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Maximizing Outcome of Multiple Sclerosis Transplantation (MOST)

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ClinicalTrials.gov Identifier: NCT03342638
Recruitment Status : Recruiting
First Posted : November 17, 2017
Last Update Posted : April 8, 2019
Sponsor:
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 predominantly an immune-mediated and inflammatory disease. While current immune based therapies delay disability, no intervention has been proven to prevent progressive disability.The investigators propose a randomized study of autologous unmanipulated peripheral blood hematopoietic stem cell transplant (HSCT) comparing two different conditioning regimens: (1) cyclophosphamide and rabbit anti-thymoglobulin (rATG) versus (2) cyclophosphamide, rATG, and Intravenous Immunoglobulin (IVIg).

Condition or disease Intervention/treatment Phase
Multiple Sclerosis, Relapsing-Remitting Drug: Cyclophosphamide Drug: Mesna Drug: rATG Drug: Methylprednisolone Drug: G-CSF Biological: IVIg Biological: Autologous Stem Cells Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 200 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Maximizing Outcome of Multiple Sclerosis Transplantation: "MOST" Trial
Actual Study Start Date : November 8, 2017
Estimated Primary Completion Date : January 1, 2023
Estimated Study Completion Date : January 1, 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Control Arm
Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with cyclophosphamide, mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) will be administered post-transplant.
Drug: Cyclophosphamide
Potent immunosuppressive agent; an alkylating agent
Other Names:
  • Cytoxan
  • Neosar

Drug: Mesna
Medication used to decrease the risk of hemorrhagic cystitis prophylaxis
Other Name: Mesnex

Drug: rATG
A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells
Other Name: Thymoglobulin

Drug: Methylprednisolone
Steroid
Other Name: Solu-Medrol

Drug: G-CSF
Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
Other Names:
  • Neupogen
  • Filgrastim
  • Granix
  • Zarxio

Biological: Autologous Stem Cells
Infusion of participant's own stem cells

Experimental: IVIg Arm
Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with cyclophosphamide, mesna, rATG (rabbit), and methylprednisolone. IVIg and G-CSF will be administered post-transplant.
Drug: Cyclophosphamide
Potent immunosuppressive agent; an alkylating agent
Other Names:
  • Cytoxan
  • Neosar

Drug: Mesna
Medication used to decrease the risk of hemorrhagic cystitis prophylaxis
Other Name: Mesnex

Drug: rATG
A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells
Other Name: Thymoglobulin

Drug: Methylprednisolone
Steroid
Other Name: Solu-Medrol

Drug: G-CSF
Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
Other Names:
  • Neupogen
  • Filgrastim
  • Granix
  • Zarxio

Biological: IVIg
Sterile, purified immunoglobulin G (IgG) products manufactured from pooled human plasma and typically contain more than 95% unmodified IgG, which has intact Fc-dependent effector functions and only trace amounts of immunoglobulin A (IgA) or immunoglobulin M (IgM).
Other Names:
  • Gammagard
  • Carimune Nanofiltered (NF)
  • Bivagam
  • Privigen

Biological: Autologous Stem Cells
Infusion of participant's own stem cells




Primary Outcome Measures :
  1. Efficacy - Rate of Disease Activity [ Time Frame: 5 years ]
    Defined as no relapse (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 neurologist and not explained by fever, infection, stress, heat or related pseudoexacerbation; supportive confirmation by enhancement on MRI is preferred), no disease progression (defined as a 1.0-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), and no new or enhancing lesions on MRI


Secondary Outcome Measures :
  1. Survival [ Time Frame: 5 years ]
    Survival of participants

  2. Expanded Disability Status Scale (EDSS) Improvement [ Time Frame: 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 58 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Age between 18-58 years
  2. Diagnosis of MS using revised McDonald criteria of clinically definite MS (Appendix A)
  3. An EDSS score of 2.0 to 6.0 (Appendix B).
  4. An EDSS >6.0 may be included if still relapsing-remitting disease and at least two enhancing lesions on MRI within the last three months
  5. Inflammatory disease despite treatment with standard disease modifying therapy (DMT) including at least 6 months of interferon or Copaxone. Inflammatory disease is defined based on either MRI (gadolinium enhancing lesion, new T2 lesion) or *steroid-treated clinical relapses (prescribed by a neurologist)
  6. Minimum disease activity required:

    1. Failed a first line DMT (Copaxone or Interferon), defined as two or more *steroid treated clinical relapses within the last 12 months. A clinical relapse may also be evidence of active inflammation on MRI (gadolinium enhancing lesion or new T2 lesion) in the last 12 months on two MRIs at least three months apart
    2. Failed a second or third line MS Drug: Zinbryta (daclizumab), Aubagio (teriflunomide), Gilenya (fingolimod), Tecifidera (dimethyl fumarate), Lemtrada (alemtuzumab), Ocrevus (ocrelizumab), Tysabri (natalizumab), Rituxan (rituximab) or IVIg, defined as one *steroid treated clinical relapse within the last 12 months or evidence of active inflammation on MRI (gadolinium enhancing lesion or new T2 lesion) in the last 12 months.
    3. Cognitive dysfunction that prevents gainful employment, but competent to comply with treatment and informed consent

      • A steroid-treated relapse will include a relapse that was severe enough to justify treatment but due to patient intolerance of steroids, they were offered but not used.

