MOST: Maximizing Outcome of Multiple Sclerosis Transplantation

Sponsor
Northwestern University (Other)
Overall Status
Terminated
CT.gov ID
NCT03342638
Collaborator
(none)
66
1
2
23
2.9

Study Details

Study Description

Brief Summary

Randomized study of autologous un-manipulated peripheral blood hematopoietic stem cell transplant (HSCT) comparing two regimens: (1) cyclophosphamide and rabbit anti-thymoglobulin (rATG) versus (2) cyclophosphamide, rATG, and Intravenous Immunoglobulin (IVIg).

Condition or Disease Intervention/Treatment Phase
Phase 3

Detailed Description

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).

Study Design

Study Type:
Interventional
Actual Enrollment :
66 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 :
Nov 8, 2017
Actual Primary Completion Date :
Jul 23, 2019
Actual Study Completion Date :
Oct 9, 2019

Arms and Interventions

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 Names:
  • 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 Names:
  • Thymoglobulin
  • Drug: Methylprednisolone
    Steroid
    Other Names:
  • 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 Names:
  • 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 Names:
  • Thymoglobulin
  • Drug: Methylprednisolone
    Steroid
    Other Names:
  • 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

    Outcome Measures

    Primary Outcome Measures

    1. Efficacy - Rate of Disease Activity [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

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 58 Years
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    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:

    7. 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

    8. 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.

    9. 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Northwestern University Chicago Illinois United States 60611

    Sponsors and Collaborators

    • Northwestern University

    Investigators

    • Principal Investigator: Richard Burt, MD, Northwestern University

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Richard Burt, MD, Professor, Northwestern University
    ClinicalTrials.gov Identifier:
    NCT03342638
    Other Study ID Numbers:
    • DIAD.MOST.2017
    First Posted:
    Nov 17, 2017
    Last Update Posted:
    Jan 11, 2021
    Last Verified:
    Jan 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    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, Professor, Northwestern University
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Control Arm IVIg Arm
    Arm/Group Description 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. Cyclophosphamide: Potent immunosuppressive agent; an alkylating agent Mesna: Medication used to decrease the risk of hemorrhagic cystitis prophylaxis rATG: A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells Methylprednisolone: Steroid 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 Autologous Stem Cells: Infusion of participant's own stem cells Hematopoietic Stem Cell Therapy performed as follows: Autologous stem cells will be infused after conditioning with cyclophosphamide, mesna, rATG (rabbit), and methylprednisolone. IVIg and G-CSF administered post-transplant. Cyclophosphamide:immunosuppressive agent;alkylating agent Mesna: Prophylaxis decrease for hemorrhagic cystitis rATG: lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens found on the surface of T cells Methylprednisolone: Steroid G-CSF: Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes & stem cells and release them into the bloodstream IVIg: 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). Autologous Stem Cells: Infusion of one's own stem cells
    Period Title: Overall Study
    STARTED 34 32
    COMPLETED 33 31
    NOT COMPLETED 1 1

    Baseline Characteristics

    Arm/Group Title Control Arm IVIg Arm Total
    Arm/Group Description 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. Cyclophosphamide: Potent immunosuppressive agent; an alkylating agent Mesna: Medication used to decrease the risk of hemorrhagic cystitis prophylaxis rATG: A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells Methylprednisolone: Steroid 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 Autologous Stem Cells: Infusion of participant's own stem cells Hematopoietic Stem Cell Therapy performed as follows: Autologous stem cells will be infused after conditioning with cyclophosphamide, mesna, rATG (rabbit), and methylprednisolone. IVIg and G-CSF administered post-transplant. Cyclophosphamide:immunosuppressive agent;alkylating agent Mesna: Prophylaxis decrease for hemorrhagic cystitis rATG: lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens found on the surface of T cells Methylprednisolone: Steroid G-CSF: Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes & stem cells and release them into the bloodstream IVIg: 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). Autologous Stem Cells: Infusion of one's own stem cells Total of all reporting groups
    Overall Participants 34 32 66
    Age (years) [Mean (Full Range) ]
    Mean (Full Range) [years]
    36.3
    35.3
    35.8
    Sex: Female, Male (Count of Participants)
    Female
    24
    70.6%
    19
    59.4%
    43
    65.2%
    Male
    10
    29.4%
    13
    40.6%
    23
    34.8%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    0
    0%
    0
    0%
    Asian
    2
    5.9%
    0
    0%
    2
    3%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    0
    0%
    0
    0%
    Black or African American
    2
    5.9%
    2
    6.3%
    4
    6.1%
    White
    28
    82.4%
    28
    87.5%
    56
    84.8%
    More than one race
    0
    0%
    1
    3.1%
    1
    1.5%
    Unknown or Not Reported
    2
    5.9%
    1
    3.1%
    3
    4.5%
    Region of Enrollment (participants) [Number]
    United States
    34
    100%
    32
    100%
    66
    100%
    Diagnosis of Multiple Sclerosis using revised McDonald criteria (Count of Participants)
    Count of Participants [Participants]
    34
    100%
    32
    100%
    66
    100%

