Multiple Sclerosis, Relapsing-Remitting
Conditions
Keywords
Autologous Stem Cell Transplantation, Stem Cells, Hematopoietic Stem Cell Transplantation
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).
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).
Interventions
DRUGCyclophosphamide
Potent immunosuppressive agent; an alkylating agent
DRUGMesna
Medication used to decrease the risk of hemorrhagic cystitis prophylaxis
DRUGrATG
A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells
DRUGMethylprednisolone
Steroid
DRUGG-CSF
Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
BIOLOGICALIVIg
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).
BIOLOGICALAutologous Stem Cells
Infusion of participant's own stem cells
Sponsors
Northwestern University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 58 Years
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: 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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| 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.
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 | 34 |
| IVIg Arm 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 | 32 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 0 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Control Arm | IVIg Arm | Total |
|---|---|---|---|
| Age, Continuous | 36.3 years | 35.3 years | 35.8 years |
| Diagnosis of Multiple Sclerosis using revised McDonald criteria | 34 Participants | 32 Participants | 66 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 2 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 2 Participants | 1 Participants | 3 Participants |
| Race (NIH/OMB) White | 28 Participants | 28 Participants | 56 Participants |
| Region of Enrollment United States | 34 participants | 32 participants | 66 participants |
| Sex: Female, Male Female | 24 Participants | 19 Participants | 43 Participants |
| Sex: Female, Male Male | 10 Participants | 13 Participants | 23 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 33 | 0 / 31 |
| other Total, other adverse events | 0 / 33 | 0 / 31 |
| serious Total, serious adverse events | 0 / 33 | 0 / 31 |
Outcome results
Primary
Efficacy - Rate of Disease Activity
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
Population: Study Terminated due to PI taking Sabbatical: Data Not Collected