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

• ClinicalTrials.gov Identifier: NCT02282514
• Recruitment Status: Terminated
• First Posted: November 4, 2014
• Results First Posted: January 6, 2021
• Last Update Posted: January 27, 2021
• Sponsor: Northwestern University
• Information provided by (Responsible Party): Richard Burt, MD, Northwestern University

Tracking Information

• First Submitted Date: October 30, 2014
• First Posted Date: November 4, 2014
• Results First Submitted Date: November 16, 2020
• Results First Posted Date: January 6, 2021
• Last Update Posted Date: January 27, 2021
• Study Start Date: October 2014
• Actual Primary Completion Date: August 19, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: January 6, 2021)

Overall Survival [ Time Frame: Mean 3.6 years ]

Number of Participants who Did Not Experience Treatment-Related Mortality

• Original Primary Outcome Measures (submitted: October 31, 2014): Overall Survival [ Time Frame: Up to 5 years ]

Current Secondary Outcome Measures (submitted: December 9, 2020)

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

Original Secondary Outcome Measures (submitted: October 31, 2014)

• Decrease (50%) and complete discontinuation of muscle relaxation anti-spasmotic medications [ Time Frame: Up to 5 years ]
• Improvement of Chronic Pain Acceptance Questionnaire (CPAQ) [ Time Frame: Up to 5 years ]
  Improvement is defined as a statistically significant change in the CPAQ score
• Timed ambulation [ Time Frame: Up to 5 years ]
  Improvement is defined as a statistically significant change in the timed ambulation score
• Activities of Daily Living ((Barthel Index) [ Time Frame: Up to 5 years ]
  Improvement is defined as a statistically significant change in Barthel Index score
• Short-form 36 quality of life questionnaire (SF-36 QOL) [ Time Frame: Up to 5 years ]
  Improvement is defined as a statistically significant change in SF-36 QOL score
• Rankin Functional Scale [ Time Frame: Up to 5 years ]
  Improvement is defined as a statistically significant change in Rankin Functional Scale score

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Stem Cell Transplantation for Stiff Person Syndrome (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

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

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
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Stiff-Person Syndrome

Intervention

• 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
  Steroid
  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

Study Arms

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.

Interventions:

• Biological: Autologous Hematopoietic Stem Cells
• Drug: Cyclophosphamide
• Drug: Mesna
• Drug: rATG
• Drug: Methylprednisolone
• Drug: G-CSF
• Drug: Rituxan

• 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.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 29, 2019): 23
• Original Estimated Enrollment (submitted: October 31, 2014): 10
• Actual Study Completion Date: August 30, 2019
• Actual Primary Completion Date: August 19, 2019 (Final data collection date for primary outcome measure)

Eligibility Criteria

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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 60 Years (Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT02282514
• Other Study ID Numbers: DIAD.SPS.2014
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Richard Burt, MD, Northwestern University
• Original Responsible Party: Same as current
• Current Study Sponsor: Northwestern University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Richard Burt, MD; Northwestern University

• PRS Account: Northwestern University
• Verification Date: January 2021