Hematopoietic Stem Cell Transplant in Devic's Disease

• ClinicalTrials.gov Identifier: NCT00787722
• Recruitment Status: Completed
• First Posted: November 7, 2008
• Results First Posted: February 28, 2020
• Last Update Posted: February 28, 2020
• Sponsor: Northwestern University
• Information provided by (Responsible Party): Richard Burt, MD, Northwestern University

Study Description

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.

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

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 13 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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: November 2018
• Actual Study Completion Date: November 2018

Arms and Interventions

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.

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

Outcome Measures

Primary Outcome Measures :

1. 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

Secondary Outcome Measures :

1. 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.
2. 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 ]
   Number of immune - modulating medication and relapse evaluated 5 year - after the transplant
3. 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
4. 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.

5. 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.

Eligibility Criteria

• Ages Eligible for Study: 16 Years to 65 Years (Child, Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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

Contacts and Locations

Locations

United States, Illinois

Northwestern University, Feinberg School of Medicine

Chicago, Illinois, United States, 60611

Sponsors and Collaborators

Northwestern University

Investigators

• Principal Investigator: Richard Burt, MD; Northwestern University

  Study Documents (Full-Text)

Documents provided by Richard Burt, MD, Northwestern University:

Study Protocol  [PDF] April 28, 2017

Statistical Analysis Plan  [PDF] April 28, 2017

More Information

Additional Information:

American Academy of Neurology 

Publications:

Burt RK, Balabanov R, Han X, Burns C, Gastala J, Jovanovic B, Helenowski I, Jitprapaikulsan J, Fryer JP, Pittock SJ. Autologous nonmyeloablative hematopoietic stem cell transplantation for neuromyelitis optica. Neurology. 2019 Oct 29;93(18):e1732-e1741. doi: 10.1212/WNL.0000000000008394. Epub 2019 Oct 2.

• Responsible Party: Richard Burt, MD, MD, Northwestern University
• ClinicalTrials.gov Identifier: NCT00787722
• Other Study ID Numbers: DIAD Devic's Disease Auto 2008
• First Posted: November 7, 2008
• Results First Posted: February 28, 2020
• Last Update Posted: February 28, 2020
• Last Verified: November 2019

Individual Participant Data (IPD) Sharing Statement:

• 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, Northwestern University:

High dose immunosuppressive therapy; Hematopoietic stem cell support

Additional relevant MeSH terms:

Neuromyelitis Optica; Myelitis, Transverse; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Nervous System Diseases; Optic Neuritis; Optic Nerve Diseases; Cranial Nerve Diseases; Demyelinating Diseases; Eye Diseases; Autoimmune Diseases; Immune System Diseases; Methylprednisolone; Methylprednisolone Acetate; Methylprednisolone Hemisuccinate; Prednisolone; Prednisolone acetate; Cyclophosphamide; Rituximab; Thymoglobulin; Antilymphocyte Serum; Prednisolone hemisuccinate; Prednisolone phosphate; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Antirheumatic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Molecular Mechanisms of Pharmacological Action