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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT00273364
Recruitment Status : Active, not recruiting
First Posted : January 9, 2006
Last Update Posted : April 8, 2019
Uppsala University
Sheffield Teaching Hospitals NHS Foundation Trust
University of Sao Paulo
Information provided by (Responsible Party):
Richard Burt, MD, Northwestern University

Brief 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.

Condition or disease Intervention/treatment Phase
Multiple Sclerosis Procedure: Hematopoietic Stem Cell Therapy Drug: Standard treatment with a conventional drug Phase 2

Detailed Description:

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

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 110 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Hematopoietic Stem Cell Therapy for Patients With Inflammatory Multiple Sclerosis Failing Alternate Approved Therapy: A Randomized Study
Actual Study Start Date : November 16, 2005
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2024

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with Cyclophosphamide and rATG
Procedure: Hematopoietic Stem Cell Therapy
After mobilization and harvest of stem cells, stem cells will be infused following conditioning regimen
Other Name: stem cell infusion

Active Comparator: Standard therapy for MS
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), Gilenya (fingolimod) or Dimethyl fumarate (Tecfidera or BG-12)
Drug: Standard treatment with a conventional drug
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)
Other Name: standard of care

Primary Outcome Measures :
  1. Expanded Disability Status Scale (EDSS) Improvement [ Time Frame: 6 months, 1 year, 2 years, 3 years, 4 years, 5 years ]
    The EDSS scale ranges from 0 to 10 in 0.5 increments that represent higher levels of disability. Improvement in EDSS is defined by both a 0.5 or 1.0 points sustained for more than 6 months

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT00273364

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United States, Illinois
Northwestern University, Feinberg School of Medicine
Chicago, Illinois, United States, 60611
Sponsors and Collaborators
Northwestern University
Uppsala University
Sheffield Teaching Hospitals NHS Foundation Trust
University of Sao Paulo
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Principal Investigator: Richard Burt, MD Northwestern University
Publications automatically indexed to this study by Identifier (NCT Number):
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Responsible Party: Richard Burt, MD, MD, Northwestern University Identifier: NCT00273364    
Obsolete Identifiers: NCT03133403
Other Study ID Numbers: DI MS.Randomized2004
First Posted: January 9, 2006    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019
Keywords provided by Richard Burt, MD, Northwestern University:
stem cell, autoimmune disease, multiple sclerosis
Additional relevant MeSH terms:
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Multiple Sclerosis
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases