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

NCT00273364 | Completed Phase 2 Results DMC

• 1 other identifier: DI MS.Randomized2004
• Study Type: interventional
• Target: 110
• Locations: 1 country
• Sites: 1

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.

Conditions

Multiple Sclerosis

Keywords

stem cell, autoimmune disease, multiple sclerosis

Outcome Measures

Primary Outcomes (1)

• Expanded Disability Status Scale (EDSS) Improvement

  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.

  Pre Treatment, 6 and 12 months Post Treatment

Study Arms (2)

Hematopoietic Stem Cell Transplantation

EXPERIMENTAL

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

Standard therapy for MS

ACTIVE COMPARATOR

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

Interventions

Hematopoietic Stem Cell Therapy PROCEDURE

After mobilization and harvest of stem cells, stem cells will be infused following conditioning regimen

Also known as: stem cell infusion

Hematopoietic Stem Cell Transplantation

Standard treatment with a conventional drug 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)

Also known as: standard of care

Standard therapy for MS

Eligibility Criteria

• Age: 18 Years - 55 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• Age between18-55, inclusive.
• Diagnosis of MS using revised McDonald criteria of clinically definite MS (Appendix I).
• An EDSS score 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 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.

You may not qualify if:

• Any illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy.
• 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 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.
• Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
• Forced expiratory volume at one second (FEV1) / forced vital capacity (FVC) \< 60% of predicted after bronchodilator therapy (if necessary)
• Diffusing capacity of lung for carbon monoxide (DLCO) \< 50% of predicted (for the transplant arm)
• Resting left ventricular ejection fraction (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, white blood cell count (WBC) \< 1,500 cells/mm3

Sponsors & Collaborators

• Northwestern University: lead
• Uppsala University: collaborator
• Sheffield Teaching Hospitals NHS Foundation Trust: collaborator
• University of Sao Paulo: collaborator

Study Sites (1)

Northwestern University, Feinberg School of Medicine

Chicago, Illinois, 60611, United States

Location

Related Publications (2)

• Burt RK, Balabanov R, Burman J, Sharrack B, Snowden JA, Oliveira MC, Fagius J, Rose J, Nelson F, Barreira AA, Carlson K, Han X, Moraes D, Morgan A, Quigley K, Yaung K, Buckley R, Alldredge C, Clendenan A, Calvario MA, Henry J, Jovanovic B, Helenowski IB. Effect of Nonmyeloablative Hematopoietic Stem Cell Transplantation vs Continued Disease-Modifying Therapy on Disease Progression in Patients With Relapsing-Remitting Multiple Sclerosis: A Randomized Clinical Trial. JAMA. 2019 Jan 15;321(2):165-174. doi: 10.1001/jama.2018.18743.

  PMID: 30644983 RESULT

• Burman J, Fransson M, Totterman 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.

  PMID: 23721329 DERIVED

MeSH Terms

Conditions

Multiple Sclerosis; Autoimmune Diseases

Interventions

Standard of Care

Condition Hierarchy (Ancestors)

Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Demyelinating Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Limitations and Caveats

Limitations to the study are the relatively small number of patients who were treated compared with pharmaceutical sponsored trials, and the relatively small sample size resulted in small numbers of patients available to assess longer term outcomes.

Results Point of Contact

• Title: Kathleen Quigley
• Organization: Northwestern University

k-quigley@northwestern.edu

312-695-8192

Study Officials

• Richard Burt, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: January 5, 2006
• First Posted: January 9, 2006
• Study Start: November 16, 2005
• Primary Completion: January 5, 2017
• Study Completion: August 30, 2019
• Last Updated: August 12, 2020
• Results First Posted: August 12, 2020

Record last verified: 2019-04

Locations

US (1)