Hematopoietic Stem Cell Transplant in Devic's Disease
Trial of High Dose Immunosuppressive Therapy With Hematopoietic Stem Cell Support in Devic's Disease
Study Overview
Status
Conditions
Detailed Description
Neuromyelitis optica (NMO, Devic's disease) is an autoimmune, inflammatory, demyelinating central nervous system disorder in which a person's own immune system attacks the optic nerves and spinal cord and is characterized by concurrence of optic neuritis and transverse myelitis, typically associated with a lesion in the spinal cord extending over three or more vertebral segments. Although it is most commonly relapsing, it is distinct from multiple sclerosis in that it is more severe, tends to spare the brain, and is associated with a longitudinally extensive lesion on spinal cord MRI. Furthermore, NMO is associated with a highly specific serum autoantibody marker, NMO-immunoglobulin G (IgG), which targets the water channel aquaporin-4. The disease follows a relapsing course in more than 90% of patients.
At present, parenteral corticosteroids are widely employed as first-line treatment of optic neuritis and myelitis attacks, whereas therapeutic plasmapheresis is applied in the case of corticosteroids failure. Various strategies for the prevention of NMO relapses have been employed in small case series with modest activity. Immune based therapies, in order to be effective, need to be started early in the disease course while Devic's disease is predominantly an immune-mediated and inflammatory disease. Since 50% of patients with NMO are confined to a wheelchair within 5 years of onset, new therapies are needed in this disease.
We now propose, as a phase I study, complete immune ablation and subsequent reconstitution with autologous stem cells.
Based on the experience of the pilot studies, the current protocol will mobilize stem cells with granulocyte-colony stimulating factor (G-CSF) and cyclophosphamide and collect stem cells by apheresis. A subsequent bone marrow harvest will be performed only if needed to supplement the peripheral blood stem cells (PBSC). Based on experience of autoimmune flares in patients receiving G-CSF alone for mobilization, patients will be mobilized with cyclophosphamide 2.0 g/m2 and G-CSF 5- 10 mcg /kg.
In order to avoid cumulative cardiac toxicity from cyclophosphamide and to allow culture of hematopoietic stem cell (HSC) product, three weeks must separate the administration of cyclophosphamide for mobilization and for conditioning.
Cyclophosphamide 50 mg/kg/day will be given IV over 2 hours in 500 cc of normal saline. If actual weight is < ideal weight, cyclophosphamide will be given based on actual weight. If actual weight is > ideal weight, cyclophosphamide will given as adjusted weight. Adjusted weight = ideal weight + 25% (actual weight minus ideal weight).
Hydration-guidelines, normal saline (NS) at 150-200 ml/hr should be given 2 hours before cyclophosphamide and continued until 24 hours after the last cyclophosphamide dose. The rate of hydration will be aggressively adjusted. Twice daily weights will be obtained. Amount of fluid can be modified based on patient's fluid status.
r ATG 0.5 mg/kg given on day -5, then 1.0 mg/kg given on day -4, then 1.5 mg/kg given on days -3 through -1. rATG is infused over 10 hours. Premedicate with Acetaminophen 650 mg po and Diphenhydramine 25 mg po/IV 30 minutes before the infusion.
Rituxan ( Rituximab ) - The dose of 500 mg of Rituximab will be diluted in 500 ml 0.9 % NS and infused per standard Rituximab infusion guidelines, given on days -6 and on day + 1. Following the guidelines, Rituximab will be started at 50 mg/hr. If no reaction occurs, the dose will be increased by 50 mg/hr every 30 minutes to a maximum of 400 mg/hr.
G-CSF - guidelines, 5-10 mcg/kg/day will be started day + 5 and continued until the absolute neutrophil counts reaches at least 1,000/µl.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 1
Contacts and Locations
Study Locations
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Illinois
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Chicago, Illinois, United States, 60611
- Northwestern University, Feinberg School of Medicine
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Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Age between 16-65, at the time of pretransplant evaluation
- An established diagnosis of Devic's disease (more than one acute attack)
- NMO- IgG aquaporin-4 autoantibody positive
Exclusion Criteria:
- Paraplegia or quadriplegia and legal blindness (defined as visual acuity of 20/200 or less in the better eye with the best correction possible)
- 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. 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 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 (FEV1) / forced vital capacity (FVC) < 60% of predicted after bronchodilator therapy (if necessary)
- Diffusing capacity of lung for carbon monoxide (DLCO) < 50% of predicted
- Resting left ventricular ejection fraction (LVEF) < 50 %
- Serum creatinine > 2.0 mg/dl
- Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins
- Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams
- Bilirubin > 2.0 mg/dl
- Platelet count < 100,000/ul or absolute neutrophil count (ANC) < 1000/ul
- Psychiatric illness, mental deficiency or cognitive dysfunction making compliance with treatment or informed consent impossible
- Active infection except asymptomatic bacteriuria
- Inability to give informed consent
- HIV positive
- Transaminases > 3x of normal limits, liver cirrhosis
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: N/A
- Interventional Model: Single Group Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
|---|---|
|
Experimental: Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell transplantation will be performed after conditioning regimen of cyclophosphamide, G-CSF, Mesna, rATG, rituximab, and methylprednisolone.
