A Study of Allogeneic Human UC-MSC and Liberation Therapy (When Associated With CCSVI) in Patients With RRMS
A Study of Allogeneic Human UC-MSC and Liberation Therapy (When Associated With CCSVI) in Patients With RRMS
STUDY OBJECTIVES:

 Primary Objective: Assessment of treatment safety based on incidence of any treatment
 emergent/treatment associated adverse events prior to discharge and at 1, 3, 6 and 12 months
 post treatment.

 Secondary objective: Assessment of efficacy at baseline, prior to discharge, 1 month, 3
 months, 6 months and 12 months after treatment based on the following: EDSS and 29-item
 Multiple Sclerosis Impact Scale (MSIS-29), MS Functional Composite (MSFC) consisting of (1)
 Timed 25-Foot Walk, (2) 9 Hole Peg Test, and (3) Paced Auditory Serial Addition Test and
 gadolinium-enhanced magnetic resonance imaging (MRI)
STUDY TREATMENT:

 Investigational therapy product: Wharton Jelly derived allogeneic MSCs.

 Method of administration and dose: Super selective intravenous administration of 50 million
 Allogeneic Human Umbilical Cord Tissue-Derived Mesenchymal Stem Cells (UC-MSC) and
 intrathecal administration of UC-MSCs in dose of 100 million along with liberation therapy
 (when associated with CCSVI).

 SAFETY AND EFFICACY EVALUATION:

 The proposed study will assess safety and primary and secondary efficacy endpoints after
 super selective intravenous and intrathecal administration of allogeneic umbilical cord
 mesenchymal stem cells (UC-MSC) in 69 patients with Relapsing Remitting Multiple Sclerosis.

 Safety Evaluation:

 Assessment of treatment safety based on incidence of any treatment emergent/treatment
 associated adverse events prior to discharge and at 1, 3, 6 and 12 months post treatment.

 Efficacy evaluation:

 Clinical evaluations, including EDSS and 29-item Multiple Sclerosis Impact Scale (MSIS-29)
 will be performed at baseline before stem cell mobilization, prior to discharge at 1, 3, 6
 and 12 months after stem cell therapy.

 The MS Functional Composite (MSFC) consists of the (a) Timed 25-Foot Walk, (b) 9 Hole Peg
 Test, and (c) Paced Auditory Serial Addition Test will be performed at baseline before stem
 cell mobilization and at 12 months after stem cell therapy.

 Gadolinium enhanced MRI scans of the brain will be performed at baseline before therapy and
 then 12 months after stem cell therapy. Follow-up scans will be performed on the same type of
 scanner used at baseline. Scans will be analyzed centrally. The 'baseline MRI scan' will be
 the reference for brain volume changes.

 DATA COLLECTION AND STATISTICAL ANALYSIS:

 Descriptive analyses of the adverse events will be performed. Proportion of adverse events at
 each visit will be calculated using frequency distribution. The frequency, severity, timing
 and the potential relationship to the intervention will be assessed in order to characterize
 the safety of the intervention.

 The probability of overall event-free survival (as well as progression-free, relapse-free, or
 MRI event-free survival) at baseline through 1 year will be calculated. The end point of
 progression is defined as increased Expanded Disability Status Scale (EDSS) score greater
 than 0.5 from baseline. Analyses will be conducted using Kaplan-Meier estimates with
 Wald-type 90% CIs based on Greenwood's formula for SE.

 Descriptive analyses of all primary and secondary efficacy endpoints will be performed using
 descriptive statistics. Proportion of patients with clinically significant change in this
 efficacy measurement scales (EDSS, MSIS, MSFC, MSFC-25 foot walking test, MSFC-Nine Hole Peg
 Test, MSFC-Paced Auditory Serial Addition Test) and change in gadolinium enhancing lesions,
 new T2 lesions from previous visit will be presented as a proportion.

 The percentage of change in brain volume will be calculated from screening and analyzed by
 end point status at month 12 with an exact Wilcoxon rank sum test using mean scores when the
 results are identical.The null hypothesis tests whether the median percentage of change in
 brain volume among participants who met the endpoint by month 12 is equal to the median of
 those who have not met the end point by month 12.

