fax: 1-866-681-1063 
Email: clinicalsafety@propharmagroup.com 
Medical Monitor 
Stuart Apfel, MD 
Parallax Clinical Research, LLC 
Tel: 516-712-0884 
Email: sapfel@parallaxclinical.com 
Back-up Medical Monitor 
Ralph Kern, MD, MHSc 
Tel: 917-692-0091 
Email: rkern@brainstorm-cell.com 
Brainstorm Cell Therapeutics Ltd.  
Head of Clinical Operations 
Susan Ward, PhD 
Tel: 339-234-3881 
Email: sward@brainstorm-cell.com 
Brainstorm Cell Therapeutics Ltd. 
VP Scientific and Regulatory Affairs 
Yael Gothelf, Ph.D. 
Tel: (646) 666-3188 Ext. 102 
Email: ygothelf@brainstorm-cell.com 
Brainstorm Cell Therapeutics Ltd. 
The Sponsor or designated clinical safety service provider (ProPharma Group.) will report 
Investigational New Drug (IND) Safety Reports to the FDA and Investigators in accordance with 
the FDA regulations detailed in the Code of Federal Regulations (CFR) 21CFR312.32 and in 
accordance with Guidance for Industry and Investigators: Safety Reporting Requirements for INDs 
and 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 clinical safety service provider 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.  
7.3. REPORTING RESPONSIBILITIES AND PROCEDURES FOR PREGNANCIES 
Pregnancy occurring in a female subject (and female partners of male subjects) should be reported 
to the ProPharma Safety Group by completing the Pregnancy Notification Form within 24 hours 
of becoming aware of the event. Pregnancy outcome information should be forwarded to Sponsor/ 
Clinical Safety service Provider when available.  
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Amendment 1.1, June 2019 
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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.   
Following delivery or termination of pregnancy, the Pregnancy Outcome Form should be 
completed. Follow-up information regarding the outcome of the pregnancy and any postnatal 
sequelae in the infant will be required. 
7.4. 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 the 28-week visit (Visit 7, See Appendix 3).  
8. STUDY DISCONTINUATION   
8.1. 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 from participation. 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 International Conference on Harmonization 
(ICH) - Good Clinical Practice (GCP) guidelines, or FDA guidelines and regulations;  
c) Submission of false information from the research facility to the Sponsor, the Clinical 
Monitor, the FDA, or IRB;  
d) Insufficient adherence to protocol requirements;  
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Amendment 1.1, June 2019 
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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.  
8.2. 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 in a timely manner (preferably 
within 24-48 hours).   
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 2.1). 
• 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 have participants who discontinue from the study for any reason, return to 
the site for an End of Study visit (Visit 7).  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.  
The subject will be asked if they agree to be followed over the phone at the remaining study visits. 
If a participant refuses to return for the End of Study follow up visit and declines to be followed 
with any further clinic visits or assessments, site must document this providing the reason in the 
End of Study page eCRF in the electronic database. 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 the study. 
Despite discontinuing from the study, if the site becomes aware of any adverse events or SAEs 
that occur within 12 weeks of the last transplant, they should be recorded in the database Adverse 
Event log 
8.3. TEMPORARY DISCONTINUATION FROM THE STUDY 
Study treatment can be temporarily withheld in case of any serious adverse event (SAE) or 
significant inter-current illness or cell-manufacturing and patient visit scheduling issues.  
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Amendment 1.1, June 2019 
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9. ASSESSMENT OF ENDPOINTS  
9.1. PRIMARY ENDPOINT  
9.1.1. Safety 
The primary endpoint will be to evaluate the safety and tolerability of 3 intrathecal doses of 
NurOwn® (MSC-NTF cells). 
Safety endpoints include AEs, changes in physical and neurological examination findings, 
hematology, serum chemistry, urinalysis, vital signs, and requirement of concomitant medications. 
MRI (Brain T1 and T2 weighted images) will be evaluated for safety. 
