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Hematopoietic Stem Cell Transplant in Devic's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT00787722
Recruitment Status : Active, not recruiting
First Posted : November 7, 2008
Last Update Posted : April 5, 2019
Sponsor:
Information provided by (Responsible Party):
Richard Burt, MD, Northwestern University

Tracking Information
First Submitted Date  ICMJE October 31, 2008
First Posted Date  ICMJE November 7, 2008
Last Update Posted Date April 5, 2019
Actual Study Start Date  ICMJE October 10, 2009
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 13, 2016)
  • 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
Original Primary Outcome Measures  ICMJE
 (submitted: November 6, 2008)
PASAT 25-foot walk 9-hole peg test [ Time Frame: pre-transplant, 6mo, 12mo, yearly for 5 years ]
Change History Complete list of historical versions of study NCT00787722 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE
 (submitted: July 13, 2018)
  • 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
Original Secondary Outcome Measures  ICMJE
 (submitted: November 6, 2008)
Self-administered quality of life exams (FACT-BMT and SF-36) [ Time Frame: pre-transplant, 6mo, 12mo, yearly for 5 years ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Hematopoietic Stem Cell Transplant in Devic's Disease
Official Title  ICMJE Trial of High Dose Immunosuppressive Therapy With Hematopoietic Stem Cell Support in Devic's Disease
Brief Summary This study is designed to examine whether treating Devic's disease patients with high dose cyclophosphamide together with rabbit antithymocyte globulin (rATG)/rituximab (drugs which reduce the function of the immune system), followed by return of previously collected patient's stem cells will result in improvement in Devic's disease. Stem cells are undeveloped cells that have the capacity to grow into mature blood cells, which normally circulate in the blood stream. The purpose of the intense chemotherapy is to destroy the cells in patient's immune system, which may be causing his/her disease. The purpose of the stem cell infusion is to produce a normal immune system that will no longer attack patient's body. The purpose of study is to examine the safety and efficacy of this treatment. The drugs used in this study treatment are drugs for commonly used for immune suppression.
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  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Devic's Disease
Intervention  ICMJE
  • Procedure: Hematopoietic Stem Cell Transplantation
    Infusion of participant's own stem cells
  • Drug: Cyclophosphamide
    A medication used as chemotherapy and to suppress the immune system
    Other Names:
    • Cytoxan
    • Neosar
  • Drug: G-CSF
    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
  • Drug: rATG
    A rabbit polyclonal antibody to lymphocytes
    Other Names:
    • Thymoglobulin
    • Anti-Thymocyte Globulin
  • Drug: Mesna
    A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder
    Other Name: Mesnex
  • Drug: Rituximab
    Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer
    Other Name: Rituxan
  • Drug: Methylprednisolone
    A corticosteroid medication used to suppress the immune system and decrease inflammation
    Other Names:
    • Solu-Medrol
    • Depo-Medrol
Study Arms  ICMJE Experimental: Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell transplantation will be performed after conditioning regimen of cyclophosphamide, G-CSF, Mesna, rATG, rituximab, and methylprednisolone.
Interventions:
  • Procedure: Hematopoietic Stem Cell Transplantation
  • Drug: Cyclophosphamide
  • Drug: G-CSF
  • Drug: rATG
  • Drug: Mesna
  • Drug: Rituximab
  • Drug: Methylprednisolone
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 13, 2018)
13
Original Estimated Enrollment  ICMJE
 (submitted: November 6, 2008)
10
Estimated Study Completion Date  ICMJE January 2020
Actual Primary Completion Date December 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 16 Years to 65 Years   (Child, Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00787722
Other Study ID Numbers  ICMJE DIAD Devic's Disease Auto 2008
Has Data Monitoring Committee No
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Richard Burt, MD, Northwestern University
Study Sponsor  ICMJE Northwestern University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Richard Burt, MD Northwestern University
PRS Account Northwestern University
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP