Stem Cell Therapy for Patients With Multiple Sclerosis Failing Alternate Approved Therapy- A Randomized Study

To assess the efficacy of autologous PBSCT versus FDA approved standard of care ( i.e.
interferon, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, or tecfidera) for
inflammatory multiple sclerosis (MS) failing failing alternate approved therapy. The
endpoints to be considered in this study are:

2.1 Primary Endpoint:

Disease progression, defined as a 1 point increase in the Expanded Disability Status Scale
(EDSS) on consecutive evaluations at least 6 months apart and not due to a non-MS disease
process. Patients will be followed for 5 years after randomization.

2.2 Secondary Endpoints:

1. Number of relapses, defined as acute neurologic deterioration occurring after
engraftment and lasting more than 24 hours, accompanied by objective worsening on
neurological examination that are documented by a blinded neurologist and not explained
by fever, infection, stress or heat related pseudo-exacerbation. Supportive confirmation
by enhancement on MRI is preferred but not mandatory.

2. Ambulation index

3. Twenty-five foot timed walk

4. Nine hole peg test

5. PASAT- 3 second and PASAT - 2 second

6. Multiple Sclerosis Functional Composite (MSFC)

7. MRI enhancing lesions and T1 and T2 burden of disease per MRI-AC MRI protocol

8. 36-Item Short Form Health Survey (SF-36)

9. Scripps Neurological Rating Scale (NRS)

10. Survival

Inclusion Criteria:

1. Age between18-55, inclusive.

2. Diagnosis of MS using revised McDonald criteria of clinically definite MS (Appendix
I).

3. An EDSS score of 2.0 to 6.0 (Appendix II).

4. Inflammatory disease despite treatment with standard disease modifying therapy
including at least 6 months of interferon or copaxone. Inflammatory disease is defined
based on both MRI (gadolinium enhancing lesions) and clinical activity (acute relapses
*treated with IV or oral high dose corticosteroids and prescribed by a neurologist).
Minimum disease activity required for failure is defined as: a) two or more *steroid
treated clinical relapses with documented new objective signs on neurological
examination documented by a neurologist within the year prior to the study, or b) one
*steroid treated clinical relapse within the year prior to study and evidence on MRI
of active inflammation (i.e., gadolinium enhancement) within the last 12 months on an
occasion separate from the clinical relapse (3 months before or after the clinical
relapse).

- A steroid treated relapse will include a relapse that was severe enough to
justify treatment but due to patient intolerance of steroids, or a history of
non-response to steroids, they were offered but not used.

Exclusion Criteria**

1. Any illness that in the opinion of the investigators would jeopardize the ability of
the patient to tolerate aggressive chemotherapy.

2. Prior history of malignancy except localized basal cell, squamous skin cancer or
carcinoma in situ of the cervix. Other malignancies for which the patient is judged to
be cured, such as head and neck cancer, or breast cancer will be considered on an
individual basis.

3. Positive pregnancy test

4. Inability or unwillingness to pursue effective means of birth control from the time of
evaluation for eligibility until 6 months posttransplant (if on transplant) or until
appropriate for non-transplant treatment (if on control arm). Effective birth control
is defined as 1) abstinence defined as refraining from all acts of vaginal
intercourse; 2) consistent use of birth control pills; 3) injectable birth control
methods (Depo-provera, Norplant); 4) tubal sterilization or male partner who has
undergone vasectomy; 5) placement of an intrauterine device (IUD); or 6) use, with
every act of intercourse, of diaphragm with contraceptive jelly and/or condoms with
contraceptive foam.

5. Failure to willingly accept or comprehend irreversible sterility as a side effect of
therapy

6. Forced expiratory volume at one second (FEV1) / forced vital capacity (FVC) < 60% of
predicted after bronchodilator therapy (if necessary)

7. Diffusing capacity of lung for carbon monoxide (DLCO) < 50% of predicted (for the
transplant arm)

8. Resting left ventricular ejection fraction (LVEF) < 50 %

9. Bilirubin > 2.0 mg/dl

10. Serum creatinine > 2.0 mg/dl

11. Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins, or to iron
compounds/medications

12. Presence of metallic objects implanted in the body that would preclude the ability of
the patient to safely have MRI exams

13. Diagnosis of primary progressive MS

14. Diagnosis of secondary progressive MS

15. Platelet count < 100,000/ul, white blood cell count (WBC) < 1,500 cells/mm3

16. Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with
treatment or informed consent impossible

17. Active infection except asymptomatic bacteriuria

18. Use of natalizumab (Tysabri) within the previous 6 months

19. Use of fingolimod (Gilenya) within the previous 3 months

20. Use of teriflunomide (Aubagio) within the previous 2 years unless cleared from the
body (plasma concentration < 0.02mcg/ml) following elimination from the body with
cholestyramine 8g three times a day for 11 days

21. Prior treatment with CAMPATH (alemtuzumab)

22. Prior treatment with mitoxantrone

23. Any hereditary neurological disease such as Charcot-Marie-Tooth disease (CMT) or
Spinocerebellar ataxia (SCA) are contraindications

24. Use of tecfidera within the previous 3 months

- For patients who clearly have inflammatory disease, an exception can be made if
agreed upon by study PI and at least two study neurologists.