9.2. SECONDARY ENDPOINTS  
9.2.1. Timed 25-foot walking speed (T25FW) or 9-Hole Peg Test (9-HPT) 
Proportion of subjects who improve in either T25FW or 9-HPT. Described in the statistical 
section below and in Appendix 2, Section 15.2.2. and Section 15.2.3.  
9.2.2. Modulation of Cerebrospinal Fluid (CSF) and blood Biomarkers: 
The efficacy of NurOwn® (MSC-NTF cells) will be evaluated by the modulation of CSF and 
blood biomarkers (neurotrophic factors, neurodegenerative and inflammatory biomarkers) 
following NurOwn® transplantation. 
CSF and blood samples will be collected as per the schedule of assessments to evaluate biomarkers 
(NTFs, inflammatory factors, cytokines and miRNAs) in the cerebrospinal fluid (CSF) before each 
treatment as well as in blood samples (such as neurofilament light chain) throughout the study, to 
evaluate their relationship to treatment with NurOwn® (MSC-NTF cells).   
9.2.3. The Expanded Disability Status Scale (EDSS) 
Described in the statistical section below and in Appendix 2, Section 15.2.4. 
9.2.4. The Multiple Sclerosis Walking Scale (MSWS-12)  
Described in in the statistical section below and in Appendix 2, Section 15.2.5 
9.2.5. Daily average step count and other measures of Physical Activity 
Daily average step count and other measures of physical activity as measured using an ActiGraph 
wrist wearable device. 
9.2.6. Low Contrast Letter Acuity (LCLA)  
The Low Contrast Letter Acuity test (LCLA) will be evaluated as described in in the statistical 
section below and in Appendix 2, section 15.2.6. 
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Amendment 1.1, June 2019 
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9.2.7. The Symbol Digit Modalities test (SDMT)  
The Symbol Digit Modalities test (SDMT) will be evaluated as a change from baseline in each 
treated study participant (See Appendix 2, Section 15.2.7). 
9.3. STATISTICAL METHODS AND SAMPLE SIZE DETERMINATION 
9.3.1. Sample Size Determination 
No formal sample size calculation is performed. Efficacy and safety data on 20 subjects will 
provide information to inform the design of a future randomized clinical study. 
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 3, Day 0-1).  
A detailed Statistical Analysis Plan (SAP) will be will be completed prior to the first subject being 
treated.  
9.3.3. Analysis Population  
The primary, secondary and exploratory efficacy endpoints will be analyzed using the modified 
intent to treat (mITT) and Efficacy Evaluable (EE) populations. The mITT population will be 
defined in this study as all participants who received at least one treatment and have at least one 
Timed 25-Foot Walk (T25FW) or 9-Hole Peg Test (9-HPT) assessment post baseline. Baseline 
will be defined as the most recent assessment prior to receiving the first transplantation on Day 0, 
at Visit 3. The EE population will be defined as a subset of the mITT population that receive all 3 
treatments and do not have any important protocol deviations impacting efficacy evaluation. If the 
EE population is identical or very similar to the mITT population, analyses may only be generated 
for the mITT population. 
All safety analyses will be conducted on the Safety Population, which will be defined as all 
participants who were enrolled and had at least one transplantation performed.  
9.3.4. Efficacy Analyses  
Efficacy analyses will be performed using the modified mITT and EE populations as described 
above. 
Efficacy endpoints will be based upon: T25FW, 9-HPT; blood and CSF biomarkers; EDSS 
MSWS-12; Physical function measured with wearable sensor; LCLA, and SDMT.  
Efficacy analyses of continuous data will be based upon change from baseline to each post-baseline 
timepoint.  
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A subject will be defined as a responder if over 28 weeks his/her T25FW walking speed or 9-HPT 
improves by ≥25% as compared to baseline (first transplant visit), determined to be clinically 
meaningful for MS patients1.  
