Hematopoietic Stem Cell Transplant in Devic's Disease

NCT ID: NCT00787722

Last Updated: 2020-02-28

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE1/PHASE2
• Total Enrollment: 13 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2009-10-10
• Study Completion Date: 2018-11-30

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.

Conditions

Devic's Disease

Study Design

• Allocation Method: NA
• Intervention Model: SINGLE_GROUP
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Hematopoietic Stem Cell Transplantation

Hematopoietic stem cell transplantation will be performed after conditioning regimen of cyclophosphamide, G-CSF, Mesna, rATG, rituximab, and methylprednisolone.

Group Type: EXPERIMENTAL

Hematopoietic Stem Cell Transplantation

Intervention Type: PROCEDURE

Infusion of participant's own stem cells

Cyclophosphamide

Intervention Type: DRUG

A medication used as chemotherapy and to suppress the immune system

G-CSF

Intervention Type: DRUG

A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream

rATG

Intervention Type: DRUG

A rabbit polyclonal antibody to lymphocytes

Mesna

Intervention Type: DRUG

A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder

Rituximab

Intervention Type: DRUG

Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer

Methylprednisolone

Intervention Type: DRUG

A corticosteroid medication used to suppress the immune system and decrease inflammation

Interventions

Hematopoietic Stem Cell Transplantation

Infusion of participant's own stem cells

Intervention Type: PROCEDURE

Cyclophosphamide

A medication used as chemotherapy and to suppress the immune system

Intervention Type: DRUG

G-CSF

A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream

Intervention Type: DRUG

rATG

A rabbit polyclonal antibody to lymphocytes

Intervention Type: DRUG

Mesna

A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder

Intervention Type: DRUG

Rituximab

Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer

Intervention Type: DRUG

Methylprednisolone

A corticosteroid medication used to suppress the immune system and decrease inflammation

Intervention Type: DRUG

Other Intervention Names

Cytoxan; Neosar; Neupogen; Filgrastim; Granix; Zarxio; Thymoglobulin; Anti-Thymocyte Globulin; Mesnex; Rituxan; Solu-Medrol; Depo-Medrol

Eligibility 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

• Minimum Eligible Age: 16 Years
• Maximum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Northwestern University

OTHER

Sponsor Role: lead

Responsible Party

Richard Burt, MD

MD

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Richard Burt, MD

Role: PRINCIPAL_INVESTIGATOR

Northwestern University

Locations

Northwestern University, Feinberg School of Medicine

Chicago, Illinois, United States

Countries

United States

References

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.

Reference Type: BACKGROUND

PMID: 31578302 (View on PubMed)

Provided Documents

Document Type: Study Protocol

View Document

Document Type: Statistical Analysis Plan

View Document

Other Identifiers

DIAD Devic's Disease Auto 2008

Identifier Type: -

Identifier Source: org_study_id