Autologous, Bone Marrow-Derived Mesenchymal Stem Cell-Derived Neural Progenitor Cells (MSC-NP), Expanded Ex Vivo; Administered Intrathecally
Phase: PHASE2
Conditions: Multiple Sclerosis
Sponsor: Tisch Multiple Sclerosis Research Center of New York

 
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TISCHMS-MSCNP-002 
CLINICAL STUDY PROTOCOL 
 
NCT03355365 
 
 
 
 
 
 
 
 
 
 

 
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CLINICAL PROTOCOL: Summary Information 
 
TITLE 
Autologous, Bone Marrow-Derived Mesenchymal Stem Cell-Derived 
Neural Progenitor Cells (MSC-NP), Expanded Ex Vivo; 
Administered Intrathecally 
SPONSOR 
Tisch MS Research Center of New York (Tisch MSRCNY) 
521 West 57th St, 4th floor, New York, NY 10019 
(212) 265-8070 
PROTOCOL NUMBER 
TISCHMS-MSCNP-002 
VERSION NUMBER AND 
DATE 
 V8 08/26/2021 
PHASE OF CLINICAL 
INVESTIGATION 
Phase II 
IND NUMBER 
13889 
PRINCIPAL 
INVESTIGATOR 
Saud A. Sadiq, MD, FAAN 
Director and Chief Research Scientist 
Tisch MS Research Center of New York 
NUMBER OF SITES 
1 
STUDY DESIGN 
Phase 2, Double-Blind, Placebo-Controlled, randomized, Parallel 
Study of Intrathecal autologous MSC-NP Cells in Patients With MS 
PRIMARY OBJECTIVE 
To determine efficacy of multiple (6) intrathecal administrations of 
autologous MSC-NPs compared to placebo through assessment of 
disability outcomes 
SECONDARY 
OBJECTIVES 
To determine continued safety and tolerability of multiple intrathecal 
injections of MSC-NPs in patients with MS  
NUMBER OF SUBJECTS 
50 
SUBJECT SELECTION 
CRITERIA 
Inclusion Criteria (summary): SPMS or PPMS patients who have 
significant disability (EDSS between 3.0 and 6.5) that was not 
acquired within the last 12 months. 
Exclusion Criteria (summary): EDSS > 6.5, or anyone with co-
morbidities (past or present) that would put them at a higher risk for 
safety complications. 
INVESTIGATIONAL NEW 
DRUG / INTENDED USE 
Bone Marrow-Derived Mesenchymal Stem Cell-Neural Progenitor 
Cells (MSC-NP) for use as treatment for multiple sclerosis 
CONTROL GROUP OR 
OTHER STUDY ARMS (if 
applicable) 
Placebo (LP procedure) 
DURATION OF 
SUBJECT 
Subjects will participate in the study for 3 years 

 
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PARTICIPATION AND 
DURATION OF STUDY 
• 
Pretreatment screening and bone marrow aspiration: 
potentially up to 4 months 
• 
Treatment phase: 2 years, total 12 treatments (6 MSC-NP 
injections, 6 placebo lumbar punctures) every 2 months 
• 
Follow-up: 1 year 
PRIMARY ENDPOINT 
EDSS Plus (measured at baseline, month 6, month 13, month 20, 
month 27, and month 36) 
 
SECONDARY ENDPOINTS MSFC 
EDSS 
T25FW (timed 25 foot walk) 
9HPT (9 hole peg test) 
12-item MS Walking Scale 
urodynamic studies 
6 Minute Walk Test 
Time to Progression (measured at month 13, month 27, and month 
36) 
Progression on MRI (measured by percent change from baseline in 
total volume of T2 Lesions and percent change in total brain volume 
from baseline at month 13, month 27, and month 36) 
SAFETY EVALUATIONS 
Incidence of serious adverse events 
Incidence of minor adverse events (headache pain scale, fever) 
Brain, cervical, and thoracic MRI 
 
 
 
 
 
 
Principal Investigator:  
 
Saud A. Sadiq, MD, FAAN 
 
 
 
 
 
Tisch MS Research Center of New York 
 
 
 
 
 
521 West 57th Street, 4th Floor 
New York, NY 10019 
Phone: (212) 265-8070 
Fax: (212) 265-8194 
Email: ssadiq@tischms.org 
 
Sub-Investigators (TMSRCNY):  Violaine Harris, PhD 
Tisch MS Research Center of New York 
 
 
 
 
 
521 West 57th Street, 4th Floor 
New York, NY 10019 
Phone: (212) 265-8070 
Fax: (212) 265-8194 
Email: vharris@tischms.org 
 
  
 
 
 
 
Armistead Williams, MD 
Tisch MS Research Center of New York 

 
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521 West 57th Street, 4th Floor 
New York, NY 10019 
Phone: (212) 265-8070 
Fax: (212) 265-8194 
Email: awilliams@imsmp.org 
 
James Stark, MD 
Tisch MS Research Center of New York 
 
 
 
 
 
521 West 57th Street, 4th Floor 
New York, NY 10019 
Phone: (212) 265-8070 
Fax: (212) 265-8194 
Email: jstark@imsmp.org 
 
Gabriel Sara, MD 
St. Luke’s-Roosevelt Hospital Center 
Hematology-Oncology 
1000 Tenth Ave, Suite 11C02 
New York, NY 10019 
Phone: (212) 523-7580 
Fax: (212) 523-2004 
Email: gsara@chpnet.org 
 
Neil Grafstein, MD 
5 East 98th Street, 6th Floor 
New York, NY 10029 
Phone: (212) 241-4812 
Fax: (212) 987-4675 
Email: Neil.Grafstein@mountsinai.org 
 
Linda Gerber, PhD 
Department of Healthcare Policy and Research 
Weill Cornell Medical College 
402 East 67th Street 
New York, NY 10065 
Phone: (646) 962-8020 
Fax: (646) 962-0281 
Email: lig2002@med.cornell.edu 
 
 
Yuqing Qiu, MS  
Department of Healthcare Policy and Research 
Weill Cornell Medical College 
402 East 67th Street 
New York, NY 10065 
Phone: (646) 962-8020 

 
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Fax: (646) 962-0281 
yuq2002@med.cornell.edu 
 
 
 
 
 
TMSRCNY Study Nurse(s): 
Daisy Ramos, RN 
 
 
 
 
 
Samantha McKillip, RN 
 
 
 
 
 
 
 
 
 
 
 
 
TMSRCNY Clinical Trial Manager: Aleksandra Wawrzyniak, BA 
 
TMSRCNY Study Coordinators:    Michaela Malin, BA 
 
 
 
 
 
 Morgan Roche, BA 
 
 
 
 
 
 
 
 
 
Study Locations:  
 
 
Tisch MS Research Center of New York 
 
 
 
 
 
(Treatment and Assessment site) 
 
 
 
 
 
 
 
 
 

 
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Clinical Protocol 
 
1. Introduction: 
 
1.1 Background: 
 
Multiple sclerosis (MS) is an autoimmune-mediated chronic demyelinating 
disorder, and is the leading cause of disability in young adults after trauma. At 
present, there is no treatment that reverses the effects of established disease. 
Over the last 15 years, the outlook for newly diagnosed patients with MS has 
improved considerably because of therapeutic advances that ameliorate the 
aberrant immune responses seen in these patients. However, there are 
extremely limited treatments available for progressive MS, where progressive 
disease worsening and disability are associated with neurodegenerative 
mechanisms. 
 
In attempting to develop a stem cell-based reparative therapy for MS we are 
investigating the use of autologous MSC-derived neural progenitors (MSC-
NPs) administered in multiple intrathecal doses. The objective of this novel 
cellular therapy is to promote CNS repair and regeneration in patients with 
progressive MS, with the ultimate goal of reversal of disability.  
 
 
1.2 Rationale: 
 
MSC-NPs represent a neural subpopulation of MSCs from bone marrow with 
reduced pluripotency and minimized risk of ectopic differentiation, thus are likely 
to be more suitable for CNS delivery [1, 2]. Importantly, characterization of MSC-
NPs demonstrated their immunoregulatory and trophic properties, and MSC-NPs 
derived from MS and non-MS patients alike were therapeutically viable [1]. In in 
vitro studies, the release of trophic growth factors, including hepatocyte growth 
factor (HGF), promoted the differentiation of myelin-forming oligodendrocytes, 
suggesting a possible mechanism of repair for MS. MSC-NPs also secrete 
abundant immunoregulatory cytokines, including TGF-beta and IL-6,that may 
suppress immune responses related to MS.  
 
In preclinical studies, intrathecal (IT) MSC-NP treatment in EAE, the mouse 
model of MS, resulted in significantly improved neurological function [2]. 
Importantly, MSC-NPs were injected into mice with established chronic EAE [2], 
since progressive MS patients in need of regenerative therapies have long 
passed the phase of disease onset and are well into the neurodegenerative 
phase of the disease. These experiments were designed to mimic most closely 
the clinical trial design in humans, and included the following parameters: 1) 
Cells were injected intrathecally in mice rather than intravenously in order to best 
target damaged CNS tissue, 2) Cells were injected during the chronic phase of 

 
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EAE rather than the inflammatory phase, 3) Dose range from 2x104 to 1x106 cells 
was tested to inform dosing in human trials, and 4) Single vs. multiple dosing was 
tested to inform dosing regimen in human trials.  We found that three injections of 
MSC-NPs spaced one week apart resulted in decreased cumulative EAE disease 
score in mice compared to single injections. Histopathological analysis on 
animals carried out 8 weeks after the third injection showed evidence of MSC-NP 
engraftment in the CNS. Neurological recovery was associated with increased 
spinal cord myelination, decreased immune infiltration in the CNS, and increased 
recruitment of endogenous progenitor cells. The multiple injection dosing 
regimen was well tolerated in mice.  
 
