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

This study is currently recruiting participants. (see Contacts and Locations)
Verified September 2014 by Northwestern University
Sponsor:
Collaborators:
Rush University Medical Center
University of Sao Paulo
Uppsala University
Sheffield Teaching Hospitals NHS Foundation Trust
Information provided by (Responsible Party):
Richard Burt, MD, Northwestern University
ClinicalTrials.gov Identifier:
NCT00273364
First received: January 5, 2006
Last updated: September 23, 2014
Last verified: September 2014

January 5, 2006
September 23, 2014
January 2006
December 2016   (final data collection date for primary outcome measure)
EDSS [ Time Frame: Participants with progressive disease will continue to be followed for the 5 year duration at least 6 months apart. ] [ Designated as safety issue: Yes ]
EDSS
Complete list of historical versions of study NCT00273364 on ClinicalTrials.gov Archive Site
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Not Provided
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Stem Cell Therapy for Patients With Multiple Sclerosis Failing Alternate Approved Therapy- A Randomized Study
Hematopoietic Stem Cell Therapy for Patients With Inflammatory Multiple Sclerosis Failing Alternate Approved Therapy: A Randomized Study

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 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.

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. MSFC
  7. MRI enhancing lesions and T1 and T2 burden of disease per MRI-AC MRI protocol
  8. SF-36
  9. Scripps NRS
  10. Survival
Interventional
Phase 3
Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Multiple Sclerosis
  • 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
  • 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), mitoxantrone, Tysabri (natalizumab), or GILENYATM (fingolimod)
    Other Name: standard of care
  • Experimental: Heatopoieticus Stem Cell Transplantation
    Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with Cyclophosphamide and ATG (rabbit)
    Intervention: Procedure: Hematopoietic Stem Cell Therapy
  • 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), mitoxantrone (Novantrone) , Tysabri (natalizumab), GILENYATM (fingolimod) or Dimethyl fumarate (Tecfidera or BG-12)
    Intervention: Drug: Standard treatment with a conventional drug
Burman J, Fransson M, Tötterman TH, Fagius J, Mangsbo SM, Loskog AS. T-cell responses after haematopoietic stem cell transplantation for aggressive relapsing-remitting multiple sclerosis. Immunology. 2013 Oct;140(2):211-9. doi: 10.1111/imm.12129.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruiting
110
December 2017
December 2016   (final data collection date for primary outcome measure)

Inclusion Criteria:

  1. Age between18-55, inclusive.
  2. Diagnosis of MS using McDonald criteria of clinically definite MS (Appendix I).
  3. An EDSS 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 high dose corticosteroids). Minimum disease activity required for failure is defined as: a) two or more clinical relapses with documented neurologic changes 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).

Exclusion criteria:

  1. Any illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy.
  2. More than six cycles prior therapy with mitoxantrone. If had prior mitoxantrone in past must not have had prior Tysabri and must have normal LVEF and WBC.
  3. 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.
  4. Positive pregnancy test.
  5. Inability or unwillingness to pursue effective means of birth control from the time of evaluation for eligibility until 6 months post transplant (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.
  6. Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
  7. FEV1/FVC < 60% of predicted after bronchodilator therapy (if necessary).
  8. DLCO < 50% of predicted (for the transplant arm).
  9. Resting LVEF < 50 %.
  10. Bilirubin > 2.0 mg/dl.
  11. Serum creatinine > 2.0 mg/dl.
  12. Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins, or to iron compounds/medications.
  13. Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams.
  14. Diagnosis of primary progressive MS.
  15. Diagnosis of secondary progressive MS
  16. Platelet count < 100,000/ul, WBC < 1,500 cells/mm3.
  17. Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with treatment or informed consent impossible.
  18. Active infection except asymptomatic bacteriuria.
  19. Use of natalizumab (Tysabri) within the previous 6
  20. Use of fingolimod (Gilenya) within the previous 3 months
  21. 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
  22. Treatment with prior CAMPATH (alemtuzumab)
  23. Treatment with prior mitoxantrone
Both
18 Years to 55 Years
No
Contact: Dzemila Spahovic, MD 312-695-4960 d-spahovic@northwestern.edu
United States
 
NCT00273364
DI MS.Randomized2004
Yes
Richard Burt, MD, Northwestern University
Northwestern University
  • Rush University Medical Center
  • University of Sao Paulo
  • Uppsala University
  • Sheffield Teaching Hospitals NHS Foundation Trust
Principal Investigator: Richard Burt, MD Northwestern University
Northwestern University
September 2014

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP