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Stem Cell Transplantation for Stiff Person Syndrome (SPS) (SPS)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02282514
Recruitment Status : Terminated (Could not predict who would respond, relapse or go into remission)
First Posted : November 4, 2014
Results First Posted : January 6, 2021
Last Update Posted : January 27, 2021
Information provided by (Responsible Party):
Richard Burt, MD, Northwestern University

Brief Summary:

Non-myeloablative regimens (as the investigators use herein) are designed to maximally suppress the immune system without destruction of the bone marrow stem cell compartment.

When using a non-myeloablative regimen recovery occurs without infusion of stem cells and the stem cells are autologous. While not necessary for recovery, stem cell infusion may shorten the interval of neutropenia and attendant complications. Thus in reality there is no transplant only an autologous supportive blood product.

Based on our encouraging results of non-myeloablative hematopoietic stem cell transplantation, for patients with multiple sclerosis and chronic inflammatory demyelinating polyneuropathy, the investigators will investigate the role of non-myeloablative hematopoietic stem cell transplantation for patients with SPS who require assistance to ambulate.

Condition or disease Intervention/treatment Phase
Stiff-Person Syndrome Biological: Autologous Hematopoietic Stem Cells Drug: Cyclophosphamide Drug: Mesna Drug: rATG Drug: Methylprednisolone Drug: G-CSF Drug: Rituxan Phase 1 Phase 2

Detailed Description:

Pre-study Testing

  1. History and physical
  2. Electrocardiogram (EKG)
  3. Dobutamine stress echocardiogram
  4. High-resolution computed tomography of the chest (HRCT)
  5. Blood draw for laboratory tests- these tests will include a complete blood count, evaluating liver and kidney function, assessing immune system, tissue typing, and checking for certain germs that can cause infections, including a pregnancy test for females and prostate-specific antigen (PSA) for male as well as testing for HIV
  6. Pulmonary Function Test (PFT)
  7. Electromyography (EMG)
  8. Magnetic Resonance Imaging (MRI) of the Abdomen and Pelvis
  9. Magnetic Resonance Imaging (MRI) of the Spinal Cord
  10. Magnetic Resonance Imaging (MRI) of the Brain with Gadolinium (only if PERM of cerebellar ataxia)
  11. Colonoscopy
  12. Mammogram (if female)
  13. Timed ambulation
  14. Quality of Life Questionnaires [ Short Form (36) Health Survey (SF36) and Barthel Index]
  15. Chronic Pain Acceptance Questionnaire (CPAQ)
  16. Rankin Functional Scale
  17. Modified Ashworth Scale
  18. Purkinje Cell Cytoplasmic Antibody, Type 1 (PCA-1), Purkinje Cell Cytoplasmic Antibody, Type 2 (PCA-2) antibody (only if cerebellar ataxia)
  19. Spinocerebellar ataxia (SCA) 1, 2, 3, 4, 5, 6, 7, 8 genes (only if ataxia)

Study Treatment

Stem Cell Collection: Cyclophosphamide 2.0 gm/m2 will be given on day 0, G-CSF 5-10 mcg/kg/day subcutaneous (SQ) will start on day +5 and will continue until apheresis is discontinued. Apheresis will begin when the absolute neutrophil count (ANC) > 1.0 x 109/L and continue until >2.0 x 106 cluster of differentiation 34 (CD34)+ cells/kg patient weight are cryopreserved. A 10-15 liter apheresis will be performed unless stopped earlier for clinical judgment of toxicity (e.g., numbness, tetany). A maximum of four apheresis will be performed.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 23 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Non-myeloablative Hematopoietic Stem Cell Transplantation for Stiff Person Syndrome (SPS) and Anti-GAD Antibody Variants: Progressive Encephalomyelitis With Rigidity and Myoclonus (PERM), and Adult Onset Autoimmune Anti-GAD Positive Cerebellar Ataxia
Study Start Date : October 2014
Actual Primary Completion Date : August 19, 2019
Actual Study Completion Date : August 30, 2019

Arm Intervention/treatment
Experimental: Hematopoietic Stem Cell Transplantation
The conditioning regimen will be 200 mg/kg of intravenous cyclophosphamide given in 4 equal fractions on days -5 through -2 with intravenous mesna. Rabbit antithymocyte globulin (rATG) (Thymoglobulin®) will be dosed at 0.5 mg/kg on day-5, 1.0 mg/kg on days -4 and -3, and then 1.5 mg/kg on days -2 and -1. Methylprednisolone 1000 mg will be infused intravenously before each dose of rATG. Autologous hematopoietic stem cells will be infused intravenously on day 0. A granulocyte-colony stimulating factor (G-CSF) 5-10 mcg/kg will be started on day + 5 and continued until neutrophil engraftment. Intravenous Rituxan (500mg) will be administered on days -6 and +1.
Biological: Autologous Hematopoietic Stem Cells
The stem cells will be collected from patient's blood during mobilization. Then the patient will be given high dose chemotherapy in accordance with approved recommendations for use in conditioning regimens for stem cell transplant in autoimmune diseases. Autologous Hematopoietic Stem Cell Transplantation is to re-infuse immature cells that can re-establish blood production and patient's immune system.

