Hematopoietic Stem Cell Transplant in Devic's Disease
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|ClinicalTrials.gov Identifier: NCT00787722|
Recruitment Status : Active, not recruiting
First Posted : November 7, 2008
Last Update Posted : April 5, 2019
|Condition or disease||Intervention/treatment||Phase|
|Devic's Disease||Procedure: Hematopoietic Stem Cell Transplantation Drug: Cyclophosphamide Drug: G-CSF Drug: rATG Drug: Mesna Drug: Rituximab Drug: Methylprednisolone||Phase 1 Phase 2|
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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 :||Interventional (Clinical Trial)|
|Actual Enrollment :||13 participants|
|Intervention Model:||Single Group Assignment|
|Masking:||None (Open Label)|
|Official Title:||Trial of High Dose Immunosuppressive Therapy With Hematopoietic Stem Cell Support in Devic's Disease|
|Actual Study Start Date :||October 10, 2009|
|Actual Primary Completion Date :||December 2018|
|Estimated Study Completion Date :||January 2020|
Experimental: Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell transplantation will be performed after conditioning regimen of cyclophosphamide, G-CSF, Mesna, rATG, rituximab, and methylprednisolone.
Procedure: Hematopoietic Stem Cell Transplantation
Infusion of participant's own stem cells
A medication used as chemotherapy and to suppress the immune system
A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
A rabbit polyclonal antibody to lymphocytes
A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder
Other Name: Mesnex
Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer
Other Name: Rituxan
A corticosteroid medication used to suppress the immune system and decrease inflammation
- 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
- Visual Acuity [ Time Frame: 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant ]Visual Acuity will be evaluated by neurologist
- Decreased weakness in limb (MRS) [ Time Frame: 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant ]Decreased weakness in limb will be assessed by using muscle strength testing scale
- Functional Assessment of Cancer Therapy-Bone Marrow Transplant [ Time Frame: pre-transplant, 6mo, 12mo, yearly for 5 years ]The Functional Assessment of Cancer Therapy-Bone Marrow Transplant (FACT-BMT) is a self-administered quality of life exam.
- 36-Item Short Form Health Survey [ Time Frame: pre-transplant, 6mo, 12mo, yearly for 5 years ]The 36-Item Short Form Health Survey (SF-36) is a self-administered quality of life exams.
- Number of acute attacks [ Time Frame: 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant ]Number of acute attacks will be evaluated at 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant
- Time to confinement to wheelchair [ Time Frame: 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant ]Time to confinement to wheelchair will be evaluated at 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant
- Time to legal blindness(visual acuity of 20/200 or less in the better eye with best correction possible [ Time Frame: 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant ]Time to legal blindness(visual acuity of 20/200 or less in the better eye with best correction possible) will be evaluated at 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant
- Disability scores [ Time Frame: 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant ]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
- NMO-IgG aquaporin- 4 autoantibody titer [ Time Frame: 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant ]NMO-IgG aquaporin- 4 autoantibody titer will be tested at 6 months, 1 year, 2 year, 3 year, 4 year, 5 year - after the transplant
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): NCT00787722
|United States, Illinois|
|Northwestern University, Feinberg School of Medicine|
|Chicago, Illinois, United States, 60611|
|Principal Investigator:||Richard Burt, MD||Northwestern University|