In a pilot feasibility study, 6 MS patients with advanced disease were treated with 
2-5 injections of escalating doses of autologous MSC-NPs administered 
intrathecally [3]. Patients were followed for an average of 7.4 years after initial 
injection. There were no safety concerns noted and no serious adverse events 
supporting both short-term and long-term safety of this experimental approach. 
Importantly, the data showed that multiple (up to 5) treatments were well 
tolerated. Incidentally, four of the six patients showed a measurable clinical 
improvement following MSC-NP treatment, providing further justification for 
phase I/II clinical trials.  
 
Based on these pre-clinical and early clinical data supporting safety and efficacy, 
we are conducting an FDA-approved Phase I clinical trial to test safety and 
tolerability of 3 separate doses of up to 10 million MSC-NPs administered 
intrathecally with doses spaced 3 months apart [4]. Twenty subjects with 
progressive MS were enrolled. Inclusion criteria included those with established 
disability (EDSS 3.5 to 8.0) and stable disability (no progression 6-12 months 
prior to enrollment). All 20 patients received the 3 MSC-NP treatments spaced 3  
months apart with 3 month follow-up assessments. The dosing regimen was 
found to be well tolerated, with only minor adverse events including transient 
headache (lasting only up to 48 hours post-treatment) and less commonly a 
transient fever (less than 100oF; always over within 24 hours). There were no 
safety concerns associated with the treatment. Efficacy trends show that 15 of 
the 20 patients have improved in at least one of the following categories: ≥ 0.5 
improvement in EDSS; at least 20% improvement in 25 feet timed walk, greater 
than 20% positive change in none hole PEG test, moderate to marked 
improvement in muscle strength, or symptomatic and/or urodynamic 
improvement in bladder function. These results are remarkable because such 
reversal of disability in long standing SPMS and PPMS has not previously been 
reported.    
 
Based on our phase I trial results that establish safety and tolerability and 
suggest efficacy, we have designed a phase II study with the primary goal of 
establishing efficacy.  We propose to use the intrathecal (IT) route of injection of 
administration. This is because the IT route in our phase I study has proved safe, 
tolerable and given positive results and it has not been established that these 

 
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cells given by other routes such as IV is effective. In our clinical studies to date, 
doses of up to 10 million MSC-NPs are well tolerated [3, 4], therefore we propose 
to continue the same dosage for this phase II study.   
 
The dosing regimen of the Phase II trial will consist of 6 separate intrathecal 
doses, spaced 2 months apart. This extended dosing is designed to achieve 
optimal results based on the dosing experience of the phase I trial and the 6-
patient pilot study. The outcomes of the 6-patient pilot study suggested that 
multiple dosing of up to 5 separate doses was safe and well-tolerated [3]. This 
pilot study informed dosing for the Phase I clinical trial, which consisted of 3 
doses spaced 3 months apart. The three doses were extremely well tolerated. 
Notably, we observed transient improvements in some patients that were not 
sustained after the third dose, suggesting that the peak response had not yet 
been reached. We propose doubling the amount of treatments and increasing the 
frequency to every 2 months as a way of reaching a plateau of response in 
patients.  The peak of response needs to be established in the Phase II study.   
 
 
 
2. Clinical Study Objectives: 
 
2.1 Primary objective: 
 
• To determine efficacy of multiple (6) intrathecal administrations of autologous 
MSC-NPs compared to placebo through assessment of disability outcomes. 
 
2.2 Secondary objectives: 
 
• To determine continued safety and tolerability of multiple intrathecal injections 
of MSC-NPs in patients with MS.  
 
 
 
3. Study Design: 
 
The study is a Phase II, double-blind, placebo-controlled, randomized, parallel study 
design with a compassionate crossover element. The IT-MSC-NP treatments and all 
clinical assessments will take place at a single center (Tisch MSRCNY). Both the 
patient and the examining neurologist will be blinded to the treatment. The treating 
clinician (Dr. Sadiq, principal investigator) and the cell manufacturing coordinator 
(Dr, Harris, co-PI) will not be blinded. Study subjects will be assigned to blocks 
stratified by baseline EDSS score (3.0-4.0, 4.5-5.5, 6.0, and 6.5) and disease 
subtype (SPMS or PPMS). The total number of subjects in each block is shown 
below. Subjects in each block will be randomized into placebo or treatment group in 
order of date of consent based on randomization scheme designated by Dr Linda 

 
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Gerber (Professor of Healthcare Policy & Research and Professor of Epidemiology 
in Medicine at Weill Cornell Medicine). In the second year, treated subjects will cross 
over to the placebo group and placebo subjects will cross over to the treated group. 
Study subjects are randomized in an equal fashion to study treatment and placebo 
at initial randomization. 
 
Stratified block randomization scheme for Phase II trial: 
EDSS 
SPMS 
PPMS 
3.0-4.0 
10 
4 
4.5-5.5 
10 
2 
6.0 
10 
2 
6.5 
10 
2 
Total # of patients: 
40 
10 
 
 
The total study duration will be 3 years upon enrollment. Each study subject will be 
required to attend up to 18 study visits, including 1 screening visit, 1 bone marrow 
visit, 1 baseline visit, followed by study visits every 2 months during the treatment 
period of two years (12 treatment/LP procedure visits and 2 outcome visits), and an 
additional follow-up visit at the end of year 3.  
 
 
 
3.1 Study design schematic  
 
  
  
 
 

 
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3.2 Allocation to treatment   
 
A total of 50 study subjects will be enrolled according to inclusion/exclusion criteria. 
Subjects will be randomly assigned to placebo or treatment group according to the 
stratified block randomization scheme described above in section 3. A master 
randomization assignment list will be generated and kept in a locked secure location 
accessible only by PI (Sadiq) and co-PI (Harris), who are the only two un-blinded 
investigators in the study. Dr. Harris will remain un-blinded in order to coordinate 
autologous cell manufacturing for subjects in the treatment group. The PI will be 
responsible for maintaining the blind.  
   
 
3.3 Breaking the blind  
 
In the event of any serious adverse effects that are deemed to be a direct result of 
the treatment, the examining neurologist or DSMB may request for the patient to be 
un-blinded.  
 
 
 
4. Subject Selection: 
 
Fifty subjects for this study will be selected based upon their clinical disease status. 
Only patients with primary progressive or secondary progressive MS who have 
significant disability (EDSS between 3.0 and 6.5) that was not acquired within the 
last 12 months will be eligible. Patients should have a relatively stable disease state 
(duration of MS <20 years at time of screening), which will allow better discernment 
between natural disease progression and treatment-related events. Disease stability 
will be determined by less than a 1.0-point change in EDSS in the last 12 months, 
and lack of gadolinium-enhancing lesions on an MRI and by a stable MRI disease 
burden (number and size of T2 lesions) in the last six months.  
Enrollment criteria will also include specific clinical phenotypes which showed 
preliminary evidence of improvement during Phase I testing. Patients with 
symptomatic evidence of bladder dysfunction will be enrolled, and urodynamics 
testing will be conducted before and after treatment.  
Exclusion criteria includes patients who have taken systemic chemotherapeutic 
or anti-mitotic agents within three months of the study start date due to possibility of 
interference with the bone marrow procedure and the potential negative impact on 
MSC-NP viability. Because of the experimental nature of this treatment, we are 
excluding patients who may be at greater risk for complications. Patients with central 
nervous system infections and blood diseases are at particular risk due to the route 
of administration of cells and the invasive nature of bone marrow aspiration. Patients 
who are anticipated to have difficultly accessing the intrathecal space related to 
scoliosis, obesity, or any other relevant factors determined by the PI. Participation in 
the trial will be terminated if a subject meets any of the exclusion criteria during the 

 
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course of the study. Detailed description of inclusion/exclusion criteria for this study 
will be provided in the clinical protocol.  
 
 Based on the close collaboration between Tisch MSRCNY and IMSMP, we do 
not anticipate difficulty in patient recruitment. Enrollment criteria include patients 
either within the geographical area or who are able to arrange reliable travel during 
the study period. To be enrolled, patients must consent to participate in all study 
visits, which include MRI. Enrollment into the study is defined as providing informed 
consent for study participation. 
 