Drug: Cyclophosphamide
An alkylating agent which causes prevention of cell division by forming adducts with DNA
Other Names:
  • Cytoxan
  • Neosar
  • Endoxan

Drug: Mesna
Medication used to decrease the risk of hemorrhagic cystitis prophylaxis
Other Name: Mesnex

Drug: rATG
A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells
Other Name: Thymoglobulin

Drug: Methylprednisolone
Other Name: Solu-Medrol

Drug: G-CSF
Granulocyte-colony stimulating factor; 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: Rituxan
A chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders
Other Name: Rituximab

Primary Outcome Measures :
  1. Overall Survival [ Time Frame: Mean 3.6 years ]
    Number of Participants who Did Not Experience Treatment-Related Mortality

Secondary Outcome Measures :
  1. Reduction of Muscle Relaxation Anti-spasmatic Medications [ Time Frame: Mean 3.6 years ]
    Decrease (50%) and complete discontinuation of muscle relaxation anti-spasmatic medications

  2. Short-form 36 Quality of Life Questionnaire (SF-36 QOL) [ Time Frame: mean 3.6 years ]
    Improvement is defined as a statistically significant change in SF-36 QOL score. The scale is 0-100. The lower the score the worse quality of life.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   18 Years to 60 Years   (Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  1. Diagnosis of Stiff-person Syndrome and

    • Age between 18 and 60 years old
    • Failure of medically tolerable doses (20-40 mg/day) of diazepam
    • Failure of either intravenous immunoglobulin (IVIg) and or plasmapheresis
    • Stiffness in the axial muscles, prominently in the abdominal and thoracolumbar paraspinal muscle leading to a fixed deformity (hyperlordosis)
    • Superimposed painful spasms precipitated by unexpected noises, emotional stress, tactile stimuli
    • Confirmation of the continuous motor unit activity in agonist and antagonist muscles by electromyography when off diazepam and anti-spasmatic medications
    • Absence of neurological or cognitive impairments that could explain the stiffness
    • Inability to run or walk, or abnormal gait
  2. Diagnosis of a SPS variant- Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM) defined as:

    Acute onset of painful rigidity and muscle spasms in the limbs and trunk

    • Brainstem dysfunction (nystagmus, opsoclonus, ophthalmoparesis, deafness, dysarthria, dysphagia)
    • Profound autonomic disturbance.
    • Positive serology for GAD65 (or amphiphysin) autoantibodies, assessed by immunocytochemistry, western blot or radioimmunoassay (>1000 u/ml)
    • MRI may show increased signal intensity throughout the spinal cord and the brainstem
  3. Diagnosis of a SPS variant - anti-GAD positive cerebellar ataxia

    • Subacute or chronic onset of cerebellar symptoms-gait or limb ataxia, dysarthria, nystagmus
    • Positive serology for GAD65 (or amphiphysin) autoantibodies, assessed by immunocytochemistry, western blot or radioimmunoassay (>1000 u/ml)
    • Anti-GAD antibody in cerebrospinal fluid
    • Abnormal MRI imaging of brainstem or cerebellum other than cerebellar atrophy
    • Negative history of toxin or alcohol
    • Absence of Vitamin B12 or Vitamin E deficiency
    • Absence of positive HIV, syphilis or whipple disease
    • Absence of consanguinity, positive family history for ataxia or positive genetic screen for spinocerebellar ataxia (SCA) 1, SCA 2, SCA 3, SCA 6, SCA 7 or SCA 8 mutation

Exclusion Criteria:

  • Current or prior history of a malignancy or paraneoplastic syndrome
  • Inability to sign and understand consent and be compliant with treatment
  • Positive pregnancy test
  • Inability to or comprehend irreversible sterility as a possible side effect
  • Amphiphysin antibody positive
  • Left ventricular ejection fraction (LVEF) < 45% or ischemic coronary artery disease on dobutamine stress echocardiogram
  • Diffusing capacity of the lungs for carbon monoxide (DLCO) < 60% predicted
  • Serum creatinine > 2.0 mg/dl
  • Bilirubin >2.0 mg/dl
  • Platelet count < 100,000 / ul, white blood cell count (WBC) < 1,500 cells/mm3
  • History of toxin or alcohol abuse
  • History of Vitamin B12 or Vitamin E deficiency
  • Positive HIV, syphilis, or whipple disease
  • Consanguinity, positive family history for ataxia or positive genetic screen for SCA1, SCA2, SCA3, SCA6, SCA 7 or SCA8 mutation (if ataxia present)
  • Absence of at least one SPS associated antibody such as anti-GAD, or gamma-aminobutyric acid (GABA)-A receptor associated protein, or synaptophysin, or gephyrin, or GABA-transaminase

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02282514

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United States, Illinois
Northwestern University
Chicago, Illinois, United States, 60611
Sponsors and Collaborators
Northwestern University
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Principal Investigator: Richard Burt, MD Northwestern University
  Study Documents (Full-Text)

Documents provided by Richard Burt, MD, Northwestern University:
Additional Information:
Publications of Results:
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Responsible Party: Richard Burt, MD, Professor, Division Chief, Northwestern University Identifier: NCT02282514    
Other Study ID Numbers: DIAD.SPS.2014
First Posted: November 4, 2014    Key Record Dates
Results First Posted: January 6, 2021
Last Update Posted: January 27, 2021
Last Verified: January 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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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:
Autoimmune Diseases
Autologous Hematopoietic Stem Cell Transplantation
Additional relevant MeSH terms:
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Stiff-Person Syndrome
Pathologic Processes
Autoimmune Diseases of the Nervous System
Nervous System Diseases
Spinal Cord Diseases
Central Nervous System Diseases
Neuromuscular Diseases
Autoimmune Diseases
Immune System Diseases
Methylprednisolone Hemisuccinate
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antineoplastic Agents, Immunological
Anti-Inflammatory Agents
Autonomic Agents
Peripheral Nervous System Agents