Stem Cell Therapy for Patients With Multiple Sclerosis Failing Alternate Approved Therapy- A Randomized Study
Condition: Multiple Sclerosis
MeSH terms: Multiple Sclerosis; Sclerosis
Intervention: Hematopoietic Stem Cell Therapy; Standard treatment with a conventional drug
Intervention description: After mobilization and harvest of stem cells, stem cells will be infused following conditioning regimen; Standard treatment with a conventional drug is the treatment with one of the following drugs: Avonex (interferon beta 1a), Betaseron (interferon beta 1b), Copaxone (glatiramer acetate), Aubagio (teriflunomide), Tysabri (natalizumab), or Gilenya (fingolimod)
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 110.0
Sex: All
Minimum age: 18 Years
Maximum age: 55 Years
Healthy volunteers: No
Keywords: stem cell, autoimmune disease, multiple sclerosis

Summary:

      Multiple sclerosis (MS) is at onset an immune-mediated demyelinating disease. In most cases,
      it starts as a relapsing-remitting disease with distinct attacks and no symptoms between
      flares. Over years or decades, virtually all cases transition into a progressive disease in
      which insidious and slow neurologic deterioration occurs with or without acute flares.
      Relapsing-remitting disease is often responsive to immune suppressive or modulating
      therapies, while immune based therapies are generally ineffective in patients with a
      progressive clinical course. This clinical course and response to immune suppression, as well
      as neuropathology and neuroimaging studies, suggest that disease progression is associated
      with axonal atrophy. Disability correlates better with measures of axonal atrophy than immune
      mediated demyelination. Therefore, immune based therapies, in order to be effective, need to
      be started early in the disease course while MS is predominately an immune-mediated and
      inflammatory disease. While current immune based therapies delay disability, no intervention
      has been proven to prevent progressive disability. We propose, as a randomized study,
      autologous unmanipulated PBSCT using a conditioning regimen of cyclophosphamide and rabbit
      antithymocyte globulin (rATG) versus FDA approved standard of care (i.e. interferon,
      glatiramer acetate, mitoxantrone, natalizumab, fingolimod, or tecfidera) in patients with
      inflammatory (relapsing) MS despite treatment with alternate approved therapy.
    

Eligibility criteria:

        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.