 
4.1 Subject inclusion criteria 
 
To be eligible for enrollment in this study, a subject must meet the following 
inclusion criteria.  
• Diagnosis of MS as defined by the McDonald criteria 
• Diagnosis of primary progressive or secondary progressive MS 
• Between the ages of 18-65 years 
• Significant disability shown by an Expanded Disability Status Score (EDSS, [5]) 
≥3.0 and ≤6.5 that was not acquired within the last 12 months 
• Stable disease state as evidenced by a lack of gadolinium-enhancing lesions on 
an MRI and by a stable MRI disease burden (number of T2 lesions and size of 
lesions) in the last six months and no significant change in EDSS (1 point or 
more) in the last 12 months 
• Must agree to undergo four MRIs: at the time of enrollment, after year 1, after 
year 2, and after year 3 
• Patients either within the geographical area or who are able to arrange reliable 
travel during the study period  
 
 
4.2 Subject exclusion criteria 
 
Any of the following criteria exclude a subject from this study. 
• EDSS >6.5 
• Duration of disease >20 years at time of screening (duration of disease will be 
determined by onset of symptoms when symptom onset is clearly defined. In 
cases where symptom onset is difficult to determine, duration of disease will be 
based on date of diagnosis). 
• Change of disease modifying agent <12 months prior to beginning treatment. 
Additionally, no changes in disease modifying agent will be made during the 
course of the study. 
• Change in MS symptom management treatments, including Ampyra 
(dalfampridine) <6 months prior to beginning treatment. Additionally, no changes 
in MS symptom management treatments will be made during the course of the 
study, unless there has been clinical improvement, in which case, a patient may 
discontinue a medication 

 
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• Start of any new orthotic device or durable medical equipment <6 months prior to 
beginning treatment or during the course of the study (patients may discontinue 
use of these devices during the course of the study if they show clinical 
improvement). 
• All patients who have ever been on Lemtrada (alemtuzumab) 
• All patients who have had any prior stem cell treatments in the past five years 
• All patients who have had any prior HSCT treatments 
• Pregnant or nursing mothers or any woman intending to become pregnant in the 
next three years 
• All patients will have screening blood tests done. Only patients whose values are 
in the normal range as determined by the laboratory norms based on age and sex 
will be allowed to participate. Exceptions may be made for borderline normal 
laboratory values manifesting no clinical symptoms at the discretion of the 
Principal Investigator. 
• Use of systemic chemotherapeutic or anti-mitotic medications within three months 
of study start date due to the possibility of interference with bone marrow 
procedure 
• Any patients with a history of or with active malignancy 
• Use of steroids within three months of the study start date, as this would suggest 
an active disease state 
• History of cirrhosis due to increased risk of CNS infection 
• Significantly uncontrolled hypertension because of increased risk for stroke or 
CNS hemorrhage.  
• Patients with active thyroid disease resulting in hyperthyroidism or hypothyroidism  
(Only well controlled patients with labs in the normal range will be included) 
because of hormone influence on cell growth 
• History of central nervous system infection or immunodeficiency syndromes due 
to increased risk of CNS infection 
• Preexisting blood disease (such as bone marrow hypoplasia, leukopenia, 
thrombocytopenia, or significant anemia) due to invasive nature of bone-marrow 
aspiration 
• Previous or current history of a coagulation disorder 
• Any metal in the body, which is contraindicated for MRI studies 
• Allergy to any of the antibiotics used in this study, e.g.tobramycin, vancomycin, or 
gentamicin 
• Allergy to, or have had adverse reactions to gadolinium or other contrast agents 
to be used in the study 
• Patients with alcohol or other substance abuse problems that may affect stem cell 
growth; habitual drug (including marijuana and nicotine) abusers, will be excluded 
from the study 
• Other major disease that, in the opinion of the Principal Investigator, would 
preclude participation in the study 
• Patients with HBV, HCV, syphilis, HIV-1, or HIV-2.  

 
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• Any evidence of significant cognitive dysfunction based on a screening history 
and physical examination because it would preclude giving a truly informed 
consent 
• Patients who are enrolled in another clinical trial for MS treatment or who have 
received any study drug/biologics within the last 6 months. Additionally, while in 
the trial, patients may not enroll in any other clinical trial for MS or any other 
condition. 
• Patients who are anticipated to have difficultly accessing the intrathecal space 
related to scoliosis, obesity, or any other relevant factors determined by the PI. 
 
 
 
5. Study Drug(s): 
 
Drug: Clinical-grade autologous bone marrow mesenchymal stem cell-derived neural 
progenitors (MSC-NPs) are manufactured according to Chemistry, Manufacturing and 
Controls (CMC) section of IND 13889 (approved by FDA in August 2013). Briefly, 
mesenchymal stem cells (MSCs) are isolated from the bone marrow mononucleated cell 
fraction based on plastic adherence, and expanded in media containing 5% human 
platelet lysate (PLT). MSCs were cryopreserved after 2 and 3 passages, generating a 
stock of cells sufficient for at least 10 subsequent expansions. For each treatment, a vial 
of MSCs is thawed, expanded for 2 to 3 more passages, then cultured for 2-3 weeks in 
neural progenitor maintenance medium containing growth factors EGF and bFGF to 
generate neural progenitors (MSC-NPs). Just prior to the injection, MSC-NPs are 
collected, washed, counted, and resuspended in saline for immediate intrathecal 
administration. All manufacturing procedures were conducted in a cGMP clean-room 
facility by specifically trained personnel.  
 
Product Release testing: Quality testing is conducted at multiple steps during MSC-NP 
manufacturing. Bone marrow-derived MSCs are tested for MSC characteristics 
including growth, morphology, cell surface expression (CD105+/CD73+/CD90+/CD45-
/CD34-/CD14-/CD20-/HLA-DR-), osteogenic and adipogenic differentiation potential, and 
sterility. During each expansion of cells for dosing, cells were tested for chromosomal 
stability, neurosphere morphology of MSC-NPs, cell number, cell viability, and sterility 
(fungal and bacterial/mycoplasma). In addition, identity testing of MSC-NPs is 
performed to confirm gene upregulation of CXCR4, Nestin, TLR2, and HGF and 
downregulation of SMA (smooth muscle isoform of alpha actin) and Thy1 (CD90) in 
MSC-NPs compared to the MSCs from which they were derived.  
 
Dose: Between 5 to 10 million MSC-NPs will be administered intrathecally in each dose. 
10 million cells is the maximum dose. Treatment will consist of 6 doses spaced 2 
months apart. 
 
 
 
 

 
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5.1 Study drug compliance/adherence 
 
All lumbar punctures will be performed by the treating clinician (the study PI, Dr. 
Sadiq) on an outpatient basis at Tisch MSRCNY. These appointments will be 
confirmed months in advance to ensure compliance. Whether the subject is 
receiving intrathecal injections of autologous MSC-NPs or getting placebo (only 
undergoing a lumbar puncture), each procedure will take approximately 20 
minutes. Prior to all lumbar punctures, a trained infusion nurse will infuse patients 
with 1 gram of vancomycin and 80 mg of tobramycin to prevent the occurrence of 
meningitis. This infusion takes approximately four hours. Vancomycin is the drug 
of choice for S. epidermidis, a potential contaminant from the skin during the 
lumbar puncture procedure. It is also the drug used to treat penicillin-resistant S. 
pneumoniae. Vancomycin is also indicated in empiric use in meningitis until an 
organism has been identified. Tobramycin is synergistic with vancomycin and is 
also the treatment of choice for pseudomonas infections. Vancomycin and 
tobramycin are indicated for empiric treatment of neurosurgery-related meningitis 
at most institutions. Vital signs will be performed on both groups to monitor 
safety.  These visits will last approximately 5 hours.  Study subjects will be 
instructed to stay in bed and limit any physical activity for the 24 hours following 
each procedure. Patients will be asked to take Tylenol every 6 hours for two days 
after each treatment. Based on the data from our Phase I trial it is anticipated 
that patients may show signs of headache when given stem cells. Hence 
providing patients with Tylenol will help maximize patient blinding. 
 
5.1.1 Withdrawal of subjects due to non-compliance/adherence 
 
Subjects have the right to voluntarily withdraw from the study at any time for 
any reason.  If a subject becomes non-compliant, defined as failure to 
complete study treatment visits, they will be discontinued from the trial and a 
new subject from the same EDSS block would receive the non-compliant 
subject’s treatment allocation. Additionally, a subject could become non-
compliant if a urine screen tests positive suggesting abuse of drugs, including 
nicotine. If this were to happen, they will be discontinued from the trial and a 
new subject would receive the non-compliant subject’s treatment allocation. 
 
5.2  Study drug supplies 
 
5.2.1 Formulation and packaging 
 
Treatment group: Freshly harvested autologous MSC-NPs will be resuspended 
in approximately 1.0 ml preservative-free saline and transferred to a sterile 
1.5ml tube, which is capped and placed inside a sterile, pre-labeled transport 

 
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tube (50ml conical tube). The cell suspension has the appearance of a white 
cloudy suspension. The study subject will not see the drug prior to 
administration. The transport tube will be labeled as follows: 
 
ID: 
 
 
 
  
 
Date:  
 
 
 
 
Sample: MSCNP cells in saline 
Cell number: 
 
 
 
Viability:  
 
 
     
Expiration: for use on the above date only 
FOR AUTOLOGOUS USE ONLY 
CAUTION: New Drug - Limited by Federal  (or United States) law to investigational use 
 
 
Placebo group: Approximately 1.0ml of saline will be placed in 1.5ml tube, 
which will be placed inside a pre-labeled transport tube. The study subject will 
not see the tube. The contents of the tube will not be administered. Placebo will 
be labeled with the following label: 
 
ID: 
 
 
 
  
 
Date:  
 
 
 
 
Sample: saline 
Cell number: 
n/a 
 
 
Viability:  
n/a 
 
     
Expiration: for use on the above date only 
NOT FOR ADMINISTRATION 
CAUTION: New Drug - Limited by Federal  (or United States) law to investigational use 
 
 
 
