Stem Cell Therapy for Patients With Multiple Sclerosis Failing Interferon A Randomized Study - Full Text View

Purpose

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, copaxone, or mitoxantrone) in patients with inflammatory (relapsing) MS despite treatment with interferon.

Condition	Intervention	Phase
Multiple Sclerosis	Procedure: Hematopoietic Stem Cell Therapy Drug: Standard treatment with a conventional drug	Phase 3

Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	Hematopoietic Stem Cell Therapy for Patients With Inflammatory Multiple Sclerosis Failing Interferon: A Randomized Study

Resource links provided by NLM:

Genetics Home Reference related topics: multiple sclerosis

MedlinePlus related topics: Autoimmune Diseases Multiple Sclerosis

Drug Information available for: Interferon Glatiramer Interferon Beta-1b Interferon Beta-1a Glatiramer acetate

U.S. FDA Resources

Further study details as provided by Northwestern University:

Primary Outcome Measures:

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 ]

Estimated Enrollment:	110
Study Start Date:	January 2006
Estimated Study Completion Date:	December 2015
Estimated Primary Completion Date:	December 2014 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: Autologous 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)	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, stem cell transplant, stem cell transplantation
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, Tysabri (natalizumab), or GILENYATM (fingolimod)	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

Detailed Description:

To assess the efficacy of autologous PBSCT versus FDA approved standard of care ( i.e. interferon, copaxone, or mitoxantrone) for inflammatory multiple sclerosis failing interferon therapy. The endpoints to be considered in this study are:

2.1 Primary Endpoint:

Disease progression, defined as a 1 point increase in the 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:

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 pseudoexacerbation. Supportive confirmation by enhancement on MRI is preferred but not mandatory. We recognize that blinding during the first year will be compromised by patient hair loss but efforts will be made to mask hair loss by covering the heads of study patients during their first year neurology assessments.
Ambulation index
Twenty-five foot timed walk
Nine hole PEG test
PASAT- 3 second and PASAT - 2 second
MRI enhancing lesions and T1 and T2 burden of disease per CombiRx MRI protocol
SF-36 and MSQOL
Scripps NRS
Survival

Eligibility

Ages Eligible for Study:	18 Years to 55 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

Age between18-55, inclusive.
Diagnosis of MS using McDonald criteria of clinically definite MS (Appendix I).
An EDSS of 2.0 to 6.0 (Appendix II).
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:

Any illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy.
Prior therapy with mitoxantrone
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.
Positive pregnancy test.
Inability or unwillingness to pursue effective means of birth control. Effective birth control is defined as 1) refraining from all acts of vaginal intercourse (ABSTINENCE); 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 IUD (intrauterine device); or 6) use, with every act of intercourse, of diaphragm with contraceptive jelly and/or condoms with contraceptive foam.
Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
FEV1/FVC < 60% of predicted after bronchodilator therapy (if necessary).
DLCO < 50% of predicted (for the transplant arm).
Resting LVEF < 50 %.
Bilirubin > 2.0 mg/dl.
Serum creatinine > 2.0 mg/dl.
Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins, or to iron compounds/medications.
Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams.
Diagnosis of primary progressive MS.
Diagnosis of secondary progressive MS
Platelet count < 100,000/ul, WBC < 1,500 cells/mm3.
Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with treatment or informed consent impossible.
Active infection except asymptomatic bacteriuria.
Use of natalizumab within the previous 6 months.

Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT00273364

Contacts

Contact: Dzemila Spahovic, MD

312-908-0059

d-spahovic@northwestern.edu

Locations

United States, Illinois
Northwestern University, Feinberg School of Medicine	Recruiting
Chicago, Illinois, United States, 60611
Contact: Dzemila Spahovic, MD 312-908-0059 d-spahovic@northwestern.edu
Principal Investigator: Richard Burt, MD

Sponsors and Collaborators

Richard Burt, MD

Rush University Medical Center

University of Sao Paulo

Uppsala University

Investigators

Principal Investigator:	Richard Burt, MD	Northwestern University
Principal Investigator:	Bruce Cohen, MD	Northwestern University
Principal Investigator:	Dusan Stefoski, MD	Rush Saint Lukes Presbyterian, Chicago, IL
Principal Investigator:	Roumen D. Balabanov, MD	Rush University Medical Center, Chicago, Il

More Information

No publications provided

Responsible Party:	Richard Burt, MD, MD, Northwestern University
ClinicalTrials.gov Identifier:	NCT00273364 History of Changes
Other Study ID Numbers:	DI MS.Randomized2004
Study First Received:	January 5, 2006
Last Updated:	April 4, 2013
Health Authority:	United States: Food and Drug Administration

Keywords provided by Northwestern University:

stem cells, autoimmune diseases, multiple sclerosis

Additional relevant MeSH terms:

Multiple Sclerosis
Sclerosis
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Pathologic Processes
Interferon-beta
Interferons
Interferon beta-1b

Interferon beta 1a
Copolymer 1
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Adjuvants, Immunologic
Immunosuppressive Agents

ClinicalTrials.gov processed this record on May 23, 2013