Maximizing Outcome of Multiple Sclerosis Transplantation
Condition: Multiple Sclerosis, Relapsing-Remitting
MeSH terms: Multiple Sclerosis; Multiple Sclerosis, Relapsing-Remitting; Sclerosis
Intervention: Cyclophosphamide; Mesna; rATG; Methylprednisolone; G-CSF; IVIg; Autologous Stem Cells
Intervention description: Potent immunosuppressive agent; an alkylating agent; Medication used to decrease the risk of hemorrhagic cystitis prophylaxis; A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells; Steroid; Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream; Sterile, purified immunoglobulin G (IgG) products manufactured from pooled human plasma and typically contain more than 95% unmodified IgG, which has intact Fc-dependent effector functions and only trace amounts of immunoglobulin A (IgA) or immunoglobulin M (IgM).; Infusion of participant's own stem cells
Intervention MeSH terms: Methylprednisolone; Methylprednisolone Hemisuccinate; Cyclophosphamide; Thymoglobulin
Phase: Phase 3
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 66.0
Sex: All
Minimum age: 18 Years
Maximum age: 58 Years
Healthy volunteers: No
Keywords: Autologous Stem Cell Transplantation; Stem Cells; Hematopoietic Stem Cell Transplantation

Summary:

      Randomized study of autologous un-manipulated peripheral blood hematopoietic stem cell
      transplant (HSCT) comparing two regimens: (1) cyclophosphamide and rabbit anti-thymoglobulin
      (rATG) versus (2) cyclophosphamide, rATG, and Intravenous Immunoglobulin (IVIg).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Age between 18-58 years

          2. Diagnosis of MS using revised McDonald criteria of clinically definite MS (Appendix A)

          3. An EDSS score of 2.0 to 6.0 (Appendix B).

          4. An EDSS >6.0 may be included if still relapsing-remitting disease and at least two
             enhancing lesions on MRI within the last three months

          5. Inflammatory disease despite treatment with standard disease modifying therapy (DMT)
             including at least 6 months of interferon or Copaxone. Inflammatory disease is defined
             based on either MRI (gadolinium enhancing lesion, new T2 lesion) or *steroid-treated
             clinical relapses (prescribed by a neurologist)

          6. Minimum disease activity required:

               1. Failed a first line DMT (Copaxone or Interferon), defined as two or more *steroid
                  treated clinical relapses within the last 12 months. A clinical relapse may also
                  be evidence of active inflammation on MRI (gadolinium enhancing lesion or new T2
                  lesion) in the last 12 months on two MRIs at least three months apart

               2. Failed a second or third line MS Drug: Zinbryta (daclizumab), Aubagio
                  (teriflunomide), Gilenya (fingolimod), Tecifidera (dimethyl fumarate), Lemtrada
                  (alemtuzumab), Ocrevus (ocrelizumab), Tysabri (natalizumab), Rituxan (rituximab)
                  or IVIg, defined as one *steroid treated clinical relapse within the last 12
                  months or evidence of active inflammation on MRI (gadolinium enhancing lesion or
                  new T2 lesion) in the last 12 months.

               3. Cognitive dysfunction that prevents gainful employment, but competent to comply
                  with treatment and informed consent

                    -  A steroid-treated relapse will include a relapse that was severe enough to
                       justify treatment but due to patient intolerance of steroids, they were
                       offered but not used.

        Exclusion Criteria:

          1. Any adult who is unable to consent (for adults who are cognitively impaired due to MS,
             consent may be obtained from the closest living relative or person who has power of
             attorney)

          2. Individuals under the age of 18 or over the age of 58

          3. Diagnosis of Primary Progressive MS, Secondary Progressive MS, or Clinically Isolated
             Syndrome (CIS)

          4. Pregnant women (positive serum or urine human chorionic gonadotropin (HCG) test)

          5. Women who are breastfeeding

          6. Prisoners

          7. Any illness that in the opinion of the investigators would jeopardize the ability of
             the patient to tolerate aggressive chemotherapy

          8. Prior history of malignancy except localized basal cell, squamous skin cancer or
             carcinoma in situ of the cervix

          9. Any prior chemotherapy or radiation therapy (except for cyclophosphamide used to treat
             MS disease)

         10. History of sickle cell disease (SS), SC disease, coagulopathy, or if actively
             receiving anticoagulation therapy

         11. History of insulin-dependent diabetes

         12. Inability or unwillingness to pursue effective means of birth control from the time of
             evaluation for eligibility until 6 months post-transplant. 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) with every act of
             intercourse, use of diaphragm with contraceptive jelly and/or use of condom with
             contraceptive foam

         13. Failure to willingly accept or comprehend irreversible sterility as a side effect of
             therapy

         14. Forced expiratory volume at one second (FEV1)/ forced vital capacity (FVC) < 60% of
             predicted after bronchodilator therapy (if necessary)

         15. Diffusing capacity of the lungs for carbon monoxide (DLCO) < 60% of predicted

         16. Resting left ventricular ejection fraction (LVEF) < 50 %

         17. Bilirubin > 2.0 mg/dl

         18. Serum creatinine > 2.0 mg/dl

         19. Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins or to iron
             compounds/medications

         20. Presence of metallic objects implanted in the body that would preclude the ability of
             the patient to safely have MRI exams

         21. Platelet count < 100,000/ul

         22. White blood cell count (WBC) < 1,500 cells/mm3

         23. Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with
             treatment or informed consent impossible

         24. Active infection except asymptomatic bacteriuria

         25. Use of Tysabri (natalizumab) within the previous six months

         26. Use of Gilenya (fingolimod) within the previous three months

         27. Use of Tecfidera (dimethyl fumarate) within the previous three months

         28. Use of Aubagio (teriflunomide) 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

         29. Use of Lemtrada/Campath (alemtuzumab) within previous 12 months

         30. Use of Rituxan (rituximab) or Ocrevus (ocrelizumab) within previous four months

         31. Prior treatment with Novantrone (mitoxantrone)

         32. Any hereditary neurological disease such as Charcot-Marie-Tooth disease (CMT),
             Spinocerebellar ataxia (SCA), or Parkinson's Disease

         33. Severe or symptomatic cervical spinal stenosis unless surgically corrected

         34. Myocardial infarction within last 12 months; if longer than 12 months, must pass
             dobutamine stress test and be cleared by cardiology