5.2.2 Drug administration 
 
Treatment group: Intrathecal injections of autologous MSC-NPs will be performed 
by the treating clinician (the study PI, Dr. Sadiq), according to the following 
standard procedure. However, if necessary, a board-certified neurologist (clinical 
fellow) at the IMSMP will perform the LP procedure. Any personnel involved in 
product/placebo administration will not be performing subject assesments, and 
will not be involved in the study otherwise. The patient is either seated and bent 
over or positioned lying down with their knees to their chest.  A nurse will assist 
to maintain this position. The lumbar region is cleaned with betadine and a sterile 
drape is applied. As a local anesthetic, 1 cc of lidocaine (1%) is administered 
subcutaneously at the L3-L4 interspace. A sterilized lumbar puncture adult tray 
(CareFusion/ Henry Schien, Cat. number 4301C) will be used. A standard LP kit 
has a 20 gauge needle; however, in this study a 24 gauge, non-traumatic BD 
Whitacre pencil point Spinal needle (Ref number 405133) will be used to lower 
the incidence of headaches associated with spinal taps. Dr. Sadiq will aspirate 10 
mL of CSF at the L3-L4 level using a sterile 24 gauge needle to confirm accurate 
access to the intrathecal space. CSF will be transferred to a 15ml specimen tube 

 
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and transported to the laboratory for processing. If access is limited at the L3-L4 
level, the L2-L3 level will be used as an alternative site. The cells will be removed 
from the 1.5 ml transport vial using a 22 gauge needle 10cc syringe, re-
suspended in 3 mL of preservative-free sterile saline and gently mixed by 
passage through a 22 gauge needle several times to break up any remaining cell 
clusters to ensure a uniform suspension. The cell/saline suspension will be 
injected intrathecally and chased by up to 7 mL of preservative-free sterile saline 
to ensure complete deposition of stem cells into the intrathecal space and to 
prevent material from concentrating at the site of injection. This procedure will 
take approximately 20 minutes. The entirety of the procedure will take place 
posterior to the study subject, thus ensuring they remain blinded to the treatment.  
 
Patients who have an intrathecal Medtronic pump installed for spasticity and pain 
management will be given the stem cells through the side port of the pump. The 
patient will be lying flat for the procedure with their pump exposed.  The 
abdominal region where the pump is located is cleaned with betadine and a 
sterile drape is applied.  A sterilized Medtronic Catheter Access Port Kit 
(Medtronic Inc product number 8540) will be used. The side port will be accessed 
with a 25-gauge non-coring needle.  Dr. Sadiq will aspirate 1.5 mL of fluid from 
the side port to clear the catheter of any therapeutic drug in pathway that will be 
disposed of. CSF will be transferred to a 15ml specimen tube and transported to 
the laboratory for processing. The cells will be removed from the 1.5 ml transport 
vial using a 22-gauge needle 10cc syringe, re-suspended in 3 mL of 
preservative-free sterile saline and gently mixed by passage through a 22 gauge 
needle several times to break up any remaining cell clusters to ensure a uniform 
suspension. After the cells are injected through the side port, extra saline will be 
flushed through to make sure that the stem cells have been cleared out of the 
side port catheter. Following the procedure, a prime bolus will be administered 
via Medtronic programmer to ensure continuous supply of the patient’s medicine. 
For the entirety of the procedure, the subject will be blindfolded, thus ensuring 
they remain blinded to the treatment.  
 
 
Placebo group: For the six placebo treatment visits, subjects will undergo 
standard lumbar punctures as described above but with no cell injections. Ten 
mL of CSF will be collected for biomarker analysis at each lumbar puncture. The 
treating physician (Dr. Sadiq) will perform a mock procedure to imitate cell 
resuspension and delivery. Three ml of preservative-free sterile saline will be 
injected, and this will be given with up to 7 mL flush of preservative-free sterile 
saline. The entire procedure will take approximately 20 minutes. All subjects in 
the placebo group will get treated with antibiotics as well in the same regimen 
indicated above for the treatment group. The entirety of the procedure will take 
place posterior to study subject, thus ensuring they remain blinded to the 
treatment. 
 

 
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Patients who have an intrathecal Medtronic pump installed for spasticity and pain   
management will be given the placebo through the side port of the pump as 
described above. 
 
 
5.4 Study drug storage and accountability 
 
The study drug (autologous MSC-NPs) is a biologic and each batch of drug is 
prepared according to each study subject’s treatment schedule. Each study 
subject is given a unique alphanumeric ID that is used to label all cells derived 
from that patient. Each ID is recorded in a study subject ID assignment log that 
documents the patient’s name and information. The log will be kept in a secure 
data base accessible only by un-blinded investigators.  
 Cryopreserved cells (MSCs) can be stored indefinitely with no expiration date. 
Any unused, cryopreserved cells will be donated for research purposes after the 
trial is completed, as detailed in the informed consent form. Expanded cells 
(MSC-NPs) are harvested just prior to the injection and injected within an hour 
after preparation. There is no storage period and no shipping. A sample of the 
final product MSCNP cells is preserved for quality testing purposes. These cells 
are lysed for RNA extraction. All commercial reagents will be used within 
manufacturers’ expiration dates. 
 
5.5 Concomitant Medications 
 
 
Patients will be allowed to continue with their regular course of therapy excluding 
any systemic chemotherapeutic and anti-mitotic agents. Patients who are on 
such medications will not be enrolled in this study. Patients are excluded from the 
study if there is a change of disease modifying agent <12 months prior to 
beginning treatment, or if there is a change in MS symptom management 
treatment, including Ampyra (dalfampridine) <6 months prior to beginning 
treatment. Additionally, no changes to disease modifying agent or MS symptom 
management treatment will be made during the course of the study. However, if 
there is clinical improvement, a patient may discontinue their MS symptom 
management drug. Patients will be asked to take Tylenol every 6 hours for two 
days after each treatment. Based on the data from our Phase I trial it is 
anticipated that patients may show signs of headache when given stem cells. 
Hence providing Tylenol will help maximize patient blinding. 
 
5.6 Specimen Collection 
 
 
CSF and blood specimens will be collected from all patients for exploratory 
biomarker discovery and validation. Approximately 10 mL of CSF will be 
collected at each of the 12 lumbar puncture procedures (treatment and placebo 
visits), just prior to intrathecal injections of the same volume of cells or saline. 
One additional CSF sample will be withdrawn at the month 27 follow up visit. 
Blood samples will also be collected at the same time as CSF collection. One 
approximately 6 mL blood sample will be collected in a tube with EDTA for 

 
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plasma isolation, and another approximately 6 mL blood sample will be collected 
in a tube without EDTA for serum isolation. All specimens will be used for 
research purposes to identify and/or verify biomarkers that correlate with disease 
progression or clinical response to IT-MSC-NP therapy. Candidate protein 
biomarkers, including neurofilament light, will be analyzed by single analyte 
ELISA or multi analyte Luminex. 
 
5.7  MRI Protocol 
 
 
 
Brain, cervical and thoracic spine MRI scans will be scheduled at baseline, and 
 
at months 13, 27, and 36 using 3Tesla Siemens MAGNETOM VERIO scanners. 
 
Assessments will include the following: 
• Proton density and T2-weighted two-dimensional (2D) multislice turbo/fast 
spin-echo 
• T1-weigted three-dimensional (3D) spoiled gradient recalled echo both pre-
contrast and after a 10 minute delay following injection of gadolinium post-
contrast sequencing 
• 2D T2 weighted Fluid -Attenuated Inversion Recovery (FLAIR) 
• MTR MR tractography dependent on the number of tracts followed  
• DTI – A T2 SPC 3D Flair sagittal sequence, EP diffusion, and a gradient filed 
 
mapping 
Using the CorTechs NeuroQuant software package a multi-structure atrophy 
 
report will be generated for all brain MRI scans as well as a Lesion Quant Flair 
 
assessment of total number and volume of lesions; the total number and volume 
 
of enlarging lesions and the total number and volume of new lesions. 
All lesions to be counted would have to be at least 3 voxels in size. For lesions 
 
to be considered enhancing an increase in intensity by at least 20% on the post-
 
contrast images compared to the baseline T1 sequence lesions.  
The total number of new or enlarging T2 hyperintense lesions as detected by 
 
MRI will be assessed by a negative binomial model. Percentage change in total 
 
brain volume from baseline will be assessed using an MMRM analysis.   
 
 
 
6. Research Study Procedures: 
 
Please see Schedule of activities (Study Table) Section 6.4 for the schedule of 
assessments performed during the study.   
 
6.1 Screening procedures (Month 4; within 4 months prior to first 
treatment): 
 
• Candidates believed to meet the inclusion/exclusion criteria will first attend a 
pre-enrollment visit where the details of the informed consent form (ICF) will be 
explained in depth.  

 
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• Subjects will be told that their participation is voluntary and that their regular MS 
treatment will continue whether or not they enter the study. Consent for 
participation in the study will be obtained by any of the examining neurologists, 
the clinical trials manager, or by one of the study nurses, and documented in the 
subject’s study file during the initial screening visit. An explanation and 
justification for the study will be given to the participant at this time. Consenting 
will occur after having had ample time to read the ICF, speak to family and 
friends, and review the consent with and ask questions of the consenting 
neurologist or study nurse. Patients will be given a copy for their records. 
• Subjects will then undergo the following examinations to confirm eligibility for 
study participation 
o Complete physical examination with vital signs 
o Complete neurological examination 
o EDSS 
o Infectious Disease Questionnaire 
o Pregnancy test (for female patients of child-bearing age)  
o Infectious disease testing including HIV Test 
o Urine tests for drug/nicotine abuse (In addition to the screening period, 
a drug/nicotine urine test could be done at any time during the study 
for random testing) 
 
• The EDSS evaluations will be done by the examining neurologists at Tisch 
MSRCNY. Every attempt will be made to have the same examining neurologist 
for each patient for the study duration. Examining neurologists will perform 
objective physical and neurological examinations during the study to evaluate 
efficacy, and will be blinded to the treatment 
• All patients will be required to go to a clinical laboratory facility to undergo a 
panel of infectious disease screening. The results will be sent to the screening 
neurologist, and any patient positive for any infectious diseases will be 
excluded from the study.   
• Screening Blood Draw  
• The initial screening will last 1 hour. 
 