 Other primary and secondary efficacy endpoints (EDSS, MSIS, MSFC, MSFC-25 foot walking test,
 MSFC-Nine Hole Peg Test, MSFC-Paced Auditory Serial Addition Test) will be analyzed using a
 Wilcoxon signed rank test. Change from baseline outcomes for all the endpoints will be
 calculated for each patient who underwent stem cell transplant as the post transplant value
 minus the baseline value. The null hypothesis tests whether the median difference from
 baseline measurement in the values at the month 1, month 3, month 6 and month 12 visits was
 significantly different from zero,with baseline measurement defined as the screening
 assessment for the percentage of change in brain volume and the baseline visit for all other
 end points.

 To calculate MSFC, results from each of the 3 components will be transformed into a z score
 and averaged to yield a composite for each patient at each timepoint. The z scores that
 compose the MSFC score will be calculated using the reference population from the National
 Multiple Sclerosis Society Task Force database.
Main inclusion criteria: Males and Females between age 18 and 60 years with confirmed
 diagnosis of Relapsing Remitting Multiple Sclerosis made by a neurology expert/MS expert
 with lesions demonstrated on brain MRI that are consistent with MS and having an EDSS
 (Kurtzke Expanded Disability Status Scale) score between 3.5 & 6

 Inclusion Criteria:

 -  Males and Females between age 18 and 60 years

 -  Diagnosis of Relapsing Remitting Multiple Sclerosis made by a neurology expert/MS
 expert with lesions demonstrated on brain MRI that are consistent with MS

 -  Duration of disease: >5 years

 -  Having an EDSS (Kurtzke Expanded Disability Status Scale) score between 3.5 & 6

 -  History of 2 or more relapses within last 2 years with increase in EDSS scale of > 0.5
 sustained for > 4 weeks

 -  Failure to respond or intolerance to the currently available Multiple Sclerosis (MS)
 immunomodulatory treatments): the lack of response to these treatments will be
 determined/defined by history of 2 or more relapses within last 2 years with increase
 in EDSS scale of > 0.5 sustained for > 4 weeks

 -  Must have proof of health insurance in country of residence

 Exclusion Criteria:

 -  Primary progressive, secondary progressive or progressive relapsing MS as defined by
 Lublin and Reingold, 1996. These conditions require the presence of continuous
 clinical disease worsening over a period of at least 3 months. Subjects with these
 conditions may also have superimposed relapses but are distinguished from relapsing
 remitting subjects by the lack of clinically stable periods of clinical improvement.

 -  Unable to perform Timed 25-Foot Walk, 9 Hole Peg Test (HPT) (with both upper
 extremities) and Paced Auditory Serial Addition Test (PASAT 3)

 -  Females who are pregnant or nursing or females of childbearing potential who are
 unwilling to maintain contraceptive therapy for the duration of the study

 -  Life expectancy < 6 months due to concomitant illnesses

 -  Exposure to any investigational drug or procedure within 1 month prior to study entry
 or enrolled in a concurrent study that may confound results of this study.

 -  Active infectious disease: For patients who have tested positive, an expert will be
 consulted as to patient eligibility based on the patient's infectious status

 -  Any illness which, in the Investigator's judgment, will interfere with the patient's
 ability to comply with the protocol, compromise patient safety, or interfere with the
 interpretation of the study results

 -  Patients on chronic immunosuppressive transplant therapy

 -  Patients with unstable cardiac status (unstable angina, attack of myocardial
 infarction within last 6 months, uncontrolled high blood pressure, hypotension,
 cardiomyopathy)

 -  Cerebrovascular accident within 6 months prior to study entry

 -  Patients with poorly controlled diabetes mellitus

 -  Patients with renal insufficiency (Creatinine> 2.5) or failure

 -  Known drug or alcohol dependence or any other factors which will interfere with the
 study conduct or interpretation of the results or who in the opinion of the
 investigator is not suitable to participate.

 -  History of cancer (other than non-melanoma skin cancer or in-situ cervical cancer) in
 the last five years

 -  Unwilling and/or not able to give written informed consent.