Responder analyses will compare the proportion of responders using various definitions of 
responders using T25FW or 9-HPT, blood and CSF biomarkers, EDSS, MSWS-12, Physical 
function measured with wearable sensor, LCLA and SDMT. 
All deaths related to disease progression will be defined as non-responders. Details of all statistical 
analyses will be provided in the SAP, which will be completed prior to the first subject being 
treated. 
The timed 25-foot walking speed (T25FW) is a quantitative mobility and leg function performance 
test based on a timed 25 foot-walk. T25FW score is the average in seconds of the two successive 
trials. The T25FW has high inter-rater and test-retest reliability and shows evidence of good 
concurrent 
validity 
(https://www.nationalmssociety.org/For-
Professionals/Researchers/Resources-for-Researchers/Clinical-Study-Measures/Timed-25-Foot-
Walk-(T25-FW, See Appendix 2, Section 15.2.2). 
The T25FW2, and 9-HPT3, are performed as part of the Multiple Sclerosis Functional Composite 
(MSFC) and the MSFC is a validated outcome measure in MS clinical trials4. A modified version 
of the MSFC consists of a 4-component test battery that includes T25FW, 9HPT, LCLA, and 
SDMT. A 25% change in T25FW and 9-HPT are considered clinically meaningful improvements. 
CSF and serum biomarkers will include neurotrophic factors, neurodegenerative, and 
inflammatory biomarkers and MS specific biomarkers, such as Neurofilament Light Chain (NfL) 
and Neurofilament Heavy Chain (NfH).  
The EDSS is an objective approach to quantify the level of physical disability in MS. It provides 
a total score on a scale that ranges from 0 (no disability) through 1 to 10 (death due to MS) in 0.5-
point steps. EDSS is widely used as an outcome measure in MS. A 1.0-point change in the EDSS 
(EDSS <6) or 0.5-point change in EDSS (EDSS 6.0-6.5) are considered clinically meaningful 5. 
Additional details are included in Appendix 2, Section 15.2.4.  
                                                 
 
1 Motl et al, Validity of the timed 25-foot walk as an ambulatory performance outcome measure for multiple sclerosis. 
Multiple Sclerosis Journal 2017, Vol. 23(5) 704–710  
2 Hobart J, Blight AR, Goodman A, Lynn F, Putzki N. Timed 25-foot walk: direct evidence that improving 20% or 
greater is clinically meaningful in MS. Neurology. 2013 Apr 16;80(16):1509-17. 
3 Peter Feys, Ilse Lamers, Gordon Francis, Ralph Benedict, Glenn Phillips, Nicholas LaRocca, Lynn D Hudson, 
Richard Rudick and Multiple Sclerosis Outcome Assessments Consortium. The Nine-Hole Peg Test as a manual 
dexterity performance measure for multiple sclerosis.  Multiple Sclerosis Journal 2017, Vol. 23(5) 711–720  
4 Polman and Rudick.  The Multiple Sclerosis Functional Composite. A clinically meaningful measure of disability.  
Neurology April 27, 2010; 74 (17 Supplement 3) 
5 Cohen JA, Reingold SC, Polman CH and Wolinsky JS; International Advisory Committee on Clinical Trials in 
Multiple S. Disability outcome measures in multiple sclerosis clinical trials: current status and future prospects. Lancet 
Neurol 2012; 11: 467–476. 
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IND#018615 
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Amendment 1.1, June 2019 
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Additional supportive endpoints will include:  
The 12 item Multiple Sclerosis Walking Scale (MSWS-12), a patient reported outcome measure 
that focuses on patient perceived walking and mobility.  
The Low contrast letter acuity (LCLA), a validated endpoint to measure visual function in MS 1 A 
7 letter change in LCLA is considered a clinically meaningful improvement (See Appendix 2, 
Section 15.2.6). 
The SDMT is a validated clinical endpoint for measuring cognition in MS2. A 4-point change in 
SDMT is considered a clinically meaningful improvement (See Appendix 2, Section 15.2.7). 