 
6.2  Study drug procedures 
 
Bone Marrow Visit (Month -3): 
 
• This visit will occur approximately one month after enrollment and 
approximately 3 months prior to the first treatment.  
• Vital signs will be documented 
• A bone marrow aspiration will be performed by Dr. Gabriel Sara, an 
experienced, board certified hematologist affiliated with the Tisch MSRCNY. 
Dr. Sara will obtain a bone marrow aspirate from the sternum or the iliac crest 
under sterile conditions following standard procedure. An adult bone marrow kit 
with a heparinized syringe will be used. 

 
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• Bone marrow aspirate will be obtained from the manubrium of the sternum, at 
the level of the second intercostal space. Alternatively, aspirate may be 
obtained from the iliac crest. Bone marrow will be aspirated using an adult 
bone marrow kit with a heparinized syringe.  
• Each research subject’s sterile bone marrow sample will be placed in a pre-
labeled bag and immediately transferred from the clinic to the stem cell culture 
laboratory. Patients will be told not to shower or get their bandage wet for 24 
hours following the procedure. In order for patients to move to the next phase 
of the study, their cells must be viable and pass bone marrow release testing. If 
for some reason cells do not thrive, the patient’s involvement in the study will 
be reevaluated.  
• Total duration of the Bone Marrow Visit is approximately 2 hours and will be 
conducted at the Tisch MSRCNY due to necessary proximity to the cell 
manufacturing laboratory. 
• Cells from subjects who have had bone marrow harvested under the long-term 
ongoing research protocol, “Harvesting Bone Marrow for Neural Stem Cells” 
(Former St. Luke’s-Roosevelt IRB# 08-049) (Current WIRB# 20162012), can 
be used for implantation as long they are deemed acceptable for use (and 
eliminate any risk from an unnecessary marrow harvesting procedure). This 
includes bone marrow harvested under this long-term ongoing research 
protocol harvested prior to enrollment in this study. 
 
Baseline Visit (Month-1; within one month prior to first treatment):  
 
• The purpose of the baseline visit is to establish baseline values of outcome 
assessments prior to treatment.  
• The following baseline visit exams will be conducted by study subject’s 
examining neurologist and study coordinator (duration approximate 1 hour) 
• Vital signs-Only if not performed at screening 
• Physical exam-Only if not performed at screening 
• Neurological exam-Only if not performed at screening 
• Headache pain scale 
• EDSS-Only if not performed at screening 
• MSFC 
• 6 Minute Walk Test 
• 12 Item MS Walking Scale 
• Bladder Survey 
• Urinalysis and Culture to screen for UTI 
• The following exams will be scheduled to occur within one month prior to the 
first treatment 
• MRI (brain, C and T spine) ± Gadolinium enhancement  
• Urodynamic testing of bladder compliance (ability of bladder to fill without 
accompanying rise in bladder pressure) 
 
Treatment Phase visits, year 1 (Month 0, 2, 4, 6, 8, and 10): 

 
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• Treatment/placebo visits will be conducted at the Tisch MSRCNY every 2 
months (± 1 week)  
• Details regarding treatment/placebo procedures detailed in section 5.2.2 above 
• Treatment visits will be conducted by the treating neurologist, Dr. Sadiq 
• Duration of treatment visits will last approximately 5 hours  
• Study subjects will be instructed to stay in bed and limit any physical activity for 
the 24 hours following each procedure. 
• CSF for biomarker analysis discussed in 5.2.2   
• Blood draw for serum and plasma biomarker analysis  
• Vital Signs 
• EDSS and MSFC (Month 6 Only) Follow-up by phone will occur 48 hours, 1 
week and 1 month after each treatment visit. The purpose of the follow-up 
phone call is safety assessment and to document any adverse events. Calls 
will be made either by the clinical trial manager, the clinical research 
assistants, or the adverse event physician. Assessment will include the 
following: 
• Headache pain scale 
     
 Outcome assessments I (Month 13) 
 
• The purpose of outcome assessment I visit is to evaluate effects of the 
treatment compared to the baseline visit, as well as to serve as a baseline visit 
for the crossover treatment phase.  
• The following exams will be conducted 3 months following the 6th treatment 
phase visit (± 1 week)  
o Vital signs 
o Physical exam 
o Neurological exam 
o Headache pain scale 
o EDSS 
o MSFC 
o 6 Minute Walk Test 
o 12 Item MS Walking Scale 
o Bladder Survey 
o Urinalysis and Culture to screen for UTI 
 
• The following exams will be scheduled to occur 3 months following the 6th 
treatment visit (± 1 week) 
o MRI (brain, C and T spine) ± Gadolinium enhancement 
o Urodynamic testing of bladder compliance (ability of bladder to fill 
without accompanying rise in bladder pressure) 
 
 
Treatment Phase visits, year 2 (Month 14, 16, 18, 20, 22, and 24): 

 
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• Crossover treatment/placebo visits will be conducted at the Tisch MSRCNY 
every 2 months (± 1 week)  
• Details regarding treatment/placebo procedures detailed in section 5.2.2 above 
• Treatment visits will be conducted by the treating neurologist, Dr. Sadiq 
• Duration of treatment visits will last approximately 5 hours 
• Study subjects will be instructed to stay in bed and limit any physical activity for 
the 24 hours following each procedure. 
• CSF for biomarker analysis discussed in 5.2.2  
• Blood draw for serum and plasma biomarker analysis  
• Vital Signs 
• EDSS and MSFC (Month 20 Only). Follow-up by phone will occur 48 hours, 1 
week, and 1 month after each treatment visit. The purpose of the follow-up 
phone call is safety assessment and to document any adverse events. Calls 
will be made either by the clinical trial manager, the clinical research 
assistants, or the adverse event physician. Assessment will include the 
following: 
• Headache pain scale 
 
Outcome assessments II (Month 27): 
• The purpose of outcome assessment II visit is to evaluate effects of the 
treatment group in year 2 compared to the baseline visit at the beginning of 
year 2. In addition, these assessments will be used to evaluate any sustained 
effects of the treatment in year 1. 
• The following exams will be conducted 3 months following the 12th treatment 
visit (± 1 week) by the study subject’s examining neurologist and study 
coordinator 
• Vital signs 
• Physical exam 
• Neurological exam 
• Headache pain scale 
• EDSS 
• MSFC 
• 6 Minute Walk Test 
• 12 Item MS Walking Scale 
• Bladder Survey 
• Urinalysis and Culture to screen for UTI 
• Lumbar Puncture with CSF Aspiration for biomarker analysis 
• Blood draw for serum and plasma biomarker analysis 
• The following exams will be scheduled to occur 3 months following the 12th 
treatment visit (± 1 week)  
• MRI (brain, C and T spine) ± Gadolinium enhancement 
• Urodynamic testing of bladder compliance (ability of bladder to fill without 
accompanying rise in bladder pressure) 
 
 

 
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6.3  Follow-up procedures   
 
• Treatment phase follow-up: Follow-up by phone will occur 48 hours,1 week and 1 
month after each treatment visit. A total of 24 follow-up calls will be made over 
the duration of the study. The purpose of the follow-up phone call is safety 
assessment and to document any adverse events. Calls will be made either by 
the clinical trial manager, the clinical research assistants, or the adverse event 
physician. Assessment will include the following: 
o Headache pain scale 
 
• Long-term follow-up (Month 36, ± 3 weeks): The purpose of the follow-up is to 
assess long-term safety and efficacy at the end of the study. The following exams 
will be conducted by the study subject’s examining neurologist and study 
coordinator: (duration approximate 1 hour)  
• Vital signs 
• Physical exam 
• Neurological exam 
• Headache pain scale 
• EDSS 
• MSFC 
• 6 Minute Walk Test 
• 12 Item MS Walking Scale 
• MRI (brain, C and T spine) ± Gadolinium enhancement will be scheduled to occur 
at end of study  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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6.4 Schedule of activities (Study Table) 
    
 
 
1Screening Blood Draw will include CBC with differential, ESR, Comprehensive Metabolic Panel, PT/PTT, and 
Thyroid Function Tests 
2+/- 1 Week Window allowed for all Treatment Phase Visits and Outcome Assessments    
3+/- 3 Week Window for all Final Follow-Up  
Abbreviations: ICF, informed consent form; FU, follow-up; LP, lumbar puncture; UD, urodynamic testing 
4Only required if not done during screening visit 
5In addition to the screening period, a drug & nicotine urine testing could be done for random testing at any time 
during the study 
6Only in month 6 
7Only in month 20 
 
 
 
 

 
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7. Safety and Effectiveness Assessments:  
 
7.2 Safety assessments 
 
Research subjects will be routinely assessed for safety at all study visits and 
during follow-up telephone calls. Subjects will also be consistently asked to 
complete the headache pain scale. Safety assessments include monitoring for 
adverse events, vital signs, physical and neurological examination, and MRIs.  
 
Information regarding a history of a previous positive COVID-19 test or inoculation with 
a COVID-19 vaccine will be collected. 
 
7.2 Effectiveness assessments 
 
Research subjects will be evaluated for effectiveness by EDSS, urodynamic 
testing, MSFC, 12 item MS walking scale, time to disability progression, 
progression on MRI (total T2 lesion volume and total brain volume), and 6-minute 
walk test. 
 
 
8. Adverse Event Reporting: 
 
8.1 Adverse event definitions   
 
Adverse event means any untoward medical occurrence associated with the use 
of the drug in humans, whether or not considered drug related. 
 
