Stiff-Person Syndrome
Conditions
Keywords
Autoimmune Diseases, Autologous Hematopoietic Stem Cell Transplantation
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.
Interventions
BIOLOGICALAutologous 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.
DRUGCyclophosphamide
An alkylating agent which causes prevention of cell division by forming adducts with DNA
DRUGMesna
Medication used to decrease the risk of hemorrhagic cystitis prophylaxis
DRUGrATG
A predominantly lymphocyte-specific immunosuppressive agent which contains antibodies specific to the antigens commonly found on the surface of T cells
DRUGMethylprednisolone
Steroid
DRUGG-CSF
Granulocyte-colony stimulating factor; a glycoprotein that stimulates the bone marrow to produce granulocytes and stem cells and release them into the bloodstream
DRUGRituxan
A chimeric monoclonal antibody used in the treatment of B cell non-Hodgkin's lymphoma, B cell leukemia, and some autoimmune disorders
Sponsors
Northwestern University
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival | Mean 3.6 years | Number of Participants who Did Not Experience Treatment-Related Mortality |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Reduction of Muscle Relaxation Anti-spasmatic Medications | 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) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Hematopoietic Stem Cell Transplantation Conditioning regimen will be 200 mg/kg of IV cyclophosphamide given in 4 equal fractions on days -5 through -2 with IV 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 IV before each dose of rATG. Autologous hematopoietic stem cells (HSCT) will be infused IV 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.
HSCT: cells will be collected from 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 HSCT is to re-infuse immature cells that can re-establish blood production and patient's immune system.
Cyclophosphamide: Alkylating agent which causes prevention of cell division by forming adducts with DNA Mesna: Medication used to decrease the risk of hemorrhagic cystitis rATG: lymphocyte-specific immunosuppressive agent Methylprednisolone: Steroid 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 Rituxan: Chimeric monoclonal antibody | 23 |
| Total | 23 |
Baseline characteristics
| Characteristic | Hematopoietic Stem Cell Transplantation |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 23 Participants |
| Age, Continuous | 48.3 Years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 2 Participants |
| Race (NIH/OMB) Black or African American | 3 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) White | 17 Participants |
| Region of Enrollment United States | 23 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 1 / 23 |
| other Total, other adverse events | 5 / 23 |
| serious Total, serious adverse events | 1 / 23 |
Outcome results
Primary
Overall Survival
Number of Participants who Did Not Experience Treatment-Related Mortality
Time frame: Mean 3.6 years
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hematopoietic Stem Cell Transplantation | Overall Survival | 23 participants |
Secondary
Reduction of Muscle Relaxation Anti-spasmatic Medications
Decrease (50%) and complete discontinuation of muscle relaxation anti-spasmatic medications
Time frame: Mean 3.6 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Hematopoietic Stem Cell Transplantation | Reduction of Muscle Relaxation Anti-spasmatic Medications | 14 Participants |
Secondary
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.
Time frame: mean 3.6 years
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Hematopoietic Stem Cell Transplantation | Short-form 36 Quality of Life Questionnaire (SF-36 QOL) | Pre Treatment | 37.75 units on a scale | Standard Deviation 12.81 |
| Hematopoietic Stem Cell Transplantation | Short-form 36 Quality of Life Questionnaire (SF-36 QOL) | Post Treatment | 58.35 units on a scale | Standard Deviation 22.81 |