A Study of Autologous Bone Marrow-Derived Mononuclear Stem Cells (BM-MNC) 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: Autologous Bone Marrow-Derived Mesenchymal Stem Cells (BM-MNC).

Method of administration and dose: Super selective intravenous administration of 50 million Autologous Bone Marrow-Derived Mononuclear Stem Cells (BM-MNC) and intrathecal administration of BM-MNCs 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 Autologous Bone Marrow-Derived Mononuclear Stem Cells (BM-MNC) 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 than0.5 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 end point 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 time point. The z scores that compose the MSFC score will be calculated using the reference population from the National Multiple Sclerosis Society Task Force database.

Eligibility Criteria:
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.