Autologous Hematopoietic Stem Cell Transplant in Neuromyelitis Optica

Study Overview
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Brief Summary
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Neuromyelitis Optica (NMO) is a demyelinating and degenerative disorder of the CNS affecting vision and spinal cord function. This disease is rare compared to Multiple Sclerosis (MS), but it is devastating and often leads to accumulating disability with a 5 year-mortality of approximately 30%. Survivors are typically left with severe morbidity secondary to blindness, quadriparesis and respiratory failure. No agent has been found to be highly effective in halting disease activity. Based on recent outcomes of stem cell transplant trials and reports in autoimmune diseases including MS, and based on the mechanisms of NMO, we anticipate that stem cell transplantation may provide lasting disease stability for NMO patients. The hypothesis of the present trial is that autologous hematopoetic stem cell transplantation in patients with NMO will provide lasting benefit in relapse prevention. Specifically, we anticipate a 50% reduction in the proportion of patients experiencing relapse over a three year period. We will be following patients for a total of five years after transplantation.

Detailed Description
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Patients who are deemed eligible will be enrolled and undergo a two stage transplant process followed by neurological assessments every 6 months for the following 5 years assessing EDSS, visual metrics, MRI, AQP-4 antibodies, MSFC and SF36.

Official Title
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Autologous Hematopoietic Stem Cell Transplant in Patients With Neuromyelitis Optica

Conditions
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Neuromyelitis Optica

Intervention / Treatment
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* Procedure: AHSCT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age between 18-65, inclusive Diagnosis of NMO using Wingerchuk 2006 NMO Criteria EDSS 0-6.5 Treatment with a minimum of one NMO therapy in past 12 months One objective and documented relapse in the past 12 months and two relapse events in the past 24 months despite medical therapy ECOG performance status 0-3 Platelets ≥100 x 109/L ALT ≤3 x ULN Total bilirubin ≤2.0 x ULN, except in patients with Gilbert syndrome or in patients in whom the bilirubin rise is of non-hepatic origin Serum creatinine <1.5 x ULN or creatinine clearance ≥50 cc/min Patients must reside in Alberta, Canada for the duration of the transplant period of the trial Exclusion Criteria: Any illness that would jeopardize the ability of the patient to complete study protocol Prior malignancy unless non-melanoma skin cancer, carcinoma in-situ of the cervix (CIN) or breast, or malignancy treated more than 5 years previously with no evidence of recurrent disease since initial treatment Pregnant or lactating females. Women of childbearing potential must have a negative serum or urine β-hCG pregnancy test at screening Inability or unwillingness to pursue effective means of birth control FEV1/FVC < 50% of predicted DLCO < 50% of predicted Resting LVEF < 50 % Known hypersensitivity to mouse, rabbit, or E. Coli derived proteins, or to iron compounds/medications Presence of metallic objects implanted in the body that would preclude the ability of the patient to safely have MRI exams Unable or unwilling to provide written informed consent for participation Active infection except asymptomatic bacteriuria Any use of investigational therapies within 4 weeks prior to initiation of study treatment Patients dependent on prednisone who cannot be successfully tapered to a maximum of 0.5mg/kg/d prior to mobilization therapy

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

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: AHSCT<br>All patients undergo autologous hematopoietic stem cell transplantation in a two stage process. | Procedure: AHSCT<br>* AHSCT Procedure: Mobilization and Harvesting: Cyclophosphamide Rituximab GSCF Dexamethasone Apheresis Conditioning and Infusion (3-4 weeks after Mobilization and Harvesting): Cyclophosphamide MESNA Rabbit ATG Rituximab Methylprednisolone Stem Cell infusion GSCF<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion relapse-free at three years | The proportion of surviving patients who are relapse-free at three years after transplant | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion relapse-free at five years | The proportion of surviving patients relapse-free at year five | 5 years | 
| Relapse count | Number of NMO relapse events | Annually over 5 years | 
| Disability progression | Time to progression of EDSS by one step | Over 5 years | 
| Retinal nerve fiber layer (RFNL) status | Change in RNFL by optical coherence tomography over trial | 5 years | 
| 25 foot timed walk test | Change in 25 ft timed walk test over trial | 5 years | 
| PASAT | Annual and change from baseline to end of trial in Paced Auditory Serial Addition Test to assess cognitive function. | Annually over 5 years | 
| Hospitalization | Number of hospitalizations, days in hospital over trial period | Over 5 years | 
| Overall survival | Survival over trial period | Over 5 years | 
| Time to next relapse | Time to next relapse after transplant | Over 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NMO, Neuromyelitis Optica, Devic's Disease, Stem Cell Transplant