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

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ClinicalTrials.gov Identifier: NCT00273364
Recruitment Status : Active, not recruiting
First Posted : January 9, 2006
Last Update Posted : April 8, 2019
Sponsor:
Collaborators:
Uppsala University
Sheffield Teaching Hospitals NHS Foundation Trust
University of Sao Paulo
Information provided by (Responsible Party):
Richard Burt, MD, Northwestern University

Tracking Information
First Submitted Date  ICMJE January 5, 2006
First Posted Date  ICMJE January 9, 2006
Last Update Posted Date April 8, 2019
Actual Study Start Date  ICMJE November 16, 2005
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 12, 2018)
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
Original Primary Outcome Measures  ICMJE
 (submitted: January 5, 2006)
EDSS
Change History Complete list of historical versions of study NCT00273364 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Stem Cell Therapy for Patients With Multiple Sclerosis Failing Alternate Approved Therapy- A Randomized Study
Official Title  ICMJE Hematopoietic Stem Cell Therapy for Patients With Inflammatory Multiple Sclerosis Failing Alternate Approved Therapy: A Randomized Study
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.
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
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Multiple Sclerosis
Intervention  ICMJE
  • 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), Aubagio (teriflunomide), Tysabri (natalizumab), or Gilenya (fingolimod)
    Other Name: standard of care
Study Arms  ICMJE
  • 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
    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), Aubagio (teriflunomide), Tysabri (natalizumab), Gilenya (fingolimod) or Dimethyl fumarate (Tecfidera or BG-12)
    Intervention: Drug: Standard treatment with a conventional drug
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Estimated Enrollment  ICMJE
 (submitted: January 5, 2006)
110
Original Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE September 2024
Estimated Primary Completion Date September 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 55 Years   (Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00273364
Other Study ID Numbers  ICMJE DI MS.Randomized2004
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Richard Burt, MD, Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE
  • Uppsala University
  • Sheffield Teaching Hospitals NHS Foundation Trust
  • University of Sao Paulo
Investigators  ICMJE
Principal Investigator: Richard Burt, MD Northwestern University
PRS Account Northwestern University
Verification Date April 2019

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