Exclusion Criteria:

  1. Any adult who is unable to consent (for adults who are cognitively impaired due to MS, consent may be obtained from the closest living relative or person who has power of attorney)
  2. Individuals under the age of 18 or over the age of 58
  3. Diagnosis of Primary Progressive MS, Secondary Progressive MS, or Clinically Isolated Syndrome (CIS)
  4. Pregnant women (positive serum or urine human chorionic gonadotropin (HCG) test)
  5. Women who are breastfeeding
  6. Prisoners
  7. Any illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive chemotherapy
  8. Prior history of malignancy except localized basal cell, squamous skin cancer or carcinoma in situ of the cervix
  9. Any prior chemotherapy or radiation therapy (except for cyclophosphamide used to treat MS disease)
  10. History of sickle cell disease (SS), SC disease, coagulopathy, or if actively receiving anticoagulation therapy
  11. History of insulin-dependent diabetes
  12. Inability or unwillingness to pursue effective means of birth control from the time of evaluation for eligibility until 6 months post-transplant. 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) with every act of intercourse, use of diaphragm with contraceptive jelly and/or use of condom with contraceptive foam
  13. Failure to willingly accept or comprehend irreversible sterility as a side effect of therapy
  14. Forced expiratory volume at one second (FEV1)/ forced vital capacity (FVC) < 60% of predicted after bronchodilator therapy (if necessary)
  15. Diffusing capacity of the lungs for carbon monoxide (DLCO) < 60% of predicted
  16. Resting left ventricular ejection fraction (LVEF) < 50 %
  17. Bilirubin > 2.0 mg/dl
  18. Serum creatinine > 2.0 mg/dl
  19. Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins or to iron compounds/medications
  20. Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams
  21. Platelet count < 100,000/ul
  22. White blood cell count (WBC) < 1,500 cells/mm3
  23. Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with treatment or informed consent impossible
  24. Active infection except asymptomatic bacteriuria
  25. Use of Tysabri (natalizumab) within the previous six months
  26. Use of Gilenya (fingolimod) within the previous three months
  27. Use of Tecfidera (dimethyl fumarate) within the previous three months
  28. Use of Aubagio (teriflunomide) 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
  29. Use of Lemtrada/Campath (alemtuzumab) within previous 12 months
  30. Use of Rituxan (rituximab) or Ocrevus (ocrelizumab) within previous four months
  31. Prior treatment with Novantrone (mitoxantrone)
  32. Any hereditary neurological disease such as Charcot-Marie-Tooth disease (CMT), Spinocerebellar ataxia (SCA), or Parkinson's Disease
  33. Severe or symptomatic cervical spinal stenosis unless surgically corrected
  34. Myocardial infarction within last 12 months; if longer than 12 months, must pass dobutamine stress test and be cleared by cardiology

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 ClinicalTrials.gov identifier (NCT number): NCT03342638


Contacts
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Contact: Kathleen Quigley, RN 312-695-8192 kathleen.quigley@nm.org

Locations
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United States, Illinois
Northwestern University Recruiting
Chicago, Illinois, United States, 60611
Contact: Kathleen Quigley, RN    312-695-8192    kathleen.quigley@nm.org   
Sponsors and Collaborators
Northwestern University
Investigators
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Principal Investigator: Richard Burt, MD Northwestern University

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Responsible Party: Richard Burt, MD, Professor, Northwestern University
ClinicalTrials.gov Identifier: NCT03342638     History of Changes
Other Study ID Numbers: DIAD.MOST.2017
First Posted: November 17, 2017    Key Record Dates
Last Update Posted: April 8, 2019
Last Verified: April 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Richard Burt, MD, Northwestern University:
Autologous Stem Cell Transplantation
Stem Cells
Hematopoietic Stem Cell Transplantation

Additional relevant MeSH terms:
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Sclerosis
Multiple Sclerosis
Multiple Sclerosis, Relapsing-Remitting
Pathologic Processes
Demyelinating Autoimmune Diseases, CNS
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Demyelinating Diseases
Autoimmune Diseases
Immune System Diseases
Cyclophosphamide
Thymoglobulin
Immunosuppressive Agents
Methylprednisolone Hemisuccinate
Prednisolone
Sargramostim
Lenograstim
Methylprednisolone
Methylprednisolone Acetate
Prednisolone acetate
Prednisolone hemisuccinate
Prednisolone phosphate
Mesna
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents