Stem Cell Transplantation for Stiff Person Syndrome (SPS)

NCT02282514 | Terminated Phase 1 Results DMC FDA Drug

• 1 other identifier: DIAD.SPS.2014
• Study Type: interventional
• Target: 23
• Locations: 1 country
• Sites: 1

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.

Conditions

Stiff-Person Syndrome

Keywords

Autoimmune Diseases; Autologous Hematopoietic Stem Cell Transplantation

Outcome Measures

Primary Outcomes (1)

• Overall Survival

  Number of Participants who Did Not Experience Treatment-Related Mortality

  Mean 3.6 years

Secondary Outcomes (2)

• Reduction of Muscle Relaxation Anti-spasmatic Medications

  Mean 3.6 years

• Short-form 36 Quality of Life Questionnaire (SF-36 QOL)

  mean 3.6 years

Study Arms (1)

Hematopoietic Stem Cell Transplantation

EXPERIMENTAL

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; Drug: Cyclophosphamide; Drug: Mesna; Drug: rATG; Drug: Methylprednisolone; Drug: G-CSF; Drug: Rituxan

Interventions

Autologous Hematopoietic Stem Cells BIOLOGICAL

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.

Hematopoietic Stem Cell Transplantation

Cyclophosphamide DRUG

An alkylating agent which causes prevention of cell division by forming adducts with DNA

Also known as: Cytoxan, Neosar, Endoxan

Hematopoietic Stem Cell Transplantation

Mesna DRUG

Medication used to decrease the risk of hemorrhagic cystitis prophylaxis

Also known as: Mesnex

Hematopoietic Stem Cell Transplantation

rATG DRUG

A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells

Also known as: Thymoglobulin

Hematopoietic Stem Cell Transplantation

Methylprednisolone DRUG

Steroid

Also known as: Solu-Medrol

Hematopoietic Stem Cell Transplantation

G-CSF DRUG

Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream

Also known as: Neupogen, Filgrastim, Granix, Zarxio

Hematopoietic Stem Cell Transplantation

Rituxan DRUG

A chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders

Also known as: Rituximab

Hematopoietic Stem Cell Transplantation

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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

You may not qualify if:

• 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

Sponsors & Collaborators

• Northwestern University: lead

Study Sites (1)

Northwestern University

Chicago, Illinois, 60611, United States

Location

Related Publications (1)

• 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.

  PMID: 33318163 RESULT

MeSH Terms

Conditions

Stiff-Person Syndrome; Autoimmune Diseases

Interventions

Cyclophosphamide; Mesna; thymoglobulin; Methylprednisolone; Methylprednisolone Hemisuccinate; Granulocyte Colony-Stimulating Factor; Filgrastim; Rituximab

Condition Hierarchy (Ancestors)

Autoimmune Diseases of the Nervous System; Nervous System Diseases; Spinal Cord Diseases; Central Nervous System Diseases; Neuromuscular Diseases; Immune System Diseases

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Alkanesulfonates; Alkanesulfonic Acids; Alkanes; Hydrocarbons, Acyclic; Sulfhydryl Compounds; Sulfur Compounds; Sulfonic Acids; Sulfur Acids; Prednisolone; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Colony-Stimulating Factors; Glycoproteins; Glycoconjugates; Carbohydrates; Hematopoietic Cell Growth Factors; Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins

Results Point of Contact

• Title: Kathleen Quigley
• Organization: Northwestern University

k-quigley@northwestern.edu

312-695-8192

Study Officials

• Richard Burt, MD

  Northwestern University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Professor, Division Chief

Study Record Dates

• First Submitted: October 30, 2014
• First Posted: November 4, 2014
• Study Start: October 1, 2014
• Primary Completion: August 19, 2019
• Study Completion: August 30, 2019
• Last Updated: January 27, 2021
• Results First Posted: January 6, 2021

Record last verified: 2021-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)