    Outcome Measures

    1. Primary Outcome
    Title Efficacy - Rate of Disease Activity
    Description 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
    Time Frame 5 years

    Outcome Measure Data

    Analysis Population Description
    Study Terminated due to PI taking Sabbatical: Data Not Collected
    Arm/Group Title Control Arm IVIg Arm
    Arm/Group Description 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. Cyclophosphamide: Potent immunosuppressive agent; an alkylating agent Mesna: Medication used to decrease the risk of hemorrhagic cystitis prophylaxis rATG: A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells Methylprednisolone: Steroid 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 Autologous Stem Cells: Infusion of participant's own stem cells Hematopoietic Stem Cell Therapy performed as follows: Autologous stem cells will be infused after conditioning with cyclophosphamide, mesna, rATG (rabbit), and methylprednisolone. IVIg and G-CSF administered post-transplant. Cyclophosphamide:immunosuppressive agent;alkylating agent Mesna: Prophylaxis decrease for hemorrhagic cystitis rATG: lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens found on the surface of T cells Methylprednisolone: Steroid G-CSF: Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes & stem cells and release them into the bloodstream IVIg: 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). Autologous Stem Cells: Infusion of one's own stem cells
    Measure Participants 0 0

    Adverse Events

    Time Frame up to 1 year post transplant
    Adverse Event Reporting Description
    Arm/Group Title Control Arm IVIg Arm
    Arm/Group Description 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. Cyclophosphamide: Potent immunosuppressive agent; an alkylating agent Mesna: Medication used to decrease the risk of hemorrhagic cystitis prophylaxis rATG: A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells Methylprednisolone: Steroid 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 Autologous Stem Cells: Infusion of participant's own stem cells Hematopoietic Stem Cell Therapy performed as follows: Autologous stem cells will be infused after conditioning with cyclophosphamide, mesna, rATG (rabbit), and methylprednisolone. IVIg and G-CSF administered post-transplant. Cyclophosphamide:immunosuppressive agent;alkylating agent Mesna: Prophylaxis decrease for hemorrhagic cystitis rATG: lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens found on the surface of T cells Methylprednisolone: Steroid G-CSF: Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes & stem cells and release them into the bloodstream IVIg: 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). Autologous Stem Cells: Infusion of one's own stem cells
    All Cause Mortality
    Control Arm IVIg Arm
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/33 (0%) 0/31 (0%)
    Serious Adverse Events
    Control Arm IVIg Arm
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/33 (0%) 0/31 (0%)
    Other (Not Including Serious) Adverse Events
    Control Arm IVIg Arm
    Affected / at Risk (%) # Events Affected / at Risk (%) # Events
    Total 0/33 (0%) 0/31 (0%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Kathleen Quigley
    Organization Northwestern University
    Phone 312-695-8192
    Email k-quigley@northwestern.edu
    Responsible Party:
    Richard Burt, MD, Professor, Northwestern University
    ClinicalTrials.gov Identifier:
    NCT03342638
    Other Study ID Numbers:
    • DIAD.MOST.2017
    First Posted:
    Nov 17, 2017
    Last Update Posted:
    Jan 11, 2021
    Last Verified:
    Jan 1, 2021