9.3.5. Safety analyses  
All safety analyses will be based upon 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.  
A TEAE is an AE that occurs for the first time after initiation of treatment or if it 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 first transplantation (i.e., prior to initiation of treatment).  
Abnormalities in hematology, blood chemistry and ECG assessments will be summarized.  
MRI (T1 and T2 weighted images) will be assessed for study safety at baseline and at the end of 
the study. 
9.3.6. Biomarker Analysis 
CSF and/or serum samples will be analyzed for the concentration of biomarkers and their 
relationship to efficacy outcomes at each visit. In addition, relationships between neurotropic 
                                                 
 
1 Laura J. Balcer, David H. Miller, Stephen C. Reingold and Jeffrey A. Cohen.  Vision and vision-related outcome 
measures in multiple sclerosis.  Brain 2015: 138; 11–27 
2 Benedict RHB, DeLuca J, Phillips G, et al. Validity of the Symbol Digit Modalities Test as a cognitive performance 
outcome measure for multiple sclerosis. Mult Scler 2017; 23:721–733.  
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Amendment 1.1, June 2019 
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Page 47 of 59 
 
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factors, inflammatory markers, miRNA expression and clinical outcomes will be evaluated to 
determine if any biomarkers can be predictive of treatment outcome. Analyses will be detailed in 
the SAP. 
10. STUDY COMMITTEES AND COMMUNICATIONS  
10.1. 
DATA AND SAFETY MONITORING BOARD (DSMB) 
An independent, four-member Data Safety and Monitoring Board (DSMB) will be assembled for 
this Phase 2 clinical trial. Previous clinical studies with NurOwn® (MSC-NTF cells) did not result 
in any treatment-related SAEs or fatal SAEs. The DSMB will review key safety and efficacy data 
(at intervals and as requested) as outlined in the DSMB charter. 
11. LABORATORY REQUIREMENTS  
Each study site’s local laboratory will analyze the clinical laboratory safety samples (hematology, 
serum chemistry) the serum pregnancy test and Urinalysis. 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.  
12. INVESTIGATOR AND ADMINISTRATIVE REQUIREMENTS  
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.  
The only circumstance in which a deviation from the current IRB-approved clinical 
protocol/consent form(s) may be initiated in the absence of prospective IRB approval is to 
eliminate an apparent immediate hazard to the research subject(s). In such circumstances, the 
Sponsor/Investigator will promptly notify the clinical sites IRB of the deviation.  
The clinical sites IRB operate in compliance with FDA regulations at 21 CFR Parts 50 and 21 CFR 
56, and in conformance with applicable International Conference on Harmonization (ICH) 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.  
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• 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.  
12.2. 
DATA QUALITY ASSURANCE  
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.  
12.2.2. Electronic Case Report Forms (eCRFs)  
The study will use an electronic data capture (EDC) system. All personnel accessing the electronic 
data capture system will be trained on the use of the system by the EDC vendor. The vendor 
responsible for clinical data management will develop eCRFs 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.  
12.2.3. Study Monitoring  
The Sponsor or designee will monitor this study in accordance with ICH E6 GCP guidelines as 
detailed in the clinical 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.  
12.3. 
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 
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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.  
12.4. 
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 
upon Sponsor approval.  
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.  
12.5. 
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.  
12.6. 
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.  
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 
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IND#018615 
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Amendment 1.1, June 2019 
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personal information made available for inspection will be handled in strictest confidence and in 
accordance with local data protection laws.  
12.7. 
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 
investigational drug, until 2 years after investigations under the IND have been discontinued and 
the FDA so notified.  
12.8. 
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.  
13. USE OF STUDY INFORMATION AND PUBLICATION  
All information and data obtained during the conduct of the study will be considered confidential. 
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. 
14. REFERENCES  
Please refer to the EndNotes throughout the document. 