Adverse reaction means any adverse event caused by a drug. 
 
Suspected adverse reaction means any adverse event for which there is a 
reasonable possibility that the drug caused the adverse event.  Suspected 
adverse reaction implies a lesser degree of certainty about causality than 
“adverse reaction.” 
 
• Reasonable possibility.  For the purpose of IND safety reporting, “reasonable 
possibility” means there is evidence to suggest a causal relationship between 
the drug and the adverse event. 
 
Life-threatening, suspected adverse reaction.  A suspected adverse reaction is 
considered “life-threatening” if, in the view of either the Investigator (i.e., the 
study site principal investigator) or Sponsor, its occurrence places the patient or 

 
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research subject at immediate risk of death.  It does not include a suspected 
adverse reaction that had it occurred in a more severe form, might have caused 
death. 
 
Serious, suspected adverse reaction. A suspected adverse reaction is 
considered “serious” if, in the view of the Investigator (i.e., the study site principal 
investigator) or Sponsor, it results in any of the following outcomes: death, a life-
threatening adverse reaction, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant incapacity or substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect. 
 
• Important drug-related medical events that may not result in death, be life-
threatening, or require hospitalization may be considered “serious” when, 
based upon appropriate medical judgment, they may jeopardize the research 
subject and 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 the 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. 
 
Unexpected, suspected adverse reaction.  A suspected adverse reaction is 
considered “unexpected” if it is not listed in the general investigational plan, 
clinical protocol, or elsewhere in the current IND application; or is not listed at 
the specificity or severity that has been previously observed and/or specified.  
 
8.2 Recording/Reporting requirements   
 
8.2.1 Eliciting adverse event information 
 
Research subjects will be routinely questioned about adverse events at all 
study visits and during follow-up telephone calls. Subjects will also be 
routinely asked to complete the headache pain scale. 
 
8.2.2 Recording requirements   
 
All observed or volunteered adverse events (serious or non-serious) and 
abnormal test findings, regardless of study group or suspected causal 
relationship to the study drug(s) will be recorded in the subjects’ case 
histories.  For all adverse events, sufficient information will be pursued and/or 
obtained so as to permit 1) an adequate determination of the outcome of the 
event (i.e., whether the event should be classified as a serious adverse event) 
and; 2)  an assessment of the casual relationship between the adverse event 
and the study drug(s).    
 
Adverse events or abnormal test findings felt to be associated with the study 
drug(s) will be followed until the event (or its sequelae) or the abnormal test 

 
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27 
finding resolves or stabilizes at a level acceptable to the safety assessing 
neurologist (Dr. Williams or Dr. Stark). Whichever neurologist is seeing the 
subject for assessments will not be the neurologist assessing safety for that 
subject. Each subject will have a separate examining neurologist and safety 
assessing neurologist. Monitoring and adjudication of all adverse events 
(serious or non-serious) will be performed in a sequential reporting manner. 
All patients will be provided a 24-hour hotline for reporting of any adverse 
effects. Initial screening will be performed by the clinical nursing team and all 
adverse events will be reported to the corresponding safety assessing 
neurologist for further evaluation. The treating and examining neurologists will 
not be involved in the notification of any adverse effects. Adjudication of all 
adverse events (serious or non-serious will be determined by one of the 
safety assessments neurologist (sub-investigators Dr. Williams or Dr. Stark). 
Additionally, all serious adverse events will be reported to the DSMB 
immediately (24 to 48 hours) and they will adjudicate the adverse event and 
recommend unblinding, if necessary. Any non-serious adverse events will be 
reported to the DSMB on a half-yearly basis. 
 
8.2.2.1 Abnormal test findings   
 
An abnormal test finding will be classified as an adverse event if one or 
more of the following criteria are met: 
 
• The test finding is accompanied by clinical symptoms 
 
• The test finding necessitates additional diagnostic evaluation(s) or 
medical/surgical intervention; including significant additional 
concomitant drug treatment or other therapy  
 
o Note: simply repeating a test finding, in the absence of any of the 
other listed criteria, does not constitute an adverse event.   
 
• The test finding leads to a change in study drug dosing or 
discontinuation of subject participation in the clinical research study 
 
• The test finding is considered an adverse event by the Sponsor-
Investigator of the IND application 
 
 
8.2.2.2 Causality and severity assessment   
 
One of the safety assessments neurologist (sub-Investigators Dr. Williams 
or Dr. Stark) of the trial will promptly review documented adverse events 
and abnormal test findings to determine 1) if the abnormal test finding 
should be classified as an adverse event; 2) if there is a reasonable 
possibility that the adverse event was caused by the study drug(s); and 3) 
if the adverse event meets the criteria for a serious adverse event. 

 
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If the final determination of causality is “unknown and of questionable 
relationship to the study drug(s)”, the adverse event will be classified as 
associated with the use of the study drug(s) for reporting purposes.  If the 
final determination of causality is “unknown but not related to the study 
drug(s)”, this determination and the rationale for the determination will be 
documented in the respective subject’s case history.  
 
8.3 Reporting of adverse reactions   
 
8.3.1 Reporting of adverse reactions to the FDA 
 
8.3.1.1 Written IND Safety Reports 
 
The Sponsor-Investigator will submit a written IND Safety Report (i.e., 
completed FDA Form 3500 A) to the responsible new drug review division 
of the FDA for any observed or volunteered adverse event that is 
determined to be a serious and unexpected, suspected adverse reaction.  
Each IND Safety Report will be prominently labeled, “IND Safety Report”, 
and a copy will be provided to all participating investigators (if applicable) 
and sub-investigators.   
 
Written IND Safety Reports will be submitted to the FDA as soon as 
possible and, in no event, later than 15 calendar days following the 
Sponsor-Investigator’s receipt of the respective adverse event information 
and determination that it meets the respective criteria for reporting. 
 
For each written IND Safety Report, the Sponsor-Investigator will identify 
all previously submitted IND Safety Reports that addressed a similar 
suspected adverse reaction experience and will provide an analysis of the 
significance of newly reported, suspected adverse reaction in light of the 
previous, similar report(s) or any other relevant information. 
 
Relevant follow-up information to an IND Safety Report will be submitted 
to the applicable review division of the FDA as soon as the information is 
available and will be identified as such (i.e., “Follow-up IND Safety 
Report”).   
 
If the results of the Sponsor-Investigator’s follow-up investigation show 
that an adverse event that was initially determined to not require a written 
IND Safety Report does, in fact, meet the requirements for reporting; the 
Sponsor-Investigator will submit a written IND Safety Report as soon as 
possible, but in no event later than 15 calendar days, after the 
determination was made. 
 

 
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8.3.1.2 Telephoned IND Safety Reports – Fatal or life-
threatening suspected adverse reactions 
 
 
In addition to the subsequent submission of a written IND Safety Report 
(i.e., completed FDA Form 3500A), the Sponsor-Investigator will notify the 
responsible review division of the FDA by telephone or facsimile 
transmission of any unexpected, fatal or life-threatening suspected 
adverse reaction.  
 
The telephone or facsimile transmission of applicable IND Safety Reports 
will be made as soon as possible but in no event later than 7 calendar 
days after the Sponsor-Investigator’s receipt of the respective adverse 
event information and determination that it meets the respective criteria for 
reporting. 
 
 
 
8.3.2 Reporting adverse events to the responsible IRB 
 
In accordance with applicable policies of WIRB (Western Institutional Review 
Board), the Sponsor-Investigator will report, to the IRB, any observed or 
volunteered adverse event that is determined to be 1) associated with the 
investigational drug or study treatment(s); 2) serious; and 3) unexpected.  
Adverse event reports will be submitted to the IRB in accordance with the 
respective IRB procedures.  
 
Applicable adverse events will be reported to the IRB as soon as possible 
and, in no event, later than 10 calendar days following the sponsor-
investigator’s receipt of the respective information.  Adverse events which are 
1) associated with the investigational drug or study treatment(s); 2) fatal or 
life-threatening; and 3) unexpected will be reported to the IRB within 24 hours 
of the Sponsor-Investigator’s receipt of the respective information.  
 
Follow-up information to a reported adverse event will be submitted to the IRB 
as soon as the relevant information is available.  If the results of the Sponsor-
Investigator’s follow-up investigation show that an adverse event that was 
initially determined to not require reporting to the IRB does, in fact, meet the 
requirements for reporting; the Sponsor-Investigator will report the adverse 
event to the IRB as soon as possible, but in no event later than 10 calendar 
days, after the determination was made. 
 
8.4 Withdrawal of subjects due to adverse events 

 
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If any of the following events occur during treatment, patients will be discontinued 
from the study: 
§ Acute worsening of MS symptoms 
§ Any neurological deficit that is unexplained by another condition and is non-
reversible within 24 hours of its development 
§ Any sign of nervous system infection 
§ Any changes in cognitive function 
§ Any unexpected adverse medical event that is unexplained by another medical 
condition 
§ Any time the Data Safety Monitoring Board feels a patient should be withdrawn 
from the study 
§ Patient meets an exclusion criterion 
§ Pregnancy  
 
Should a patient meet any of the above criteria for early termination, he or she 
will be discontinued from the trial and will be replaced. Subjects that are 
discontinued from the study will continue to undergo the follow-up visits relative 
to their last treatment. They will also undergo long-term follow-up safety visits as 
described. All data gathered at these appointments will be included in the CRF 
and data set. Should a study subject terminate the study due to pregnancy, no 
MRI will be performed during the course of the pregnancy. 
 
