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

Primary Purpose

Stiff-Person Syndrome

Status
Terminated
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Autologous Hematopoietic Stem Cells
Cyclophosphamide
Mesna
rATG
Methylprednisolone
G-CSF
Rituxan
Sponsored by
Northwestern University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Stiff-Person Syndrome focused on measuring Autoimmune Diseases, Autologous Hematopoietic Stem Cell Transplantation

Eligibility Criteria

18 Years - 60 Years (Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Northwestern University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Hematopoietic Stem Cell Transplantation

Arm Description

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.

Outcomes

Primary Outcome Measures

Overall Survival
Number of Participants who Did Not Experience Treatment-Related Mortality

Secondary Outcome Measures

Reduction of Muscle Relaxation Anti-spasmatic Medications
Decrease (50%) and complete discontinuation of muscle relaxation anti-spasmatic medications
Short-form 36 Quality of Life Questionnaire (SF-36 QOL)
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.

Full Information

First Posted
October 30, 2014
Last Updated
January 6, 2021
Sponsor
Northwestern University
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1. Study Identification

Unique Protocol Identification Number
NCT02282514
Brief Title
Stem Cell Transplantation for Stiff Person Syndrome (SPS)
Acronym
SPS
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 Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Terminated
Why Stopped
Could not predict who would respond, relapse or go into remission
Study Start Date
October 2014 (undefined)
Primary Completion Date
August 19, 2019 (Actual)
Study Completion Date
August 30, 2019 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Northwestern University

4. Oversight

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
Data Monitoring Committee
Yes

5. Study Description

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.
Detailed Description
Pre-study Testing History and physical Electrocardiogram (EKG) Dobutamine stress echocardiogram High-resolution computed tomography of the chest (HRCT) 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 Pulmonary Function Test (PFT) Electromyography (EMG) Magnetic Resonance Imaging (MRI) of the Abdomen and Pelvis Magnetic Resonance Imaging (MRI) of the Spinal Cord Magnetic Resonance Imaging (MRI) of the Brain with Gadolinium (only if PERM of cerebellar ataxia) Colonoscopy Mammogram (if female) Timed ambulation Quality of Life Questionnaires [ Short Form (36) Health Survey (SF36) and Barthel Index] Chronic Pain Acceptance Questionnaire (CPAQ) Rankin Functional Scale Modified Ashworth Scale Purkinje Cell Cytoplasmic Antibody, Type 1 (PCA-1), Purkinje Cell Cytoplasmic Antibody, Type 2 (PCA-2) antibody (only if cerebellar ataxia) 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Stiff-Person Syndrome
Keywords
Autoimmune Diseases, Autologous Hematopoietic Stem Cell Transplantation

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
23 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Hematopoietic Stem Cell Transplantation
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Autologous Hematopoietic Stem Cells
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Cyclophosphamide
Other Intervention Name(s)
Cytoxan, Neosar, Endoxan
Intervention Description
An alkylating agent which causes prevention of cell division by forming adducts with DNA
Intervention Type
Drug
Intervention Name(s)
Mesna
Other Intervention Name(s)
Mesnex
Intervention Description
Medication used to decrease the risk of hemorrhagic cystitis prophylaxis
Intervention Type
Drug
Intervention Name(s)
rATG
Other Intervention Name(s)
Thymoglobulin
Intervention Description
A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells
Intervention Type
Drug
Intervention Name(s)
Methylprednisolone
Other Intervention Name(s)
Solu-Medrol
Intervention Description
Steroid
Intervention Type
Drug
Intervention Name(s)
G-CSF
Other Intervention Name(s)
Neupogen, Filgrastim, Granix, Zarxio
Intervention Description
Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
Intervention Type
Drug
Intervention Name(s)
Rituxan
Other Intervention Name(s)
Rituximab
Intervention Description
A chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders
Primary Outcome Measure Information:
Title
Overall Survival
Description
Number of Participants who Did Not Experience Treatment-Related Mortality
Time Frame
Mean 3.6 years
Secondary Outcome Measure Information:
Title
Reduction of Muscle Relaxation Anti-spasmatic Medications
Description
Decrease (50%) and complete discontinuation of muscle relaxation anti-spasmatic medications
Time Frame
Mean 3.6 years
Title
Short-form 36 Quality of Life Questionnaire (SF-36 QOL)
Description
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.
Time Frame
mean 3.6 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
60 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: 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 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Richard Burt, MD
Organizational Affiliation
Northwestern University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Northwestern University
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60611
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
33318163
Citation
Burt RK, Balabanov R, Han X, Quigley K, Arnautovic I, Helenowski I, Rose J, Siddique T. Autologous Hematopoietic Stem Cell Transplantation for Stiff-Person Spectrum Disorder: A Clinical Trial. Neurology. 2021 Feb 9;96(6):e817-e830. doi: 10.1212/WNL.0000000000011338. Epub 2020 Dec 14.
Results Reference
result

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Stem Cell Transplantation for Stiff Person Syndrome (SPS)

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