 
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Amendment 1.1, June 2019 
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15. APPENDICES  
15.1. 
APPENDIX 1: LISTING OF STUDY ACTIVITIES  
15.1.1. Scheduled monitoring events  
The schedule of assessments table provides an overview of the protocol visits and procedures. 
Refer to the Study Assessments section of the protocol for detailed information on each procedure 
and assessment required for compliance with the protocol.   
Unscheduled visits may be required in the course of the study in addition to those listed. 
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IND#018615 
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Amendment 1.1, June 2019 
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Table 1. 
Schedule of Assessments: 
 
Study Period
Visit 
V1
V2
V3T
V4
V4T
V5
V5T
V6
V711
Procedure 
Screening/
Enrollment 
BMA
Telephone Call 
visit 
Cell Transplantation 
(T2)
Telephone Call 
visit 
Cell 
Transplantation 
(T3)
Telephone Call 
visit 
Follow-up visit
End of Study 
Visit
Time Schedule
Week -10-6*
Week -5 to -6
Week 1-2 
Week 8
(± 14 days)12 
Week 9-10
Week 16 
(± 14 days)12
Week 17-18 
Week 22 
(± 5 days)
Week 28 
(± 5 days)
Informed consent 
√
Eligibility criteria 
√
Demographic data 
√
Height 
√
Medical History 
√
MS Medical History 1
√
12 lead ECG 
√
Neurological Examination 
√
√
Viral safety testing (HIV 1 and 2, HBV and HCV)** 
√
Body weight 
√
√
Pregnancy test (for women with childbearing potential) 
√
√
Bone marrow aspiration 
√
Transplant (IT) 
√
√
CSF collection 
√
√
Visual inspection of injection site 
√
√
Blood collection for biomarkers
√
√
√
Physical examination 
√
√
√
√
√
Vital signs2 
√
√
√
√
√
√
Hematology3
√
√
√
√
√
Blood biochemistry 4
√
√
√
√
Coagulation tests 5 
√
√
√
√
√
Prior/Concomitant medication review 
√
√
√
√
√
√
√
√
√
Adverse events review
√
√
√
√
√
√
√
√
√
Urinalysis 6 
√
√
EDSS7 
√
√
√
√
√
C-SSRS 
√
√
MRI
√
√
Low Contrast Letter Acuity (LCLA)
√
√
√
√
√
MS functional composite8 
√
√
√
√
√
SDMT9
√
√
√
√
√
MSWS-1210
√
√
√
√
√
Wearable sensor device  issued and training
√
Wearable sensor device
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
√
Pre-treatment period 
Cells Transplantation period 
Post-transplantation follow-up
V3
Cell Transplantation 
(T1)
Day 0 - Day 112
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Abbreviations: MS- Multiple Sclerosis; EDSS-Expanded Disability Status Scale; 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, QOL = Quality of 
Life 
*Screening Visits scheduling is coordinated with the manufacturing facility 
** If applicable must be repeated within up to 7 days prior to BMA 
1       MS Medical History to collect type and duration of MS symptoms and Date of Diagnosis 
2       Pulse rate, Blood pressure (Respiratory rate, Body temperature) 
3       Hematology: Complete blood count (red blood cells with indices, white blood cells with differential and platelet count, hemoglobin, hematocrit)  
4     Blood Biochemistry: At V1 and V7: Sodium, potassium, chloride, glucose, BUN, creatinine, bicarbonate, calcium, total bilirubin, AST, ALT, alkaline 
phosphatase, uric acid, total cholesterol, HDL, LDL.  At V3, V4 and V5: sodium, potassium, chloride, glucose, BUN, creatinine 
5      Coagulation: Prothrombin time (PT), Partial thromboplastin (PTT), INR. 
6      Urinalysis - Specific Gravity, pH, glucose, protein, ketones, blood. 
7    EDSS-Expanded Disability Status Scale. 
8    MSFC including T25FW and 9-HPT (9-hole peg test) 
9     Symbol Digit Modalities Test (SDMT). 
10    12 item MS Walking Scale (MSWS-12). 