 
9. Statistical Methods/Data Analysis: 
 
Detailed descriptions relating to data handing and statistical analysis is presented in 
the Statistical Analysis Plan (SAP). 
 
 
9.1 Study endpoints 
 
9.1.1 Primary endpoint(s) 
 
Primary efficacy outcome will be a composite score based on EDSS (our 
EDSS assessments will be based only on pyramidal and brainstem FSS, and 
performed by a blinded examiner), T25FW, and 9HPT (EDSS-Plus) [6]. 
Improvement will be defined by at least one of the following three measures: 
≥0.5 improvement in EDSS (if EDSS at entry is ≥ 6.0) or ≥ 1.0 improvement in 
EDSS (if EDSS at entry is ≤5.5), ≥20% improvement in T25FW, or ≥20% 
improvement in 9HPT in either dominant or non-dominant upper limb. Scores 
will be compared within patients between the baseline and various post-
treatment visits. Scores will also be compared between different treatment 
groups at various post-treatment visits. Assessments will be made at Baseline 
(within 4 months of first treatment/placebo), Month 6 (just prior to 4th 

 
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treatment/placebo), Month 13 (3 months post 6th treatment/placebo), Month 
20 (just prior to 10th treatment/placebo), and Month 27 (3 months post 12th 
treatment/placebo). Long-term follow-up assessment will be conducted at 
Month 36. The primary outcome will be the comparison of the composite 
scores at Month 13 (3 months after the 6th treatment/placebo) compared to 
baseline.  
 
 
 
9.1.2 Secondary endpoints 
 
• EDSS (Improvement defined by ≥0.5 improvement in EDSS if EDSS at entry 
is ≥ 6.0, or ≥ 1.0 improvement in EDSS if EDSS at entry is ≤5.5) 
• T25FW (≥20% improvement)  
• 9HPT (≥20% improvement) 
• MSFC  
• 12-item MS Walking Scale 
• Urodynamic Studies 
• Progression on MRI (measured by percent change from baseline in total 
volume of T2 Lesions and percent change from baseline in total brain 
volume at month 13, month 27, and month 36) 
• Time to Progression (measured at month 13, month 27, and month 36) 
• Six Minute Walk Test 
 
9.2 Sample size determination  
 
Power analysis was conducted by Dr. Linda Gerber, Professor of Healthcare Policy 
& Research and Professor of Epidemiology in Medicine at Weill Cornell Medicine, 
who will provide statistical consultations throughout the study. Power analysis was 
based on 20 participants in each group of the Phase II study. Group sample size of 
20 in the treatment group and 20 in the placebo group achieve more than 80% 
power to detect a difference between the group proportions of 35%, using a two-
sided Z-test with pooled variance and using a significance level of 0.05. This 
calculation assumes that 40% of patients in the treatment group and 5% of patients 
in the placebo group achieve at least one of the EDSS-Plus components. The 
prevalence of patients with improved outcome is informed by the results of our 
Phase I trial, in which 40% of patients experienced a decrease of 0.5 or more on 
EDSS. A total of 50 patients (25 patients in each group) will initially be enrolled to 
account for an expected attrition rate of 20%.  
 
 
9.3 Effectiveness analysis 
 
All statistical analysis will be performed by Dr. Linda Gerber and her team. 
Descriptive statistics will be calculated for patients at baseline for the entire cohort 

 
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as well as by treatment status. Treatment and placebo group patients will be 
compared on continuous and discrete baseline characteristics to assess 
randomization. The EDSS-Plus scale [6] will be used as our primary endpoint with 
improvement on one or more of the 3 components (EDSS, T25FW and 9HPT). 
Improvement is defined as ≥1point decrease from baseline EDSS if EDSS at entry 
is ≤5.5, and a ≥0.5 point decrease from baseline EDSS if EDSS at entry is ≥6.0, ≥ 
20% positive change in T25FW, and/or ≥ 20% positive change in 9HPT confirmed. 
The primary endpoint of improvement on one or more of the 3 EDSS-Plus 
categories between treatment and placebo groups will be assessed bi-variately 
using the chi-square or Fisher’s exact test, as appropriate, at year 1, 2, and 3 of the 
study. The three components of the EDSS-Plus composite score will also be 
assessed individually at all time points. A longitudinal linear mixed-effect model will 
be used to assess longitudinal change (percentage change in mean time) from 
baseline to 3 years for T25FW and 9HPT, with random intercepts for patients and 
taking into account treatment status (treatment vs placebo), progression status 
(SPMS vs PPMS) and time-progression status interaction. Secondary endpoints 
including 12-item walking scale and urodynamic studies (binary, >20% improvement 
in bladder capacity vs < 20%) will also be analyzed. Linear regression models for 
continuous outcomes and logistic regression models for discrete outcomes will be 
used to assess the independent effect of treatment status on secondary outcomes, 
controlling for co-variates. All analyses will be performed in SAS Version 9.4 (SAS 
Institute Inc., Cary, NC). 
 
Any deviations from the previously described statistical plan will be described and 
justified in a protocol amendment and/or in the final report submitted to the IND 
application. 
 
9.4 Safety analysis 
 
Safety analysis will be performed on the analysis population.  Safety will be 
assessed through summaries of serious adverse events, minor adverse events 
including headache and fever, and neurological disease worsening (neurological 
assessments and MRI). All adverse events occurring on or after the first lumbar 
puncture will be coded and summarized by NCI CTCAE v4.0 criteria.  
 
9.5 Data and Safety Monitoring Committee  
 
A Data Safety Monitoring Board (DSMB) will review safety data and make 
recommendations to the investigators about any existing or potential problems. The 
Data Safety Monitoring Board will be comprised of four members. The first three 
include: Norman Latov, MD, PhD, Elliot Frohman, MD, and Timothy Vartanian, MD, 
PhD (Chairman) with expertise in medicine, neurology, basic research, stem-cell 
research, and ethical and legal matters. The fourth member, Martin Lesser, PhD is 
a biostatistician independent of our trial, who has valuable expertise to add given 
his long history of serving on DSMB boards. The board will include members with 

 
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no conflict of interest and are blinded to patient identity. DSMB procedures will be 
conducted according to the DSMB charter. The DSMB will meet by teleconference 
at the beginning of the study and yearly thereafter. All serious adverse events will 
be reported to the DSMB within 24-48 hours. An ad hoc meeting of the DSMB may 
be called at any time by the DSMB Chair or the investigator if participant safety 
issues arise. If a significant safety concern arises during the study, or upon 
withdrawal of a study participant from the study, the DSMB Chair may convene a 
meeting to review safety and any other aspect of the study. At meetings, they will 
review safety data from all subjects enrolled. The DSMB has the discretion to 
remove an individual from the study or terminate the study if need be. The Data 
Safety Monitoring Board will address clinical protocol violations if they arise. 
Violations in clinical protocol will be monitored by the DSMB. The Board will speak 
with the clinical researchers about protocol violations and will have the authority to 
investigate if they feel there is a violation occurring. Violations in the laboratory 
protocol will also be monitored by the Data Safety Monitoring Board. The Board will 
speak to the head of the laboratory research and will have the authority to 
investigate if it is suspected that a violation has occurred. 
 
 
 
10. Quality Control and Quality Assurance:   
 
Monitoring of the clinical study for protocol and GCP compliance will be conducted 
periodically by the DSMB 
 
The Sponsor-Investigator will permit direct access of the DSMB and appropriate 
regulatory authorities to the study data and to the corresponding source data and 
documents to verify the accuracy of this data. 
 
Study will be monitored to insure:   
• Accuracy and Completeness 
• Compliance with the FDA, HIPAA, and other appropriate regulations 
• Compliance with ICH GCP and related standards 
• Compliance with the protocol requirements 
• Compliance with IRB requirements 
• Compliance with tissue processing and related standards and practices 
• Accuracy of Data Management practices 
 
 
11. Data Handling and Record-Keeping:   
 
11.1 Data recording/Electronic Case Report Forms   
 
 

 
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An electronic Case Report Form (eCRF) will be completed for each subject 
enrolled into the clinical study.  The Sponsor-Investigator will review, approve 
and sign/date each completed CRF; the Sponsor-Investigator’s signature serving 
as attestation of the Sponsor-Investigator’s responsibility for ensuring that all 
clinical and laboratory data entered on the CRF are complete, accurate and 
authentic.   
 
Source Data are the clinical findings and observations, laboratory and test data, 
and other information contained in Source Documents.  Source Documents are 
the original records (and certified copies of original records); including, but not 
limited to, hospital medical records, physician or office charts, physician or 
nursing notes, subject diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, x-rays, etc.  When 
applicable, information recorded on the eCRF shall match the Source Data 
recorded on the Source Documents.   
 
