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

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

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.

Study Overview

• Status: Terminated
• Conditions: Stiff-Person Syndrome
• Intervention / Treatment: Biological: Autologous Hematopoietic Stem Cells; Drug: Cyclophosphamide; Drug: Mesna; Drug: rATG; Drug: Methylprednisolone; Drug: G-CSF; Drug: Rituxan

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.

• Study Type: Interventional
• Enrollment (Actual): 23
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Northwestern University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 60 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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; 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; Endoxan; Neosar; Drug: Mesna; Medication used to decrease the risk of hemorrhagic cystitis prophylaxis; Other Names: 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 Names: Thymoglobulin; Drug: Methylprednisolone; Steroid; Other Names: 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: Filgrastim; Neupogen; Zarxio; Granix; 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 Names: Rituximab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Number of Participants who Did Not Experience Treatment-Related Mortality	Mean 3.6 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Reduction of Muscle Relaxation Anti-spasmatic Medications	Decrease (50%) and complete discontinuation of muscle relaxation anti-spasmatic medications	Mean 3.6 years
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.	mean 3.6 years

Collaborators and Investigators

• Sponsor: Northwestern University

Publications and helpful links

General Publications

• 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.

Helpful Links

• Burt RK, et al. Neurology. 2020.

Study record dates

Study Major Dates

• Study Start: October 1, 2014
• Primary Completion (Actual): August 19, 2019
• Study Completion (Actual): August 30, 2019

Study Registration Dates

• First Submitted: October 30, 2014
• First Submitted That Met QC Criteria: October 31, 2014
• First Posted (Estimate): November 4, 2014

Study Record Updates

• Last Update Posted (Actual): January 27, 2021
• Last Update Submitted That Met QC Criteria: January 6, 2021
• Last Verified: January 1, 2021

More Information

Terms related to this study

• Keywords: Autologous Hematopoietic Stem Cell Transplantation; Autoimmune Diseases
• Additional Relevant MeSH Terms: Pathologic Processes; Central Nervous System Diseases; Nervous System Diseases; Immune System Diseases; Autoimmune Diseases of the Nervous System; Autoimmune Diseases; Disease; Neuromuscular Diseases; Spinal Cord Diseases; Syndrome; Stiff-Person Syndrome; 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; Methylprednisolone; Methylprednisolone Hemisuccinate; Cyclophosphamide; Rituximab; Thymoglobulin
• Other Study ID Numbers: DIAD.SPS.2014

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
• product manufactured in and exported from the U.S.: No