11   An Early Termination (ET) visit will be conducted only for participants who discontinue the study after the first treatment, post Visit 3. The ET visit will 
include all the procedures required at study Visit 7. 
12. A more flexible window may be applied to the key study visits, BMA (V2), T1 (V3), T2 (V4) and T3 (V5) that are scheduled based on manufacturing 
availability 
 
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Table 2. 
Detailed Schedule of Assessments for Cell Transplantation Visits (V3, 
V4, and V5) 
 
 
 
*Hematology, biochemistry and coagulation labs are to be drawn and checked before transplant 
**To be determined for each study site 
1. Hematology: Complete blood count (red blood cells with indices, white blood cells with differential and Platelet 
count, hemoglobin, hematocrit) 
3. Sodium, potassium, chloride, glucose, BUN, creatinine 
4. Coagulation - PT, PTT, INR 
5. Pulse rate, Blood pressure (Respiratory rate, Body temperature 
 
 
Estimated Time 
xx:00-yy:00**
14:00
20:00
8:00
12:00
Time\ Procedure 
Up to 8 hours 
before 
transplant
Hr. 2
Hr. 8
Hr. 20
Approximately 
Hr. 
24/Discharge
Admit to In-patient Facility
√
Physical Examination 
√
 √
Concomitant medication review
√
√
Hematology1*
√
Blood biochemistry2* 
√
Coagulation3* 
√
Blood collection for biomarkers
√
√
Vital signs4
√
√
√
√
√
Adverse events review  
√
√
√
√
√
Cell Transplant IT 
Retention of CSF sample 
Visual inspection of injection site 
√
√
Discharge from Inpatient Setting 
√
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15.2. APPENDIX 2: EFFICACY OUTCOME MEASURES 
15.2.1. Multiple Sclerosis Functional Composite (MSFC) 
The original MSFC is a three-part, standardized, quantitative, assessment instrument for use in 
clinical studies, particularly clinical trials, of MS (Cutter et al, 1999). The MSFC initially included 
three components: T25FW, 9HPT, and the Paced Auditory Serial Addition Task [PASAT] and 
was designed to reflect the varied clinical expression of MS across patients and over time on three 
areas: leg function/ambulation, arm/hand function, and cognitive function.  
Modifications were made to the MSFC which now consists of a 4-component test battery that 
includes T25FW, 9HPT, LCLA, and SDMT. The PASAT was replaced with the SDMT and the 
LCLA was added to test visual acuity. The scores for each area should change relatively 
independently over time. Administration time will vary depending upon the ability of the 
participant.  
Total administration time for all three measures should be approximately 20-30 minutes. The 
MSFC can produce scores for each of the three individual measures as well as a composite score.  
15.2.2. Timed 25 Foot Walk (T25FW) 
The T25FW is a quantitative mobility and leg function performance test based on a timed 25-walk. 
It is the first component of the MFSC to be administered at each visit. The participant is directed 
to one end of a clearly marked 25-foot course and is instructed to walk 25 feet as quickly as 
possible, but safely. The time is calculated from the initiation of the instruction to start and ends 
when the participant has reached the 25-foot mark. The task is immediately administered again by 
having the patient walk back the same distance. Participants may use assistive devices when doing 
this task. 
Administration time will vary depending upon the ability of the patient. Total administration time 
should be approximately 1-5 minutes. The score for the T25FW is the average of the two 
completed trials. This score can be used individually or used as part of the MSFC composite score. 
