Autologous Transplant To End NMO Spectrum Disorder (ATTEND)

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

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.

Study Overview

• Status: Withdrawn
• Conditions: Neuromyelitis Optica; Devic's Disease; NMO Spectrum Disorder
• Intervention / Treatment: Drug: Cyclophosphamide; Drug: G-CSF; Drug: rATG; Drug: Mesna; Drug: Rituximab; Drug: Methylprednisolone; Biological: IVIg; Biological: Autologous Stem Cells

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.

• Study Type: Interventional
• Phase: Phase 2; Phase 3

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University
    • Chicago, Illinois, United States, 60611
      • Northwestern University, Feinberg School of Medicine

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 63 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Age 18 - 65 years old at the time of pre-transplant evaluation
2. An established diagnosis of NMOSD (with or without aquaporin 4 (AQP4)-IgG antibody)

Exclusion Criteria:

1. Under age of 18 or over age of 65
2. Prisoners
3. 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).
4. Paraplegia or quadriplegia (must be able to use a walker if even for only a few feet)
5. Extensive subcortical white matter lesions
6. 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
7. Myocardial infarction within the last 12 months. If longer than 12 months, must pass a dobutamine stress test and be cleared by cardiology.
8. Active systemic lupus erythematous, Sjogren's, myasthenia gravis, or another autoimmune disease
9. Sickle cell disease, sickle cell disease, or coagulopathy
10. Prior history of malignancy that required any radiotherapy, chemotherapy, or biological therapy
11. 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
12. Women who are breastfeeding
13. Untreated life-threatening cardiac arrhythmia on electrocardiogram (EKG) or 24-hour holter
14. Left ventricular ejection fraction (LVEF) <50%
15. 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
16. Serum creatinine >2.0 mg/dl
17. Liver cirrhosis, transaminases >2x of normal limits, or bilirubin >2.0 mg/dl unless due to Gilbert's disease
18. Major hematological abnormalities such as platelet count < 100,000/μl or absolute neutrophil count (ANC) < 1000/μl
19. Active infection except asymptomatic bacteriuria
20. Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have magnetic resonance imaging (MRI) exams
21. Known hypersensitivity to mouse, rabbit, or E. coli derived proteins
22. Human immunodeficiency virus (HIV) positive
23. Hepatitis B or C positive
24. Use of natalizumab (Tysabri) within the previous six months
25. Use of fingolimod (Gilenya) within the previous three months
26. Use of dimethyl fumarate (Tecfidera) within the previous three months
27. 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
28. Use of alemtuzumab (Lemtrada/Campath) within previous 12 months
29. Use of rituximab (Rituxan) or ocrelizumab (Ocrevus) within previous six months
30. Prior treatment with mitoxantrone (Novantrone)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Hematopoietic Stem Cell Transplantation; 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: Cyclophosphamide; A medication used as chemotherapy and to suppress the immune system; Other Names: Cytoxan; Drug: G-CSF; A glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream; Other Names: Filgrastim; Neupogen; Zarxio; Granix; 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 Names: Mesnex; Drug: Rituximab; Monoclonal antibody therapy used to treat certain autoimmune diseases and types of cancer; Other Names: Rituxan; Drug: Methylprednisolone; A corticosteroid medication used to suppress the immune system and decrease inflammation; Other Names: Depo-Medrol; Solu-Medrol; Biological: IVIg; Pooled immunoglobulin (IgG) from thousands of plasma donors that has immunomodulatory and anti-inflammatory effects; Other Names: Gammagard; Privigen; Octagam; Bivigam; Carimune Nanofiltered (NF); Biological: Autologous Stem Cells; Infusion of patient's own stem cells

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

Collaborators and Investigators

• Sponsor: Northwestern University

Study record dates

Study Major Dates

• Study Start (Anticipated): November 1, 2019
• Primary Completion (Anticipated): January 1, 2025
• Study Completion (Anticipated): November 28, 2025

Study Registration Dates

• First Submitted: February 1, 2019
• First Submitted That Met QC Criteria: February 1, 2019
• First Posted (Actual): February 4, 2019

Study Record Updates

• Last Update Posted (Actual): November 20, 2019
• Last Update Submitted That Met QC Criteria: November 18, 2019
• Last Verified: November 1, 2019

More Information

Terms related to this study

• Keywords: Hematopoietic Stem Cell Transplant; Autologous Stem Cell Transplantation
• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Eye Diseases; Optic Nerve Diseases; Cranial Nerve Diseases; Myelitis, Transverse; Optic Neuritis; Neuromyelitis Optica; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Neuroprotective Agents; Protective Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antineoplastic Agents, Immunological; Prednisolone; Methylprednisolone Acetate; Methylprednisolone; Methylprednisolone Hemisuccinate; Prednisolone acetate; Prednisolone hemisuccinate; Prednisolone phosphate; Cyclophosphamide; Rituximab; Thymoglobulin; Antilymphocyte Serum
• Other Study ID Numbers: DIAD.ATTEND.2018

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No