Autologous Transplant To End NMO Spectrum Disorder

Study Overview
=================
Brief Summary
-----------------
This study is designed to treat your disease with an autologous stem cell transplant using a regimen of immune suppressant drugs and chemotherapy to reset your immune system and to determine if your disease will go into long-term remission.

Detailed Description
-----------------
The autologous stem cell transplant used in this research study is an investigational procedure that uses cyclophosphamide (chemotherapy), rabbit antithymocyte globulin (rATG) (a protein that kills the immune cells that are thought to be causing your disease), rituximab (a biologic drug that targets B cells of your immune system), and intravenous immunoglobulin (IVIg) (pooled IgG antibodies from plasma donors with immunomodulatory and anti-inflammatory effects), followed by return of your own previously collected blood stem cells (autologous stem cell transplant). One day of plasmapheresis will also be performed the day prior to admission for stem cell transplant to remove disease-causing antibodies. The ability of this experimental treatment to stop relapses and progression (worsening) of your NMOSD will be assessed.

Official Title
-----------------
Autologous Hematopoietic Stem Cell Transplant for Neuromyelitis Optica Spectrum Disorder (NMOSD)

Conditions
-----------------
Neuromyelitis Optica, Devic's Disease, NMO Spectrum Disorder

Intervention / Treatment
-----------------
* Drug: Rituximab
* Drug: Cyclophosphamide
* Drug: Mesna
* Drug: rATG
* Drug: Methylprednisolone
* Drug: G-CSF
* Biological: IVIg
* Biological: Autologous Stem Cells


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age 18 - 65 years old at the time of pre-transplant evaluation An established diagnosis of NMOSD (with or without aquaporin 4 (AQP4)-IgG antibody) Exclusion Criteria: Under age of 18 or over age of 65 Prisoners Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible, or any adult who is unable to consent (for adults cognitively impaired due to disease, consent may be obtained from the closest living relative). Paraplegia or quadriplegia (must be able to use a walker if even for only a few feet) Extensive subcortical white matter lesions Uncontrolled diabetes mellitus or any other illness that in the opinion of the investigators would jeopardize the ability of the patient to tolerate aggressive treatment Myocardial infarction within the last 12 months. If longer than 12 months, must pass a dobutamine stress test and be cleared by cardiology. Active systemic lupus erythematous, Sjogren's, myasthenia gravis, or another autoimmune disease Sickle cell disease, sickle cell disease, or coagulopathy Prior history of malignancy that required any radiotherapy, chemotherapy, or biological therapy Positive pregnancy test, inability or unable to pursue effective means of birth control, or failure to willingly accept or comprehend irreversible sterility as a side effect of therapy Women who are breastfeeding Untreated life-threatening cardiac arrhythmia on electrocardiogram (EKG) or 24-hour holter Left ventricular ejection fraction (LVEF) <50% Tiffeneau-Pinelli index (FEV1/FVC) <70% of predicted after bronchodilator therapy (if necessary), or diffusing capacity of lung for carbon monoxide (DLCO) hemoglobin corrected <70 % predicted Serum creatinine >2.0 mg/dl Liver cirrhosis, transaminases >2x of normal limits, or bilirubin >2.0 mg/dl unless due to Gilbert's disease Major hematological abnormalities such as platelet count < 100,000/μl or absolute neutrophil count (ANC) < 1000/μl Active infection except asymptomatic bacteriuria Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have magnetic resonance imaging (MRI) exams Known hypersensitivity to mouse, rabbit, or E. coli derived proteins Human immunodeficiency virus (HIV) positive Hepatitis B or C positive Use of natalizumab (Tysabri) within the previous six months Use of fingolimod (Gilenya) within the previous three months Use of dimethyl fumarate (Tecfidera) within the previous three months Use of teriflunomide (Aubagio) unless cleared from the body (plasma concentration <0.02mcg/ml) following elimination from the body with cholestyramine 8g three times a day for 11 days Use of alemtuzumab (Lemtrada/Campath) within previous 12 months Use of rituximab (Rituxan) or ocrelizumab (Ocrevus) within previous six months Prior treatment with mitoxantrone (Novantrone)