15.2.3. 9-Hole Peg Test (9-HPT) 
The 9-HPT is a brief, standardized, quantitative test of upper extremity function. It is the second 
component of the MSFC to be administered at each visit. Both the dominant and non-dominant 
hands are tested twice. The participant is seated at a table with a small, shallow container holding 
nine pegs and a wood or plastic block containing nine empty holes. On a start command when a 
stopwatch is started, the participant picks up the nine pegs one at a time as quickly as possible, 
puts them in the nine holes, and, once they are in the holes, removes them again as quickly as 
possible one at a time, replacing them into the shallow container. The total time to complete the 
task is recorded. Two consecutive trials with the dominant hand are immediately followed by two 
consecutive trials with the non-dominant hand. 
Administration time will vary depending upon the ability of the participant. Total administration 
time should be approximately 10 minutes or less.  The score for the 9-HPT can be used individually 
or used as part of the MSFC composite score. 
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15.2.4. Expanded Disability Status Scale (EDSS, Kurtzke) 
The EDSS is an objective approach to quantify the level of physical disability in MS. It provides 
a total score on a scale that ranges from 0 (no disability) through 1 to 10 (death due to MS) in 0.5-
point steps. The first levels 1.0 to 4.5 refer to people with a high degree of ambulatory ability and 
the subsequent levels 5.0 to 9.5 refer to the loss of ambulatory ability.  
In addition, it also provides eight subscale measurements called Functional System (FS) scores. 
The levels of function within each category refer to the eight functional systems affected by MS: 
Pyramidal (motor function) (P); Cerebellar (C11); Brainstem (BS); Sensory (S); Bowel and 
Bladder (BB); Visual (V); Cerebral or Mental (Cb); Ambulation. 
Administration time will vary depending upon the condition of the patient and the skill of the 
examiner. Although the FSS and EDSS themselves can be rated in a few minutes, the neurological 
examination that is needed to make the ratings can take anywhere from 15 minutes to a half-hour. 
Table 3. 
Kurtzke Expanded Disability Status Scale (EDSS) 
0.0 
Normal neurological exam (all grade 0 in all Functional System (FS) scores*). 
1.0 
No disability, minimal signs in one FS* (i.e., grade 1).  
1.5 
No disability, minimal signs in more than one FS* (more than 1 FS grade 1). 
2.0 
Minimal disability in one FS (one FS grade 2, others 0 or 1). 
2.5 
Minimal disability in two FS (two FS grade 2, others 0 or 1). 
3.0 
Moderate disability in one FS (one FS grade 3, others 0 or 1) or mild disability in three or four FS 
(three or four FS grade 2, others 0 or 1) though fully ambulatory.  
3.5 
Fully ambulatory but with moderate disability in one FS (one grade 3) and one or two FS grade 2; 
or two FS grade 3 (others 0 or 1) or five grade 2 (others 0 or 1). 
4.0 
Fully ambulatory without aid, self-sufficient, up and about some 12 hours a day despite relatively 
severe disability consisting of one FS grade 4 (others 0 or 1), or combination of lesser grades 
exceeding limits of previous steps; able to walk without aid or rest greater than 500 meters.  
4.5 
Fully ambulatory without aid, up and about much of the day, able to work a full day, may 
otherwise have some limitation of full activity or require minimal assistance; characterized by 
relatively severe disability usually consisting of one FS grade 4 (others or 1) or combinations of 
lesser grades exceeding limits of previous steps; able to walk without aid or rest greater than 300 
meters.   
5.0 
Ambulatory without aid or rest for about 200 meters; disability severe enough to impair full daily 
activities (e.g., to work a full day without special provisions); (Usual FS equivalents are one 
grade 5 alone, others 0 or 1; or combinations of lesser grades usually exceeding specifications for 
step 4.0 
5.5 
Ambulatory without aid for about 100 meters; disability severe enough to preclude full daily 
activities; (Usual FS equivalents are one grade 5 alone, others 0 or 1; or combination of lesser 
grades usually exceeding those for step 4.0). 
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Table 3. 
Kurtzke Expanded Disability Status Scale (EDSS) 
6.0 
Intermittent or unilateral constant assistance (cane, crutch, brace) required to walk about 100 
meters with or without resting; (Usual FS equivalents are combinations with more than two FS 
grade 3+). 