Each study subject will have an electronic file electronic Case Report Form 
(eCRF). The eCRF will contain results from all screens used to assess patients. 
These include results from: 
 
• ICF 
• Physical examinations 
• Vital signs 
• Neurological examinations 
• Each EDSS 
• Each MSFC 
• Each 6 Minute Walk Test 
• Each 12 Item MS Walking Scale 
• Each Headache Pain Scale 
• Each Infectious Disease Questionnaire 
• Bladder Survey 
• Lab and Urine Results 
• MRI Reports  
• Pregnancy test for female patients of child-bearing age 
• Urodynamics testing reports 
• Bone Marrow Aspiration Record 
• Lumbar Puncture Record 
 
 
 
11.2 Record maintenance and retention   
 
The Sponsor-Investigator will maintain records in accordance with Good Clinical 
Practice guidelines; to include: 
 

 
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• FDA correspondence related to the IND and clinical protocol, including copies of 
submitted Safety Reports and Annual Reports  
• IRB correspondence (including approval notifications) related to the clinical protocol; 
including copies of adverse event reports and annual or interim reports 
• Current and past versions of the IRB-approved clinical protocol and corresponding 
IRB-approved consent form(s) and, if applicable, subject recruitment 
advertisements 
• Copies of initial and continuing IRB approval notifications  
• Signed FDA Form 1572 Statements of Investigator  
• Financial disclosure information (i.e., for the Sponsor-Investigator; also for all study 
site sub-investigators who will be involved in the administration of the study drugs 
and/or the evaluation of research subjects [i.e., who will contribute significantly to 
the study data]) 
• Curriculum vitae (i.e., for the Sponsor-Investigator and investigators responsible for 
the conduct of the clinical research study)  
• Certificates of required training; e.g., human subject protections, Good Clinical 
Practice, etc. (i.e., for the Sponsor-Investigator and investigators responsible for the 
conduct of the clinical research study; also for all study site sub-investigators who 
will be involved in the administration of the study drugs and/or the evaluation of 
research subjects [i.e., who will contribute significantly to the study data]) 
• Listing of printed names/signatures. (i.e., for the Sponsor-Investigator and 
investigators responsible for the conduct of the clinical research study; also for all 
study site sub-investigators who will be involved in the administration of the study 
drugs and/or the evaluation of research subjects [i.e., who will contribute 
significantly to the study data])  
• Normal value(s)/range(s) for medical/laboratory/technical procedures or tests 
included in the clinical protocol  
• Laboratory certification information for study site 
• Instructions for on-site preparation and handling of the investigational drug(s), study 
treatment(s), and other study-related materials (i.e., if not addressed in the clinical 
protocol) 
• Responsibility delegation log 
• Signed informed consent forms  
• Completed electronic Case Report Forms; signed and dated by Sponsor-
Investigator  
• Source Documents or certified copies of Source Documents  
• DSMB reports for study site 
• Copies of Sponsor-Investigator correspondence (including notifications of safety 
information) to sub-investigators 
• Subject screening and enrollment logs 
• Subject identification code list 
• Investigational drug accountability records 
• Final clinical study report 
• Decoding procedures  
• Master randomization list 

 
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• Retained biological specimen log  
• Interim data analysis report(s)  
• Copies of Sponsor-Investigator correspondence (including notifications of safety 
information) to Investigators responsible for the conduct of the clinical research 
study 
 
The Sponsor-Investigator will retain the specified records and reports for up to 2 
years after the marketing application is approved for the investigational drug; or, if a 
marketing application is not submitted or approved for the investigational drug, until 
2 years after investigations under the IND have been discontinued and the FDA so 
notified. 
 
12. Ethics: 
 
12.1 Institutional Review Board (IRB) approval 
   
The Sponsor-Investigator will obtain, from Western IRB (WIRB), prospective 
approval of the clinical protocol and corresponding informed consent form(s); 
modifications to the clinical protocol and corresponding informed consent forms, 
and advertisements (i.e., directed at potential research subjects) for study 
recruitment.    
 
The only circumstance in which a deviation from the current IRB-approved 
clinical protocol/consent form(s) may be initiated in the absence of prospective 
IRB approval is to eliminate an apparent immediate hazard to the research 
subject(s).  In such circumstances, the Sponsor-Investigator will promptly notify 
WIRB of the deviation.  
 
The Western IRB operates in compliance with FDA regulations at 21 CFR Parts 
50 and 21 CFR 56, and in conformance with applicable International Conference 
on Harmonization (ICH) Guidelines on Good Clinical Practice (CGP).  
 
In the event that WIRB requires, as a condition of approval, substantial changes 
to a clinical protocol submitted under an FDA-accepted IND application, or in the 
event of the Sponsor-Investigator’s decision to modify the previously accepted 
clinical protocol: 
 
• The Sponsor-Investigator will submit (i.e., in advance of implementing the 
change) a Protocol Amendment to the IND describing any change to the 
Phase protocol that significantly affects the safety of subjects, the scope of 
the investigation, or the scientific quality of the study. 
 
 
12.2 Ethical and scientific conduct of the clinical research study  
 

 
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The clinical research study will be conducted in accordance with the current IRB-
approved clinical protocol; ICH GCP Guidelines adopted by the FDA; and 
relevant policies, requirements, and regulations of the Western IRB, and 
applicable state and federal agencies. 
 
12.3 Subject informed consent   
 
The Sponsor-Investigator will make certain that an appropriate informed consent 
process is in place to ensure that potential research subjects are fully informed 
about the nature and objectives of the clinical study, the potential risks and 
benefits of study participation, and their rights as research subjects.  The 
Sponsor-Investigator, or a sub-investigator(s) designated by the Sponsor-
Investigator, will obtain the written, signed informed consent of each subject prior 
to performing any study-specific procedures on the subject. The date and time 
that the subject signs the informed consent form and a narrative of the issues 
discussed during the informed consent process will be documented in the 
subject’s case history.  The Sponsor-Investigator will retain the original copy of 
the signed informed consent form, and a copy will be provided to the subject, or 
to the subject’s authorized representative. 
 
The Sponsor-Investigator will make certain that appropriate processes and 
procedures are in place to ensure that ongoing questions and concerns of 
enrolled subjects are adequately addressed and that the subjects are informed of 
any new information that may affect their decision to continue participation in the 
clinical study.  In the event of substantial changes to the clinical study or the risk-
to-benefit ratio of study participation, the Sponsor-Investigator will obtain the 
informed consent of enrolled subjects for continued participation in the clinical 
study 
 
13. Study Discontinuation Criteria: 
 
13.1 Discontinuation of individual research subjects (refer also to 
sections 5.1.1 and 8.4) 
 
If any of the following events occur during treatment, patients will be discontinued 
from the study: 
• Acute worsening of MS symptoms 
• Any neurological deficit that is unexplained by another condition and is non-
reversible within 24 hours of its development 
• Any sign of debilitating infection or central nervous system infection 
• Any changes in cognitive function 
• Any unexpected adverse medical event that is unexplained by another medical 
condition 
• Any time the Data Safety Monitoring Board feels a patient should be withdrawn 
from the study 

 
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• Patient’s desire to withdraw 
• Patient’s inability to comply properly with study requirements (inability to make 
scheduled appointments, etc.) 
• Patient meets an exclusion criterion 
• Patient becomes incarcerated 
• Pregnancy  
 
Should a patient meet any of the above criteria for early termination, he or she 
will be discontinued from the trial and will not be replaced. Subjects that are 
discontinued from the study will continue to undergo the follow-up visits relative 
to their last treatment. They will also undergo follow-up long term safety visits as 
described. All data gathered at these appointments will be included in the CRF 
and data set. Should a study subject terminate the study due to pregnancy, no 
MRI will be performed during the course of the pregnancy. 
 
 
13.2 Sponsor-Investigator discontinuation of the clinical research 
study 
 
The investigator has the right to terminate this study at any time.  Reasons for 
terminating the study may include, but are not limited to, the following: 
 
• Unsatisfactory enrollment 
• Incidence of Adverse Events indicating potential risk to subjects 
 
The DSMB has the right to terminate a site at any time.  Reasons for closing a 
site may include, but are not limited to the following: 
 
• Poor protocol adherence 
• Inaccurate or incomplete data recording 
• Non-compliance with ICH guideline for GCP 
• Slow Recruitment 
 
 
 
 
 
 
 
 
 
 
 

 
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14. References: 
 
1. 
Harris, V.K., R. Faroqui, T. Vyshkina, and S.A. Sadiq, Characterization of autologous 
mesenchymal stem cell-derived neural progenitors as a feasible source of stem cells for 
central nervous system applications in multiple sclerosis. Stem Cells Transl Med, 2012. 
1(7): p. 536-47. 
2. 
Harris, V.K., Q.J. Yan, T. Vyshkina, S. Sahabi, X. Liu, and S.A. Sadiq, Clinical and 
pathological effects of intrathecal injection of mesenchymal stem cell-derived neural 
progenitors in an experimental model of multiple sclerosis. J Neurol Sci, 2012. 313: p. 
167-177. 
3. 
Harris, V.K., T. Vyshkina, and S.A. Sadiq, Clinical safety of intrathecal administration of 
mesenchymal stromal cell-derived neural progenitors in multiple sclerosis. Cytotherapy, 
2016. 18(12): p. 1476-1482. 
4. 
Harris, V.K., J. Stark, T. Vyshkina, L. Blackshear, G. Joo, V. Stefanova, G. Sara, and 
S.A. Sadiq, Phase I Trial of Intrathecal Mesenchymal Stem Cell-derived Neural 
Progenitors in Progressive Multiple Sclerosis. EBioMedicine, 2018. 29: p. 23-30. 
5. 
Kurtzke, J.F., Rating neurologic impairment in multiple sclerosis: an expanded disability 
status scale (EDSS). Neurology, 1983. 33(11): p. 1444-52. 
6. 
Cadavid, D., J.A. Cohen, M.S. Freedman, M.D. Goldman, H.P. Hartung, E. Havrdova, D. 
Jeffery, R. Kapoor, A. Miller, F. Sellebjerg, D. Kinch, S. Lee, S. Shang, and D. Mikol, 
The EDSS-Plus, an improved endpoint for disability progression in secondary 
progressive multiple sclerosis. Mult Scler, 2017. 23(1): p. 94-105.