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Hematopoietic Stem Cell Transplantation<br>Hematopoietic Stem Cell Therapy will be performed as follows: Autologous stem cells will be infused after conditioning with rituximab, cyclophosphamide, mesna, rATG (rabbit), and methylprednisolone. Granulocyte-colony stimulating factor (G-CSF) and intravenous immunoglobulin (IVIg) will be administered post-transplant. | Drug: Rituximab<br>* Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer<br>* Other names: Rituxan;Drug: Cyclophosphamide<br>* A medication used as chemotherapy and to suppress the immune system<br>* Other names: Cytoxan;Drug: Mesna<br>* A medication used in those taking cyclophosphamide or ifosfamide to decrease the risk of bleeding from the bladder<br>* Other names: Mesnex;Drug: rATG<br>* A rabbit polyclonal antibody to lymphocytes<br>* Other names: Anti-Thymocyte Globulin;Drug: Methylprednisolone<br>* A corticosteroid medication used to suppress the immune system and decrease inflammation<br>* Other names: Depo-Medrol;Drug: G-CSF<br>* A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream<br>* Other names: Zarxio;Biological: IVIg<br>* Pooled immunoglobulin (IgG) from thousands of plasma donors that has immunomodulatory and anti-inflammatory effects<br>* Other names: Octagam;Biological: Autologous Stem Cells<br>* Infusion of patient's own stem cells<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-Free Survival | Disease progression defined as: 1.0-point increase in the Expanded Disability Status Scale (EDSS) on consecutive evaluations at least six months apart and not due to a non-NMO disease process. The EDSS scale ranges from 0 to 10 in 0.5 increments that represent higher levels of disability. | 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Relapse-Free Survival | Relapse defined as: Acute neurologic deterioration occurring after engraftment and lasting more than 24 hours, accompanied by objective worsening on neurological examination that are documented by a neurologist and not explained by fever, infection, stress, heat, drugs or related pseudo-exacerbation. Supportive confirmation by enhancement on MRI is preferred but not mandatory. | 5 years | 
| Expanded Disability Status Scale (EDSS) Improvement | The EDSS scale ranges from 0 to 10 in 0.5 increments that represent higher levels of disability. Improvement in EDSS is defined by both a 0.5 or 1.0 points sustained for more than 6 months | 6 months, 1 year, 2 years, 3 years, 4 years, 5 years | 
| Scripps Neurological Rating Scale (NRS) Improvement | The NRS scale ranges from 0 to 100 in 1 point increments that represent lower levels of disability. | 6 months, 1 year, 2 years, 3 years, 4 years, 5 years | 
| Improvement in Quality of Life | Measured using the short form (SF)-36 health survey. | 6 months, 1 year, 2 years, 3 years, 4 years, 5 years | 
| Paced Auditory Serial Addition Test (PASAT) Improvement | The PASAT is a measure of cognitive function that specifically assesses auditory information processing speed and flexibility, as well as calculation ability. Improvement measured with the 2 and 3 versions | 6 months, 1 year, 2 years, 3 years, 4 years, 5 years | 
| Ambulation Index Improvement | The subject's walk of 25 feet is timed and a score from 0 to 10 is assigned based on their walk/gait and/or assistance required. | 6 months, 1 year, 2 years, 3 years, 4 years, 5 years | 
| 9 Hole Peg Test (9-HPT) Improvement | The 9-HPT is a brief, standardized, quantitative test of upper extremity function. Both the dominant and non-dominant hands are tested twice, with the total time to complete the task each time recorded and then averaged. | 6 months, 1 year, 2 years, 3 years, 4 years, 5 years | 
| Change in NMO IgG (aquaporin-4) Antibody Titer | Evaluation of the antibody titer, looking for a change from positive to negative. | 6 months, 1 year, 2 years, 3 years, 4 years, 5 years | 
| Improvement in Visual Acuity | A visual acuity test is an eye exam that checks how well one sees the details of a letter or symbol from a specific distance. | 6 months, 1 year, 2 years, 3 years, 4 years, 5 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Autologous Stem Cell Transplantation, Hematopoietic Stem Cell Transplant