6.5 
Constant bilateral assistance (canes, crutches, braces) required to walk about 20 meters without 
resting; (Usual FS equivalents are combinations with more than two FS grade 3+). 
7.0 
Unable to walk beyond approximately 5 meters even with aid, essentially restricted to 
wheelchair; wheels self in standard wheelchair and transfers alone; up and about in wheelchair 
some 12 hours a day; (Usual FS equivalents are combinations with more than one FS grade 4+; 
very rarely pyramidal grade 5 alone). 
7.5 
Unable to take more than a few steps; restricted to wheelchair; may need aid in transfer; wheels 
self but cannot carry on in standard wheelchair a full day; May require motorized wheelchair; 
(Usual FS equivalents are combinations with more than one FS grade 4+). 
8.0 
Essentially restricted to bed or chair or perambulated in wheelchair, but may be out of bed itself 
much of the day; retains many self-care functions; generally has effective use of arms; (Usual FS 
equivalents are combinations, generally grade 4+ in several systems). 
8.5 
Essentially restricted to bed much of day; has some effective use of arm(s); retains some self-care 
functions; (Usual FS equivalents are combinations, generally 4+ in several systems). 
9.0 
Helpless bed patient; can communicate and eat; (Usual FS equivalents are combinations, mostly 
grade 4+). 
9.5 
Totally helpless bed patient; unable to communicate effectively or eat/swallow; (Usual FS 
equivalents are combinations, almost all grade 4+). 
10.0 
Death due to MS 
* Excludes cerebral function grade 1. 
Note 1: EDSS steps 1.0 to 4.5 refer to patients who are fully ambulatory and the precise step number is 
defined by the Functional System score(s). EDSS steps 5.0 to 9.5 are defined by the impairment to 
ambulation and usual equivalents in Functional Systems scores are provided. 
Note 2: EDSS should not change by 1.0 step unless there is a change in the same direction of at least one 
step in at least one FS. 
 
15.2.5. Multiple Sclerosis Walking Scale (MSWS-12) 
The MSWS-12 is a patient-reported outcome measure of the walking limitations due to MS during 
the past 2 weeks. It contains 12 questions that assess the impact of MS on different aspects of 
walking function and quality.  
Total administration time should be approximately 5 minutes. Activities are rated by participant 
from 1 (not at all) to 5 (extremely) and summed to calculate a total score using a scale from 0 to 
100 (ranging from low to high impact on walking). 
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15.2.6. Low Contrast Letter Acuity (LCLA)  
Sloan LCLA charts are administered binocularly or each eye can be tested individually. The charts 
are placed on a retro-illuminated cabinet, eliminating the need for standardized room lighting, or 
on the wall in front of the participant. Participants are seated 2 m away and asked to read the letters 
aloud proceeding top to bottom and from left to right until they can no longer see the letters.  
Total administration time, for a typical MS patient, is approximately 10–15 minutes to complete, 
when testing each eye individually and binocular vision for two different contrast levels. The score 
for each chart is quantified as the number of letters identified correctly with a maximum score of 
70 letters. 
15.2.7. Symbol Digit Modalities Test (SDMT) 
The SDMT involves a simple substitution task that normal children and adults can easily perform. 
Using a reference key, the examinee has 90 seconds to pair specific numbers with given geometric 
figures.  
Total administration time should be approximately 5 minutes. The standardized score is calculated 
from the participant’s raw score. The manual provides normative mean scores and standard 
deviations by age. 
 
 
 
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Brainstorm Cell Therapeutics Ltd. 
IND#018615 
Phase 2 Clinical Protocol BCT-101-US 
Amendment 1.1, June 2019 
MSC-NTF cells (NurOwn®) 
Page 59 of 59 
 
Confidential 
15.3. APPENDIX 3: 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 
Total administration time should be approximately 5 minutes. 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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