|
Infusion of participant's own stem cells
A medication used as chemotherapy and to suppress the immune system
Other Names:
A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
Other Names:
A rabbit polyclonal antibody to lymphocytes
Other Names:
A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder
Other Names:
Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer
Other Names:
A corticosteroid medication used to suppress the immune system and decrease inflammation
Other Names:
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What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Survival
Time Frame: 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant
|
survival rate will be evaluated at 6 months,1 year, 2 year, 3 year, 4 year, 5 year after the transplant
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6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
|---|---|---|
|
Quality of Life (QOL) Short Form - 36 (SF-36)
Time Frame: pre-transplant 12mo and 5 years
|
SF- 36 is a self-administered quality of life exam.
The evaluation of the results was done by attributing scores to each question, which were then transformed into a scale ranging from 0 to 100, where 0 corresponds to the worst quality of life and 100 to the best.
|
pre-transplant 12mo and 5 years
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Post HSCT Immune -Modulating Medication and Relapse
Time Frame: Pre transplant and 6 months, 1 year, 2 year, 3 year, 4 year and 5 year after transplant
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Number of immune - modulating medication and relapse evaluated 5 year - after the transplant
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Pre transplant and 6 months, 1 year, 2 year, 3 year, 4 year and 5 year after transplant
|
|
Number of Patients Who Require No Device Assistance for Ambulation
Time Frame: 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant
|
No Device Assistance Needed for Ambulation evaluated at 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant
|
6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant
|
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Disability Score: Expanded Disability Status Scale (EDSS)
Time Frame: pretransplant 6 month, 5 year
|
Disability scores (disease improvement defined by at least a 1 point increase in the Expanded Disability Status Scale (EDSS) on consecutive evaluations at least three months apart. The EDSS scale ranges from 0 to 10 in 0.5 unit increments that represent higher levels of disability. |
pretransplant 6 month, 5 year
|
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NMO-IgG Aquaporin- 4 Autoantibody Titer
Time Frame: Pretransplant and 5 year Post Transplant
|
NMO-IgG aquaporin- 4 autoantibody titer will be tested pretransplant and post transplant.
|
Pretransplant and 5 year Post Transplant
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Collaborators and Investigators
Sponsor
Publications and helpful links
Helpful Links
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Additional Relevant MeSH Terms
- Nervous System Diseases
- Immune System Diseases
- Demyelinating Autoimmune Diseases, CNS
- Autoimmune Diseases of the Nervous System
- Demyelinating Diseases
- Autoimmune Diseases
- Eye Diseases
- Optic Nerve Diseases
- Cranial Nerve Diseases
- Myelitis, Transverse
- Optic Neuritis
- Neuromyelitis Optica
- Physiological Effects of Drugs
- Molecular Mechanisms of Pharmacological Action
- Autonomic Agents
- Peripheral Nervous System Agents
- Anti-Inflammatory Agents
- Antirheumatic Agents
- Antineoplastic Agents
- Immunosuppressive Agents
- Immunologic Factors
- Antiemetics
- Gastrointestinal Agents
- Glucocorticoids
- Hormones
- Hormones, Hormone Substitutes, and Hormone Antagonists
- Antineoplastic Agents, Hormonal
- Neuroprotective Agents
- Protective Agents
- Antineoplastic Agents, Alkylating
- Alkylating Agents
- Myeloablative Agonists
- Antineoplastic Agents, Immunological
- Prednisolone
- Methylprednisolone Acetate
- Methylprednisolone
- Methylprednisolone Hemisuccinate
- Prednisolone acetate
- Prednisolone hemisuccinate
- Prednisolone phosphate
- Cyclophosphamide
- Rituximab
- Thymoglobulin
- Antilymphocyte Serum
Other Study ID Numbers
- DIAD Devic's Disease Auto 2008
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
Drug and device information, study documents
Studies a U.S. FDA-regulated drug product
Studies a U.S. FDA-regulated device product
product manufactured in and exported from the U.S.
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